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Anoctamins are a family of Ca2+-activated proteins that may act as ion channels and/or phospholipid scramblases with limited understanding of function and disease association. Here, we identified five de novo and two inherited missense variants in ANO4 (alias TMEM16D) as a cause of fever-sensitive developmental and epileptic or epileptic encephalopathy (DEE/EE) and generalized epilepsy with febrile seizures plus (GEFS+) or temporal lobe epilepsy. In silico modeling of the ANO4 structure predicted that all identified variants lead to destabilization of the ANO4 structure. Four variants are localized close to the Ca2+ binding sites of ANO4, suggesting impaired protein function. Variant mapping to the protein topology suggests a preliminary genotype-phenotype correlation. Moreover, the observation of a heterozygous ANO4 deletion in a healthy individual suggests a dysfunctional protein as disease mechanism rather than haploinsufficiency. To test this hypothesis, we examined mutant ANO4 functional properties in a heterologous expression system by patch-clamp recordings, immunocytochemistry, and surface expression of annexin A5 as a measure of phosphatidylserine scramblase activity. All ANO4 variants showed severe loss of ion channel function and DEE/EE associated variants presented mild loss of surface expression due to impaired plasma membrane trafficking. Increased levels of Ca2+-independent annexin A5 at the cell surface suggested an increased apoptosis rate in DEE-mutant expressing cells, but no changes in Ca2+-dependent scramblase activity were observed. Co-transfection with ANO4 wild-type suggested a dominant-negative effect. In summary, we expand the genetic base for both encephalopathic sporadic and inherited fever-sensitive epilepsies and link germline variants in ANO4 to a hereditary disease.
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Anoctaminas , Mutación Missense , Humanos , Anoctaminas/genética , Anoctaminas/metabolismo , Mutación Missense/genética , Masculino , Femenino , Epilepsia/genética , Niño , Proteínas de Transferencia de Fosfolípidos/genética , Proteínas de Transferencia de Fosfolípidos/metabolismo , Estudios de Asociación Genética , Linaje , Calcio/metabolismo , Genes Dominantes , Preescolar , Células HEK293 , AdolescenteRESUMEN
INTRODUCTION: Protocadherin-19 (PCDH19)-clustering epilepsy is a distinct developmental and epileptic encephalopathy characterized by early-onset seizures that are often treatment refractory. Caused by a mutation of the PCDH19 gene on the X chromosome, this rare epilepsy syndrome primarily affects females with seizure onset commonly in the first year of life. A global, randomized, double-blind, placebo-controlled, phase 2 trial was conducted to evaluate the efficacy, safety, and tolerability of ganaxolone compared with placebo as adjunctive therapy to a standard antiseizure medication regimen in patients with PCDH19-clustering epilepsy (VIOLET; NCT03865732). METHODS: Females aged 1-17 years with a molecularly confirmed pathogenic or likely pathogenic PCDH19 variant who were experiencing ≥12 seizures during a 12-week screening period were stratified by baseline allopregnanolone sulfate (Allo-S) levels (low: ≤2.5 ng/mL; high: >2.5 ng/mL) at screening and randomized 1:1 within each strata to receive ganaxolone (maximum daily dose of 63 mg/kg/day if ≤28 kg or 1800 mg/day if >28 kg) or matching placebo in addition to their standard antiseizure treatment for the 17-week double-blind phase. The primary efficacy endpoint was the median percentage change in 28-day seizure frequency from baseline to the 17-week double-blind phase. Treatment-emergent adverse events (TEAEs) were tabulated by overall, system organ class, and preferred term. RESULTS: Of the 29 patients screened, 21 (median age, 7.0 years; IQR, 5.0-10.0 years) were randomized to receive either ganaxolone (n = 10) or placebo (n = 11). After the 17-week double-blind phase, the median (IQR) percentage change in 28-day seizure frequency from baseline was - 61.5% (-95.9% to -33.4%) among patients in the ganaxolone group and - 24.0% (-88.2% to -4.9%) among patients in the placebo group (Wilcoxon rank-sum test, p = 0.17). TEAEs were reported by 7 of 10 (70.0%) patients in the ganaxolone group and 11 of 11 (100%) patients in the placebo group. Somnolence was the most common TEAE (40.0% ganaxolone vs 27.3% placebo); serious TEAEs were more common in the placebo group (10.0% ganaxolone vs 45.5% placebo); and 1 (10.0%) patient in the ganaxolone group discontinued the study versus none in the placebo group. CONCLUSIONS: Ganaxolone was generally well tolerated and led to a greater reduction in the frequency of PCDH19-clustering seizures compared to placebo; however, the trend did not reach statistical significance. Novel trial designs are likely needed to evaluate the effectiveness of antiseizure treatments for PCDH19-clustering epilepsy.
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Anticonvulsivantes , Epilepsia Generalizada , Femenino , Humanos , Niño , Anticonvulsivantes/uso terapéutico , Pregnanolona/uso terapéutico , Resultado del Tratamiento , Convulsiones/tratamiento farmacológico , Epilepsia Generalizada/tratamiento farmacológico , Análisis por Conglomerados , ProtocadherinasRESUMEN
OBJECTIVE: Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy that is often treatment resistant. Efficacy and safety of add-on cannabidiol (CBD) to treat seizures associated with LGS was demonstrated in two randomized controlled trials (RCTs). Patients who completed the RCTs were invited to enroll in this long-term open-label extension (OLE) trial, GWPCARE5 (NCT02224573). We present the final analysis of safety and efficacy outcomes from GWPCARE5. METHODS: Patients received plant-derived highly purified CBD (Epidiolex in the United States; Epidyolex in the European Union; 100 mg/ml oral solution), titrated to a target maintenance dose of 20 mg/kg/day over 2 weeks. Based on response and tolerability, CBD could then be reduced or increased up to 30 mg/kg/day. RESULTS: Of 368 patients with LGS who completed the RCTs, 366 (99.5%) enrolled in this OLE. Median and mean treatment duration were 1090 and 826 days (range = 3-1421), respectively, with a mean modal dose of 24 mg/kg/day. Adverse events (AEs) occurred in 96% of patients, serious AEs in 42%, and AE-related discontinuations in 12%. Common AEs were convulsion (39%), diarrhea (38%), pyrexia (34%), and somnolence (29%). Fifty-five (15%) patients experienced liver transaminase elevations more than three times the upper limit of normal; 40 (73%) were taking concomitant valproic acid. Median percent reductions from baseline ranged 48%-71% for drop seizures and 48%-68% for total seizures through 156 weeks. Across all 12-week visit windows, 87% or more of patients/caregivers reported improvement in the patient's overall condition on the Subject/Caregiver Global Impression of Change scale. SIGNIFICANCE: Long-term add-on CBD treatment had a similar safety profile as in the original RCTs. Sustained reductions in drop and total seizure frequency were observed for up to 156 weeks, demonstrating long-term benefits of CBD treatment for patients with LGS.
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Cannabidiol/uso terapéutico , Epilepsias Mioclónicas , Síndrome de Lennox-Gastaut , Anticonvulsivantes/efectos adversos , Epilepsias Mioclónicas/tratamiento farmacológico , Humanos , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Convulsiones/tratamiento farmacológicoRESUMEN
OBJECTIVE: We conducted a post hoc analysis of two randomized controlled trials, GWPCARE1 (NCT02091375) and GWPCARE2 (NCT02224703), to estimate the time to onset of cannabidiol (CBD) treatment effects (seizure reduction and adverse events [AEs]) in patients with Dravet syndrome (DS). METHODS: Patients received either plant-derived highly purified CBD (Epidiolex in the United States; 100 mg/ml oral solution) 10 mg/kg/day (CBD10; GWPCARE2) or 20 mg/kg/day (CBD20; GWPCARE1&2), or matching placebo for 14 weeks. Treatment started at 2.5 mg/kg/day, reached 10 mg/kg/day on Day 7, and went up to 20 mg/kg/day on Day 11 during the 14-day titration period. Percentage change from baseline in convulsive seizure frequency was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were also evaluated. RESULTS: Overall, 124 patients received placebo and 194 received CBD (CBD10, n = 64; CBD20, n = 130). Mean age was 9.5 years (range = 2.2-18.9). Patients had discontinued a median of four antiepileptic drugs (range = 0-26) and were currently taking a median of three (range = 1-5). Differences in convulsive seizure reduction between placebo and CBD emerged during titration and became nominally significant by Day 12 for CBD20 (p = .02) and Day 13 for CBD10 (p = .03). Additionally, differences in the 50% responder rate between placebo and CBD became apparent during titration. Onset of the first reported AE occurred during the titration period in 48.4% of placebo patients and 54.1% of CBD patients. The three most common AEs of somnolence, decreased appetite, and diarrhea resolved within 4 weeks of onset in the majority of CBD-treated patients (56.3%-72.9%). SIGNIFICANCE: The therapeutic effect of CBD in DS may start within 2 weeks of treatment in some patients. Although AEs lasted longer for CBD than placebo, most resolved within the 14-week study period.
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Cannabidiol/uso terapéutico , Epilepsias Mioclónicas , Adolescente , Anticonvulsivantes/uso terapéutico , Niño , Preescolar , Método Doble Ciego , Epilepsias Mioclónicas/tratamiento farmacológico , Síndromes Epilépticos , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Convulsiones/tratamiento farmacológico , Espasmos Infantiles , Resultado del TratamientoRESUMEN
Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies. This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 previously unpublished and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: (i) EIMFS (152 individuals, 33 previously unpublished); (ii) developmental and epileptic encephalopathies other than EIMFS (non-EIMFS developmental and epileptic encephalopathies) (37 individuals, 17 unpublished); (iii) autosomal dominant or sporadic sleep-related hypermotor epilepsy (53 patients, 14 unpublished); and (iv) other phenotypes (six individuals, two unpublished). In our cohort of 66 new cases, the most common phenotypic features were: (i) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; (ii) in non-EIMFS developmental and epileptic encephalopathies, possible onset with West syndrome, occurrence of atypical absences, possible evolution to developmental and epileptic encephalopathies with sleep-related hypermotor epilepsy features; one case of sudden unexplained death in epilepsy; (iii) in autosomal dominant or sporadic sleep-related hypermotor epilepsy, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioural/psychiatric comorbidities were reported in â¼50% of the patients, sudden unexplained death in epilepsy in one individual; and (iv) other phenotypes in individuals with mutation of KCNT1 included temporal lobe epilepsy, and epilepsy with tonic-clonic seizures and cognitive regression. Genotypic analysis of the whole cohort of 248 individuals showed only missense mutations and one inframe deletion in KCNT1. Although the KCNT1 mutations in affected individuals were seen to be distributed among the different domains of the KCNT1 protein, genotype-phenotype considerations showed many of the autosomal dominant or sporadic sleep-related hypermotor epilepsy-associated mutations to be clustered around the RCK2 domain in the C terminus, distal to the NADP domain. Mutations associated with EIMFS/non-EIMFS developmental and epileptic encephalopathies did not show a particular pattern of distribution in the KCNT1 protein. Recurrent KCNT1 mutations were seen to be associated with both severe and less severe phenotypes. Our study further defines and broadens the phenotypic and genotypic spectrums of KCNT1-related epileptic conditions and emphasizes the increasingly important role of this gene in the pathogenesis of early onset developmental and epileptic encephalopathies as well as of focal epilepsies, namely autosomal dominant or sporadic sleep-related hypermotor epilepsy.
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Epilepsia/genética , Proteínas del Tejido Nervioso/genética , Canales de potasio activados por Sodio/genética , Adolescente , Niño , Preescolar , Estudios de Cohortes , Femenino , Genotipo , Humanos , Lactante , Masculino , Mutación , Fenotipo , Adulto JovenRESUMEN
PURPOSE: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. METHODS: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. RESULTS: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. CONCLUSION: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.
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Trastorno del Espectro Autista , Encefalopatías , Epilepsia , Trastorno del Espectro Autista/genética , Encefalopatías/genética , Epilepsia/genética , Femenino , Genes Ligados a X/genética , Humanos , Masculino , Proteínas del Tejido Nervioso , Convulsiones/genéticaRESUMEN
OBJECTIVES: To assess the efficacy and safety profile of add-on cannabidiol (CBD) in patients with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) on clobazam and in the overall population of four randomized, controlled phase 3 trials. METHODS: Patients received plant-derived, highly purified CBD medicine (Epidiolex® in the USA; Epidyolex® in Europe; 100 mg/ml oral solution) at a dose of 10 or 20 mg/kg/day, or placebo for 14 weeks. A subgroup analysis of patients on clobazam and meta-analysis by syndrome were conducted. The primary endpoint was percentage reduction in primary seizure type during the treatment period. RESULTS: 396 patients with LGS (49% on clobazam) and 318 patients with DS (64% on clobazam) were included. CBD treatment resulted in a reduction in primary seizure frequency vs placebo in the overall population (treatment ratio [95% confidence interval]: LGS, 0.70 [0.62-0.80]; DS, 0.71 [0.60-0.83]) and in patients receiving clobazam (LGS, 0.56 [0.47-0.67]; DS, 0.63 [0.52-0.77]). The antiseizure efficacy of CBD was also demonstrated across other endpoints vs placebo (≥50% responder rate, total seizure frequency, number of seizure-free days, and Subject/Caregiver Global Impression of Change scores) in the overall populations and in patients receiving clobazam. There were higher incidences of somnolence and sedation in patients on CBD and clobazam. Most incidences of elevated transaminases occurred in patients on concomitant valproate and, to a lesser extent, clobazam. CONCLUSIONS: Add-on CBD was effective in reducing seizures in the overall populations and in conjunction with clobazam. Somnolence and sedation occurred more frequently in patients on CBD and clobazam.
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Anticonvulsivantes/uso terapéutico , Cannabidiol/uso terapéutico , Clobazam/uso terapéutico , Epilepsias Mioclónicas/tratamiento farmacológico , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Adulto , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/efectos adversos , Cannabidiol/administración & dosificación , Cannabidiol/efectos adversos , Clobazam/administración & dosificación , Clobazam/efectos adversos , Femenino , Humanos , Masculino , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: In recent randomized, placebo-controlled, phase III trials, highly purified cannabidiol demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut syndrome or Dravet syndrome. It is anticipated that antiepileptic drugs such as stiripentol and valproate will be administered concomitantly with cannabidiol. OBJECTIVES: This trial evaluated the effect of cannabidiol on steady-state pharmacokinetics of stiripentol or valproate in patients with epilepsy, and the safety and tolerability of cannabidiol. METHODS: This phase II, two-arm, parallel-group, double-blind, randomized, placebo-controlled trial recruited male and female patients with epilepsy aged 16-55 years. Patients receiving a stable dose of stiripentol or valproate were randomized 4:1 to receive concomitant double-blind cannabidiol or placebo. Patients received plant-derived, highly purified cannabidiol medicine (Epidiolex® in the USA; Epidyolex® in the EU; 100 mg/mL oral solution) at a dose of 20 mg/kg/day from day 12 to 26, following a 10-day dose-escalation period. Blood samples for pharmacokinetic evaluations were collected on days 1 and 26 before stiripentol/valproate dosing and up to 12 h postdose. Treatment-emergent adverse events (AEs) were recorded. RESULTS: In total, 35 patients were recruited to the stiripentol arm (n = 14) or the valproate arm (n = 21). Both the safety and the pharmacokinetic populations of the stiripentol arm comprised 14 patients (2 placebo; 12 cannabidiol). The safety population of the valproate arm comprised 20 patients (4 placebo; 16 cannabidiol; one withdrew before receiving treatment); the pharmacokinetic population comprised 15 patients (3 placebo; 12 cannabidiol). Concomitant cannabidiol led to a small increase in stiripentol exposure (17% increase in maximum observed plasma concentration [Cmax]; 30% increase in area under the concentration-time curve over the dosing interval [AUCtau]). Concomitant cannabidiol also had little effect on valproate exposure (13% decrease in Cmax; 17% decrease in AUCtau) or its metabolite, 2-propyl-4-pentenoic acid (4-ene-VPA) (23% decrease in Cmax; 30% decrease in AUCtau). All changes in exposure are expressed as the dose-normalized geometric mean (CV%) day 26 to day 1 ratio. The most common AE was diarrhea; most AEs were mild. Two patients discontinued cannabidiol because of serious AEs (rash [n = 1] in the stiripentol arm; hypertransaminasemia [n = 1] in the valproate arm). A separate in vitro study investigated the bidirectional effect of cannabidiol, or its metabolite 7-carboxy-cannabidiol, on valproate plasma protein binding; no change in plasma protein binding was observed for either compound. CONCLUSIONS: The clinical relevance of the increase in stiripentol exposure is unknown; patients receiving cannabidiol and stiripentol concomitantly should be monitored for adverse reactions as individual patient responses may vary. Coadministration of cannabidiol did not affect the pharmacokinetics of valproate or its metabolite, 4-ene-VPA, in adult patients with epilepsy. Safety results were consistent with the known safety profile of cannabidiol at a dose of 20 mg/kg/day. Clinicaltrials.gov: NCT02607891.
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Cannabidiol/administración & dosificación , Dioxolanos/administración & dosificación , Epilepsia/tratamiento farmacológico , Ácido Valproico/administración & dosificación , Adolescente , Adulto , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/farmacocinética , Área Bajo la Curva , Cannabidiol/efectos adversos , Cannabidiol/farmacología , Dioxolanos/farmacocinética , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ácido Valproico/farmacocinética , Adulto JovenRESUMEN
Importance: Clinical evidence supports effectiveness of cannabidiol for treatment-resistant seizures in Dravet syndrome, but this trial is the first to evaluate the 10-mg/kg/d dose. Objective: To evaluate the efficacy and safety of a pharmaceutical formulation of cannabidiol, 10 and 20 mg/kg/d, vs placebo for adjunctive treatment of convulsive seizures in patients with Dravet syndrome. Design, Setting, and Participants: This double-blind, placebo-controlled, randomized clinical trial (GWPCARE2) recruited patients from April 13, 2015, to November 10, 2017, with follow-up completed on April 9, 2018. Of 285 patients screened from 38 centers in the United States, Spain, Poland, the Netherlands, Australia, and Israel, 86 were excluded, and 199 were randomized. Patients were aged 2 to 18 years with a confirmed diagnosis of Dravet syndrome and at least 4 convulsive seizures during the 4-week baseline period while receiving at least 1 antiepileptic drug. Data were analyzed from November 16 (date of unblinding) to December 13 (date of final outputs), 2018, based on intention to treat and per protocol. Interventions: Patients received cannabidiol oral solution at a dose of 10 or 20 mg/kg per day (CBD10 and CBD20 groups, respectively) or matched placebo in 2 equally divided doses for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were blinded to group assignment. Main Outcomes and Measures: The primary outcome was change from baseline in convulsive seizure frequency during the treatment period. Secondary outcomes included change in all seizure frequency, proportion with at least a 50% reduction in convulsive seizure activity, and change in Caregiver Global Impression of Change score. Results: Of 198 eligible patients (mean [SD] age, 9.3 [4.4] years; 104 female [52.5%]), 66 were randomized to the CBD10 group, 67 to the CBD20 group, and 65 to the placebo group, and 190 completed treatment. The percentage reduction from baseline in convulsive seizure frequency was 48.7% for CBD10 group and 45.7% for the CBD20 group vs 26.9% for the placebo group; the percentage reduction from placebo was 29.8% (95% CI, 8.4%-46.2%; P = .01) for CBD10 group and 25.7% (95% CI, 2.9%-43.2%; P = .03) for the CBD20 group. The most common adverse events were decreased appetite, diarrhea, somnolence, pyrexia, and fatigue. Five patients in the CBD20 group discontinued owing to adverse events. Elevated liver transaminase levels occurred more frequently in the CBD20 (n = 13) than the CBD10 (n = 3) group, with all affected patients given concomitant valproate sodium. Conclusions and Relevance: Adjunctive cannabidiol at doses of 10 and 20 mg/kg/d led to similar clinically relevant reductions in convulsive seizure frequency with a better safety and tolerability profile for the 10-mg/kg/d dose in children with treatment-resistant Dravet syndrome. Dose increases of cannabidiol to greater than 10 mg/kg/d should be tailored to individual efficacy and safety. Trial Registration: ClinicalTrials.gov Identifier: NCT02224703.
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Anticonvulsivantes/administración & dosificación , Cannabidiol/administración & dosificación , Epilepsias Mioclónicas/tratamiento farmacológico , Convulsiones/tratamiento farmacológico , Adolescente , Quimioterapia Adyuvante/métodos , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Epilepsias Mioclónicas/complicaciones , Femenino , Humanos , Masculino , Convulsiones/etiologíaRESUMEN
BACKGROUND: Pathogenic variants in SCN1A cause variable epilepsy disorders with different disease severities. We here investigate whether common variation in the promoter region of the unaffected SCN1A allele could reduce normal expression, leading to a decreased residual function of Nav1.1, and therefore to more severe clinical outcomes in patients affected by pathogenic SCN1A variants. METHODS: Five different SCN1A promoter-haplotypes were functionally assessed in SH-SY5Y cells using Firefly and Renilla luciferase assays. The SCN1A promoter region was analyzed in a cohort of 143 participants with SCN1A pathogenic variants. Differences in clinical features and outcomes between participants with and without common variants in the SCN1A promoter-region of their unaffected allele were investigated. RESULTS: All non-wildtype haplotypes showed a significant reduction in luciferase expression, compared to the wildtype promoter-region (65%-80%, p = 0.039-0.0023). No statistically significant differences in clinical outcomes were observed between patients with and without common promoter variants. However, patients with a wildtype promoter-haplotype on their unaffected SCN1A allele showed a nonsignificant trend for milder phenotypes. CONCLUSION: The nonsignificant observed trends in our study warrant replication studies in larger cohorts to explore the potential modifying role of these common SCN1A promoter-haplotypes.
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Epilepsia/patología , Canal de Sodio Activado por Voltaje NAV1.1/genética , Regiones no Traducidas 5' , Adolescente , Adulto , Alelos , Línea Celular Tumoral , Niño , Preescolar , Epilepsia/genética , Genes Reporteros , Estudio de Asociación del Genoma Completo , Haplotipos , Humanos , Masculino , Fenotipo , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
Pathogenic variants in KCNT1 represent an important cause of treatment-resistant epilepsy, for which an effective therapy has been elusive. Reports about the effectiveness of quinidine, a candidate precision therapy, have been mixed. We sought to evaluate the treatment responsiveness of patients with KCNT1-related epilepsy. We performed an observational study of 43 patients using a collaborative KCNT1 patient registry. We assessed treatment efficacy based upon clinical seizure reduction, side effects of quinidine therapy, and variant-specific responsiveness to treatment. Quinidine treatment resulted in a > 50% seizure reduction in 20% of patients, with rare patients achieving transient seizure freedom. Multiple other therapies demonstrated some success in reducing seizure frequency, including the ketogenic diet and vigabatrin, the latter particularly in patients with epileptic spasms. Patients with the best quinidine response had variants that clustered distal to the NADP domain within the RCK2 domain of the protein. Half of patients did not receive a quinidine trial. In those who did, nearly half did not achieve therapeutic blood levels. More favorable response to quinidine in patients with KCNT1 variants distal to the NADP domain within the RCK2 domain may suggest a variant-specific response.
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Anticonvulsivantes/uso terapéutico , Epilepsia Refractaria/genética , Proteínas del Tejido Nervioso/genética , Canales de potasio activados por Sodio/genética , Adolescente , Niño , Preescolar , Epilepsia Refractaria/tratamiento farmacológico , Femenino , Humanos , Lactante , Masculino , Quinidina/uso terapéutico , Sistema de Registros , Resultado del TratamientoRESUMEN
OBJECTIVE: Patients with Lennox-Gastaut syndrome (LGS) who completed 1 of 2 randomized, double-blind, placebo-controlled trials of add-on cannabidiol (CBD) (GWPCARE3, NCT02224560 or GWPCARE4, NCT02224690) were invited to enroll in an open-label extension (OLE) study evaluating the long-term safety and efficacy of CBD (GWPCARE5, NCT02224573). Herein we present an interim analysis of the safety, efficacy, and patient-reported outcomes from this trial. METHODS: Patients received a pharmaceutical formulation of highly purified CBD oral solution (Epidiolex; 100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2-week titration period, in addition to their existing medications. Doses could be reduced if not tolerated or increased up to 30 mg/kg/d if thought to be of benefit. RESULTS: This interim analysis was based on a November 2016 data cut. Of 368 patients who completed treatment in GWPCARE3 and GWPCARE4, 366 (99.5%) enrolled in the OLE study (GWPCARE5). Median treatment duration was 38 weeks at a mean modal dose of 23 mg/kg/d. Most patients (92.1%) experienced adverse events (AEs), primarily of mild (32.5%) or moderate (43.4%) severity. The most common AEs were diarrhea (26.8%), somnolence (23.5%), and convulsion (21.3%). Thirty-five patients (9.6%) discontinued treatment due to AEs. Liver transaminase elevations were reported in 37 patients (10.1%), of whom 29 were receiving concomitant valproic acid; 34 cases resolved spontaneously or with dose modification of CBD or concomitant medication. Median reduction from baseline in drop seizure frequency (quantified monthly over 12-week periods) ranged from 48% to 60% through week 48. Median reduction in monthly total seizure frequency ranged from 48% to 57% across all 12-week periods through week 48. Eighty-eight percent of patients/caregivers reported an improvement in the patient's overall condition per the Subject/Caregiver Global Impression of Change scale. SIGNIFICANCE: In this study, long-term add-on CBD treatment had an acceptable safety profile in patients with LGS and led to sustained reductions in seizures.
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Cannabidiol/uso terapéutico , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Adolescente , Adulto , Cannabidiol/administración & dosificación , Cannabidiol/efectos adversos , Niño , Preescolar , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Convulsiones/prevención & control , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: Differentiating between Dravet syndrome and non-Dravet SCN1A-related phenotypes is important for prognosis regarding epilepsy severity, cognitive development, and comorbidities. When a child is diagnosed with genetic epilepsy with febrile seizures plus (GEFS+) or febrile seizures (FS), accurate prognostic information is essential as well, but detailed information on seizure course, seizure freedom, medication use, and comorbidities is lacking for this milder patient group. In this cross-sectional study, we explore disease characteristics in milder SCN1A-related phenotypes and the nature, occurrence, and relationships of SCN1A-related comorbidities in both patients with Dravet and non-Dravet syndromes. METHODS: A cohort of 164 Dutch participants with SCN1A-related seizures was evaluated, consisting of 116 patients with Dravet syndrome and 48 patients with either GEFS+, febrile seizures plus (FS+), or FS. Clinical data were collected from medical records, semi-structured telephone interviews, and three questionnaires: the Functional Mobility Scale (FMS), the Pediatric Quality of Life Inventory (PedsQL) Measurement Model, and the Child or Adult Behavior Checklists (CBCL/ABCL). RESULTS: Walking disabilities and severe behavioral problems affect 71% and 43% of patients with Dravet syndrome respectively and are almost never present in patients with non-Dravet syndromes. These comorbidities are strongly correlated to lower quality-of-life (QoL) scores. Less severe comorbidities occur in patients with non-Dravet syndromes: learning problems and psychological/behavioral problems are reported for 27% and 38% respectively. The average QoL score of the non-Dravet group was comparable with that of the general population. The majority of patients with non-Dravet syndromes becomes seizure-free after 10â¯years of age (85%). CONCLUSIONS: Severe behavioral problems and walking disabilities are common in patients with Dravet syndrome and should receive specific attention during clinical management. Although the epilepsy course of patients with non-Dravet syndromes is much more favorable, milder comorbidities frequently occur in this group as well. Our results may be of great value for clinical care and informing newly diagnosed patients and their parents about prognosis.
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Epilepsias Mioclónicas/epidemiología , Epilepsias Mioclónicas/genética , Epilepsia/epidemiología , Epilepsia/genética , Canal de Sodio Activado por Voltaje NAV1.1/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Estudios de Cohortes , Comorbilidad , Estudios Transversales , Epilepsias Mioclónicas/diagnóstico , Epilepsia/diagnóstico , Síndromes Epilépticos/diagnóstico , Síndromes Epilépticos/epidemiología , Síndromes Epilépticos/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Calidad de Vida , Estudios Retrospectivos , Convulsiones Febriles/diagnóstico , Convulsiones Febriles/epidemiología , Convulsiones Febriles/genética , Espasmos Infantiles/diagnóstico , Espasmos Infantiles/epidemiología , Espasmos Infantiles/genética , Encuestas y Cuestionarios , Resultado del Tratamiento , Adulto JovenRESUMEN
The original version of this article contained an error in the spelling of the author Erik H. Niks, which was incorrectly given as Erik Niks. This has now been corrected in both the PDF and HTML versions of the article.
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PURPOSE: To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway METHODS: We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants. RESULTS: The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign. CONCLUSION: Our data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.
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Epilepsia/genética , Proteínas Activadoras de GTPasa/genética , Proteínas Represoras/genética , Proteínas Supresoras de Tumor/genética , Adolescente , Síndrome de Brugada/genética , Síndrome de Brugada/mortalidad , Síndrome de Brugada/fisiopatología , Niño , Preescolar , Variaciones en el Número de Copia de ADN/genética , Epilepsia/complicaciones , Epilepsia/epidemiología , Epilepsia/fisiopatología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Mutación INDEL/genética , Lactante , Recién Nacido , Mutación con Pérdida de Función/genética , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Complejos Multiproteicos/genética , Linaje , Convulsiones/complicaciones , Convulsiones/epidemiología , Convulsiones/genética , Convulsiones/fisiopatología , Transducción de Señal/genéticaRESUMEN
The original version of this Article contained an error in the author list where the corresponding author Stéphanie Baulac was repeated twice. This has now been corrected in the HTML, the PDF was correct at the time of publication.
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Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.
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Canales de Calcio Tipo R/genética , Proteínas de Transporte de Catión/genética , Contractura/genética , Discinesias/genética , Epilepsia/genética , Variación Genética/genética , Megalencefalia/genética , Espasmos Infantiles/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Trastornos del Neurodesarrollo/genéticaRESUMEN
OBJECTIVE: Pathogenic variants in SCN1A can give rise to extremely variable disease severities that may be indistinguishable at their first presentation. We aim to find clinical features that can help predict the evolution of seizures into Dravet syndrome and clinical features that predict cognitive outcome in Dravet syndrome. We specifically investigate the role of contraindicated medication (CIM) as a possible modifier of cognitive decline. METHODS: A cohort of 164 Dutch participants with SCN1A-related seizures was evaluated. Clinical data were collected from medical records and semistructured telephone interviews. Cognitive function was classified by a child neurologist, neuropsychologist, and clinical geneticist. Several clinical variables, including duration of CIM use in the first 5 years of disease, were evaluated in univariate and multivariate analyses. RESULTS: A longer duration of CIM use in the first 5 years after seizure onset was significantly associated with a worse cognitive outcome at time of inclusion, and with lower interpolated intelligence quotient/developmental quotient scores after the first 5 years of disease in Dravet syndrome patients. CIM use remained a significant predictor for cognitive outcome in a multivariate regression model, as did age at the first observation of developmental delay and age at first afebrile seizure. Age at first afebrile seizure was the most accurate predictor for evolution of seizures into Dravet syndrome for the complete cohort. SIGNIFICANCE: Our data suggest that a longer CIM use in the first 5 years of disease can have negative effects on cognitive outcome in Dravet syndrome. An early diagnosis is essential to avoid these drugs. Furthermore, we identified age at first afebrile seizure as an important predictor for evolution of seizures into Dravet syndrome and for the severity of Dravet syndrome, which can be used to counsel parents of young patients with SCN1A-related seizures.