Epilepsy with migrating focal seizures

To report new sporadic cases and 1 family with epilepsy of infancy with migrating focal seizures (EIMFSs) due to KCNT1 gain-of-function and to assess therapies' efficacy including quinidine. We reviewed the clinical, EEG, and molecular data of 17 new patients with EIMFS and KCNT1 mutations, in collaboration with the network of the French reference center for rare epilepsies. The mean seizure onset age was 1 month (range: 1 hour to 4 months), and all children had focal motor seizures with autonomic signs and migrating ictal pattern on EEG. Three children also had infantile spasms and hypsarrhythmia. The identified KCNT1 variants clustered as "hot spots" on the C-terminal domain, and all mutations occurred de novo except the p.R398Q mutation inherited from the father with nocturnal frontal lobe epilepsy, present in 2 paternal uncles, one being asymptomatic and the other with single tonic-clonic seizure. In 1 patient with EIMFS, we identified the p.R1106Q mutation associated with Brugada syndrome and saw no abnormality in cardiac rhythm. Quinidine was well tolerated when administered to 2 and 4-year-old patients but did not reduce seizure frequency. The majority of the KCNT1 mutations appear to cluster in hot spots essential for the channel activity. A same mutation can be linked to a spectrum of conditions ranging from EMFSI to asymptomatic carrier, even in the same family. None of the antiepileptic therapies displayed clinical efficacy, including quinidine in 2 patients

Genotype–phenotype associations in 1018 individuals with SCN1A‐related epilepsies

Objective: SCN1A variants are associated with epilepsy syndromes ranging from mild genetic epilepsy with febrile seizures plus (GEFS+) to severe Dravet syndrome (DS). Many variants are de novo, making early phenotype prediction difficult, and genotype–phenotype associations remain poorly understood. Methods: We assessed data from a retrospective cohort of 1018 individuals with SCN1A-related epilepsies. We explored relationships between variant characteristics (position, in silico prediction scores: Combined Annotation Dependent Depletion (CADD), Rare Exome Variant Ensemble Learner (REVEL), SCN1A genetic score), seizure characteristics, and epilepsy phenotype. Results: DS had earlier seizure onset than other GEFS+ phenotypes (5.3 vs. 12.0 months, p < .001). In silico variant scores were higher in DS versus GEFS+ (p < .001). Patients with missense variants in functionally important regions (conserved N-terminus, S4–S6) exhibited earlier seizure onset (6.0 vs. 7.0 months, p = .003) and were more likely to have DS (280/340); those with missense variants in nonconserved regions had later onset (10.0 vs. 7.0 months, p = .036) and were more likely to have GEFS+ (15/29, χ2 = 19.16, p < .001). A minority of protein-truncating variants were associated with GEFS+ (10/393) and more likely to be located in the proximal first and last exon coding regions than elsewhere in the gene (9.7% vs. 1.0%, p < .001). Carriers of the same missense variant exhibited less variability in age at seizure onset compared with carriers of different missense variants for both DS (1.9 vs. 2.9 months, p = .001) and GEFS+ (8.0 vs. 11.0 months, p = .043). Status epilepticus as presenting seizure type is a highly specific (95.2%) but nonsensitive (32.7%) feature of DS. Significance: Understanding genotype–phenotype associations in SCN1A-related epilepsies is critical for early diagnosis and management. We demonstrate an earlier disease onset in patients with missense variants in important functional regions, the occurrence of GEFS+ truncating variants, and the value of in silico prediction scores. Status epilepticus as initial seizure type is a highly specific, but not sensitive, early feature of DS

Genotype–phenotype associations in 1018 individuals with SCN1A-related epilepsies

Objective: SCN1A variants are associated with epilepsy syndromes ranging from mild genetic epilepsy with febrile seizures plus (GEFS+) to severe Dravet syndrome (DS). Many variants are de novo, making early phenotype prediction difficult, and genotype–phenotype associations remain poorly understood. Methods: We assessed data from a retrospective cohort of 1018 individuals with SCN1A-related epilepsies. We explored relationships between variant characteristics (position, in silico prediction scores: Combined Annotation Dependent Depletion (CADD), Rare Exome Variant Ensemble Learner (REVEL), SCN1A genetic score), seizure characteristics, and epilepsy phenotype. Results: DS had earlier seizure onset than other GEFS+ phenotypes (5.3 vs. 12.0 months, p <.001). In silico variant scores were higher in DS versus GEFS+ (p <.001). Patients with missense variants in functionally important regions (conserved N-terminus, S4–S6) exhibited earlier seizure onset (6.0 vs. 7.0 months, p =.003) and were more likely to have DS (280/340); those with missense variants in nonconserved regions had later onset (10.0 vs. 7.0 months, p =.036) and were more likely to have GEFS+ (15/29, χ2 = 19.16, p <.001). A minority of protein-truncating variants were associated with GEFS+ (10/393) and more likely to be located in the proximal first and last exon coding regions than elsewhere in the gene (9.7% vs. 1.0%, p <.001). Carriers of the same missense variant exhibited less variability in age at seizure onset compared with carriers of different missense variants for both DS (1.9 vs. 2.9 months, p =.001) and GEFS+ (8.0 vs. 11.0 months, p =.043). Status epilepticus as presenting seizure type is a highly specific (95.2%) but nonsensitive (32.7%) feature of DS. Significance: Understanding genotype–phenotype associations in SCN1A-related epilepsies is critical for early diagnosis and management. We demonstrate an earlier disease onset in patients with missense variants in important functional regions, the occurrence of GEFS+ truncating variants, and the value of in silico prediction scores. Status epilepticus as initial seizure type is a highly specific, but not sensitive, early feature of DS

L’utilisation hors AMM de traitements anti-épileptiques dans une épilepsie réfractaire de l’enfant : étude d’une grande cohorte française de patients atteints d’un Syndrome de Dravet

L’utilisation hors AMM de traitements anti-épileptiques dans une épilepsie réfractaire de l’enfant : étude d’une grande cohorte française de patients atteints d’un Syndrome de Dravet. 26. Congrès de la Société Française de Neurologie Pédiatriqu

Comparative assessment of family ́s experience of patients with Dravet Syndrome on the use of rectal diazepam and buccal midazolam

absen

Transition of patients with childhood onset epilepsy: Perspectives from pediatric and adult neurologists

International audienceTransition from pediatric to adult care systems is a major challenge in the management of adolescents with epilepsy. The comparison of pediatric and adult physicians' points of view on this issue is scarcely described. The aim of this study was to understand pediatric and adult neurologists' experience and opinions on transition in epilepsy in France. We investigate the age at which they usually transfer patients, their opinion on the factors that positively or negatively impact transition, on the help provided during this transition period, and their propositions to improve this process. We prepared a targeted questionnaire with two versions, one adapted for neurologists and the other for child neurologists. The questionnaires were diffused through the Reference Centre for Rare Epilepsies, the French Chapter of the League Against Epilepsy, the French Association for Office-based Neurologists, and the French Pediatric Neurology Society. A total of sixty-eight physicians involved mostly in epilepsy care answered this questionnaire: 39 child neurologists and 29 neurologists. Questionnaires were filled at 96.8%. Twenty-six child neurologists followed patients aged over 18 years (70%), and 18 neurologists followed patients under the age of 12 years (66.6%). Cognitive impairment in childhood led significantly to a later transfer to adult care. The major factors believed to delay the transfer were attachment between child neurologists and families as reported in 96.3% by neurologists and in 81.1% by child neurologists, p = 0.07 and lack of adaptation of adult neurology facilities to adolescents especially with intellectual disability (59.3% neurologists, 75.7% child neurologists, p = 0.16). Factors that helped a transfer around 18-19 years were mainly pharmacoresistant epilepsy (71% for neurologists vs. 19% for child neurologists, p 65% of providers) and development of care networks between pediatric and adult care for patients with epilepsy (>55%) to improve transition as well as introducing courses on transition. Few physicians were aware of transition and transfer recommendations. Although child and adult neurologists still have some preconceived beliefs, they were able to identify the strengths and weaknesses of both care systems paving the way for proposals to improve transition and transfer of patients with epilepsy from pediatric to adult care

Epilepsy of infancy with migrating focal seizures (EIMFS) due to KCNT1 mutations shows an identifiable temporal sequence and a poor outcome with pharmacoresistant epilepsy and high mortality with SUDEP

International audienc

Exome sequencing findings in 27 patients with myoclonic‐atonic epilepsy: Is there a major genetic factor?

International audienc