Rapid cortical oscillations and early motor activity in premature human neonate.

International audienceDelta-brush is the dominant pattern of rapid oscillatory activity (8-25 Hz) in the human cortex during the third trimester of gestation. Here, we studied the relationship between delta-brushes in the somatosensory cortex and spontaneous movements of premature human neonates of 29-31 weeks postconceptional age using a combination of scalp electroencephalography and monitoring of motor activity. We found that sporadic hand and foot movements heralded the appearance of delta-brushes in the corresponding areas of the cortex (lateral and medial regions of the contralateral central cortex, respectively). Direct hand and foot stimulation also reliably evoked delta-brushes in the same areas. These results suggest that sensory feedback from spontaneous fetal movements triggers delta-brush oscillations in the central cortex in a somatotopic manner. We propose that in the human fetus in utero, before the brain starts to receive elaborated sensory input from the external world, spontaneous fetal movements provide sensory stimulation and drive delta-brush oscillations in the developing somatosensory cortex contributing to the formation of cortical body maps

Everolimus dosing recommendations for tuberous sclerosis complex–associated refractory seizures

ObjectiveThe present analysis examined the exposure-response relationship by means of the predose everolimus concentration (C-min) and the seizure response in patients with tuberous sclerosis complex-associated seizures in the EXIST-3 study. Recommendations have been made for the target C-min range of everolimus for therapeutic drug monitoring (TDM) and the doses necessary to achieve this target C-min

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

KCNQ2 R144 variants cause neurodevelopmental disability with language impairment and autistic features without neonatal seizures through a gain-of-function mechanism

Prior studies have revealed remarkable phenotypic heterogeneity in KCNQ2-related disorders, correlated with effects on biophysical features of heterologously expressed channels. Here, we assessed phenotypes and functional properties associated with KCNQ2 missense variants R144W, R144Q, and R144G. We also explored in vitro blockade of channels carrying R144Q mutant subunits by amitriptyline

Delineating the GRIN1 phenotypic spectrum: a distinct genetic NMDA receptor encephalopathy

Objective:To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology.Methods:We collected molecular and clinical data from several diagnostic and research cohorts. Functional consequences of GRIN1 mutations were investigated in Xenopus laevis oocytes.Results:We identified heterozygous de novo GRIN1 mutations in 14 individuals and reviewed the phenotypes of all 9 previously reported patients. These 23 individuals presented with a distinct phenotype of profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, hyperkinetic movement disorder, oculogyric crises, cortical blindness, generalized cerebral atrophy, and epilepsy. Mutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect. In addition, we describe 2 homozygous GRIN1 mutations (1 missense, 1 truncation), each segregating with severe neurodevelopmental phenotypes in consanguineous families.Conclusions:De novo GRIN1 mutations are associated with severe intellectual disability with cortical visual impairment as well as oculomotor and movement disorders being discriminating phenotypic features. Loss of NMDA receptor function appears to be the underlying disease mechanism. The identification of both heterozygous and homozygous mutations blurs the borders of dominant and recessive inheritance of GRIN1-associated disorders.Johannes R. Lemke (32EP30_136042/1) and Peter De Jonghe (G.A.136.11.N and FWO/ESF-ECRP) received financial support within the EuroEPINOMICS-RES network (www.euroepinomics.org) within the Eurocores framework of the European Science Foundation (ESF). Saskia Biskup and Henrike Heyne received financial support from the German Federal Ministry for Education and Research (BMBF IonNeurONet: 01 GM1105A and FKZ: 01EO1501). Katia Hardies is a PhD fellow of the Institute for Science and Technology (IWT) Flanders. Ingo Helbig was supported by intramural funds of the University of Kiel, by a grant from the German Research Foundation (HE5415/3-1) within the EuroEPINOMICS framework of the European Science Foundation, and additional grants of the German Research Foundation (DFG, HE5415/5-1, HE 5415/6-1), German Ministry for Education and Research (01DH12033, MAR 10/012), and grant by the German chapter of the International League against Epilepsy (DGfE). The project also received infrastructural support through the Institute of Clinical Molecular Biology in Kiel, supported in part by DFG Cluster of Excellence "Inflammation at Interfaces" and "Future Ocean." The project was also supported by the popgen 2.0 network (P2N) through a grant from the German Ministry for Education and Research (01EY1103) and by the International Coordination Action (ICA) grant G0E8614N. Christel Depienne, Caroline Nava, and Delphine Heron received financial support for exome analyses by the Centre National de Genotypage (CNG, Evry, France)

The phenotypic spectrum of WWOX -related disorders: 20 additional cases of WOREE syndrome and review of the literature

Purpose: Germline WWOX pathogenic variants have been associated with disorder of sex differentiation (DSD), spinocerebellar ataxia (SCA), and WWOX-related epileptic encephalopathy (WOREE syndrome). We review clinical and molecular data on WWOX-related disorders, further describing WOREE syndrome and phenotype/genotype correlations. Methods: We report clinical and molecular findings in 20 additional patients from 18 unrelated families with WOREE syndrome and biallelic pathogenic variants in the WWOX gene. Different molecular screening approaches were used (quantitative polymerase chain reaction/multiplex ligation-dependent probe amplification [qPCR/MLPA], array comparative genomic hybridization [array-CGH], Sanger sequencing, epilepsy gene panel, exome sequencing). Results: Two copy-number variations (CNVs) or two single-nucleotide variations (SNVs) were found respectively in four and nine families, with compound heterozygosity for one SNV and one CNV in five families. Eight novel missense pathogenic variants have been described. By aggregating our patients with all cases reported in the literature, 37 patients from 27 families with WOREE syndrome are known. This review suggests WOREE syndrome is a very severe epileptic encephalopathy characterized by absence of language development and acquisition of walking, early-onset drug-resistant seizures, ophthalmological involvement, and a high likelihood of premature death. The most severe clinical presentation seems to be associated with null genotypes. Conclusion: Germline pathogenic variants in WWOX are clearly associated with a severe early-onset epileptic encephalopathy. We report here the largest cohort of individuals with WOREE syndrome

Epilepsie séquellaire de l'encéphalite herpétique (étude rétrospective de 18 cas)

L'encéphalite herpétique (EH) est une complication rare de l'infection par le virus herpes simplex de type 1 (HSV1) ou plus rarement HSV2, qui consiste en une nécrose hémorragique aiguë de la substance grise plus ou moins localisée et touchant préférentiellement les régions temporales. Les signes cliniques, radiologiques, électrophysiologiques et biologiques de la maladie en phase initiale sont souvent trompeurs et ce, particulièrement chez l'enfant, mais de nombreux cas ont déjà été rapportés dans la littérature. En revanche, peu de données sont disponibles sur les séquelles à moyen et à long terme de cette pathologie, en particulier lorsqu'elle survient chez l'enfant. Nous nous sommes attachés à étudier l'une d'entre elle, fréquente mais mal connue : l'épilepsie. Pour cela, nous avons réalisé une étude rétrospective sur une série de 18 patients suivis régulièrement dans le service de neuropédiatrie de l'hôpital Saint Vincent de Paul à Paris, pour une épilepsie faisant suite à une EH à HSV1 survenue entre 3 mois et 18 ans. Les patients de notre série étaient majoritairement des nourrissons au moment de l'EH, ce qui tend à montrer que l'âge précoce de survenue de l'EH est un élément déterminant pour la survenue d'une épilepsie séquellaire. Cette épilepsie se manifeste le plus souvent par des spasmes épileptiques qui surviennent avec un intervalle libre de 3 ans et mois en moyenne après l'EH. Ces spasmes constituent une entité assez homogène puisqu'ils sont tous à début tardif (après l'âge de un an), associés à d'autres types de crises. La présence d'une atteinte des noyaux gris centraux au décours de la phase aiguë est significativement associée à la survenue de spasmes épileptiques. Ainsi, l'EH, lorsqu'elle survient avant l'âge de deux ans, peut être compliquée de deux types d'épilepsie séquellaire : i) parfois (rarement), une épilepsie partielle ; ii) plus fréquemment, une épilepsie généralisée symptomatique avec spasmes tardifs. Ce dernier type d'épilepsie tend à être retrouvé chez les patients qui ont fait l'EH la plus sévère, avec un état de mal initial. Nous discutons la physiopathologie de ces spasmes à travers le rôle respectif du jeune âge des patients au moment de l'EH, de l'inflammation encéphalique prolongée et diffuse causée par le virus HSV1 et de l'atteinte nécrotique des noyaux gris centraux.PARIS7-Xavier Bichat (751182101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Activités électrophysiologiques précoces du cortex sensorimoteur (aspects physiologiques et pathologiques)

AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocSudocFranceF

Early patterns of activity in the developing cortex: Focus on the sensorimotor system

International audienceEarly development of somatotopic cortical maps occurs during the fetal period in humans and during the postnatal period in rodents. During this period, the sensorimotor cortex expresses transient patterns of correlated neuronal activity including delta waves, gamma-and spindle-burst oscillations. These early activity patterns are largely driven by the thalamus and triggered, in a topographic manner, by sensory feedback resulting from spontaneous movements. Early cortical activities are instrumental for competitive interactions between sensory inputs for the cortical territories, they prevent cortical neurons from apoptosis and their alteration may lead to disturbances in cortical network development in a number of neurodevelopmental diseases

Genetics of neonatal onset epilepsies: An overview

International audienceThe weight of monogenic abnormalities in the possible causes of epilepsy has grown significantly in recent years, due to the emergence of next-generation sequencing (NGS) techniques. Especially notable in early neonatal and infantile epilepsies, which seem to be explained by monogenic abnormalities. This short review focuses on the major genes associated with very early-onset epilepsies, where NGS techniques are most cost-effective: early infantile epileptic encephalopathy, early myoclonic encephalopathy, and other neonatal epilepsies. The discovery of the genetic mutation often follows several weeks or months of management, and rarely modifies it. However, clinical studies can sometimes better define medical treatment. The genetic causes of these epilepsies are very numerous and the pathophysiological knowledge very minimal. The big challenge for the coming years is to develop more targeted treatments based on research on animal models