Search

Primary microcephaly (PM) is defined as a significant reduction in occipitofrontal circumference (OFC) of prenatal onset. Clinical and genetic heterogeneity of PM represents a diagnostic challenge. We performed detailed phenotypic and genomic analyses in a large cohort (n = 169) of patients referred for PM and could establish a molecular diagnosis in 38 patients. Pathogenic variants in ASPM and WDR62 were the most frequent causes in non-consanguineous patients in our cohort. In consanguineous patients, microarray and targeted gene panel analyses reached a diagnostic yield of 67%, which contrasts with a much lower rate in non-consanguineous patients (9%). Our series includes 11 novel pathogenic variants and we identify novel candidate genes including IGF2BP3 and DNAH2. We confirm the progression of microcephaly over time in affected children. Epilepsy was an important associated feature in our PM cohort, affecting 34% of patients with a molecular confirmation of the PM diagnosis, with various degrees of severity and seizure types. Our findings will help to prioritize genomic investigations, accelerate molecular diagnoses, and improve the management of PM patients.

PURPOSE: To determine whether awake EEG criteria can differentiate epileptic encephalopathy with continuous spike and waves during sleep (EE-CSWS) at the time of cognitive regression from typical, self-limited focal epilepsy (SFE). METHODS: This retrospective case-control study was based on the analysis of awake EEGs and included 15 patients with EE-CSWS and 15 age-matched and sex-matched patients with typical SFE. The EEGs were anonymised and scored by four independent readers. The following qualitative and quantitative EEG indices were analysed: slow-wave index (SLWI), spike-wave index (SWI), spike-wave frequency (SWF), long spike-wave clusters (CLSW) and EEG score (between grades 0 and 4). Sensitivity and specificity were assessed using receiver operating characteristic (ROC) curves and their reproducibility with a kappa test. RESULTS: Based on a highly sensitive cut-off, EE-CSWS patients were 8.4 times more likely than those with SFE to have an SLWI > 6%, 15 times more likely to have an SWI > 10 % and six times more likely to have a CLSW of ≥ 1 s. There was substantial agreement between readers (with kappa values of 0.64, 0.69 and 0.67). EE-CSWS patients were 13 times more likely to have an SWF of > 11 % and 149 times more likely to have an EEG score of ≥ 3 than typical SFE patients. Agreement about these ratings was almost perfect (kappa 0.91 and 0.86). CONCLUSION: An EEG score of ≥ 3 on a 20-min awake EEG differentiates typical SFE from EE-CSWS at the time of cognitive regression, with good reliability across readers with different levels of expertise.

Le trouble développemental de la coordination (TDC) affecte 5 à 9 % des enfants d’âge scolaire et se manifeste par des habiletés motrices coordonnées inférieures en comparaison aux pairs à développement typique (American Psychiatric Association, 2013). Ce trouble est caractérisé par une grande hétérogénéité clinique, pouvant mener à des divergences dans les études investiguant ses mécanismes sous-jacents ou ses bases neurones. Ce projet de thèse avait dès lors trois objectifs principaux :(i) préciser le diagnostic du TDC en définissant les profils cliniques de ces enfants, (ii) investiguer les bases neurophysiologiques du trouble, et (iii) tester l’hypothèse d’un déficit d’apprentissage procédural. Pour répondre à ces objectifs, des enfants présentant un TDC et des pairs à développement typique ont réalisé un bilan moteur et neuropsychologique, des enregistrements de l’activité cérébrale au repos en magnétoencéphralographie (MEG) et électroencéphalogramme à haute densité (EEGhd) ainsi qu’une tâche d’apprentissage procédural de séquence.Au vu de l’importante hétérogénéité clinique du TDC, l’étude 1 avait pour objectif de définir les profils cliniques du trouble au regard de son importante hétérogénéité clinique. Une première approche descriptive démontrait qu’une proportion large à modérée de l’échantillon de 50 enfants porteurs d’un TDC présentait des altérations des fonctions exécutives (92%), praxies (68%), attentionnelles (52%), des habiletés perceptives visuelles et visuo-spatiales (46%), et des habiletés visuo-motrices et visuo-constructives (36%). Ensuite, une approche statistique d’analyse par clusters révélait l’existence de 5 sous-groupes (i.e. clusters) au sein de l’échantillon de 50 enfants porteurs d’un TDC et de 31 enfants à développement typique. L’étude 2 se concentrait sur le fonctionnement cérébral d’enfants à développement typique. Elle visait à déterminer si la MEG et l’EEGhd permettent d’étudier les réseaux cérébraux fonctionnels à l’état de repo, Doctorat en Sciences psychologiques et de l'éducation, info:eu-repo/semantics/nonPublished

Background: Primary microcephaly (PM) is defined as a significant reduction in occipitofrontal circumference (OFC) of prenatal onset. Clinical and genetic heterogeneity of PM represents a diagnostic challenge. Methods: We performed detailed phenotypic and genomic analyses in a large cohort (n = 169) of patients referred for PM and could establish a molecular diagnosis in 38 patients. Results: Pathogenic variants in ASPM and WDR62 were the most frequent causes in non-consanguineous patients in our cohort. In consanguineous patients, microarray and targeted gene panel analyses reached a diagnostic yield of 67%, which contrasts with a much lower rate in non-consanguineous patients (9%). Our series includes 11 novel pathogenic variants and we identify novel candidate genes including IGF2BP3 and DNAH2. We confirm the progression of microcephaly over time in affected children. Epilepsy was an important associated feature in our PM cohort, affecting 34% of patients with a molecular confirmation of the PM diagnosis, with various degrees of severity and seizure types. Conclusion: Our findings will help to prioritize genomic investigations, accelerate molecular diagnoses, and improve the management of PM patients., SCOPUS: ar.j, info:eu-repo/semantics/published

Plasticity of synaptic strength and density is a vital mechanism enabling memory consolidation, learning, and neurodevelopment. It is strongly dependent on the intact function of N-Methyl-d-Aspartate Receptors (NMDAR). The importance of NMDAR is further evident as their dysfunction is involved in many diseases such as schizophrenia, Alzheimer's disease, neurodevelopmental disorders, and epilepsies. Synaptic plasticity is thought to be reflected by changes of sleep slow wave slopes across the night, namely higher slopes after wakefulness at the beginning of sleep than after a night of sleep. Hence, a functional NMDAR deficiency should theoretically lead to altered overnight changes of slow wave slopes. Here we investigated whether pediatric patients with anti-NMDAR encephalitis, being a very rare but unique human model of NMDAR deficiency due to autoantibodies against receptor subunits, indeed show alterations in this sleep EEG marker for synaptic plasticity. We retrospectively analyzed 12 whole-night EEGs of 9 patients (age 4.3-20.8 years, 7 females) and compared them to a control group of 45 healthy individuals with the same age distribution. Slow wave slopes were calculated for the first and last hour of Non-Rapid Eye Movement (NREM) sleep (factor 'hour') for patients and controls (factor 'group'). There was a significant interaction between 'hour' and 'group' (p = 0.013), with patients showing a smaller overnight decrease of slow wave slopes than controls. Moreover, we found smaller slopes during the first hour in patients (p = 0.022), whereas there was no group difference during the last hour of NREM sleep (p = 0.980). Importantly, the distribution of sleep stages was not different between the groups, and in our main analyses of patients without severe disturbance of sleep architecture, neither was the incidence of slow waves. These possible confounders could therefore not account for the differences in the slow wave slope values, which we also saw in the analys