Author: "Service de neurologie pédiatrique" / Topic: 030217 neurology & neurosurgery - Searchworks@Jio Institute Digital Library Search Results

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115 results on '"Service de neurologie pédiatrique"'

1. Movement disorders in patients with alternating hemiplegia: 'Soft' and 'stiff' at the same time

Author: Panagiotakaki, Eleni, Doummar, Diane, Nogue, Erika, Nagot, Nicolas, Lesca, Gaetan, Riant, Florence, Nicole, Sophie, Delaygue, Charlene, Barthez, Marie Anne, Nassogne, Marie Cécile, Dusser, Anne, Vallée, Louis, Billette, Thierry, Bourgeois, Marie, Ioos, Christine, Gitiaux, Cyril, Laroche, Cécile, Milh, Mathieu, Portes, Vincent Des, Arzimanoglou, Alexis, Roubertie, Agathe, AHC–Movement Disorder Study Group, Department of Paediatric Clinical Epileptology, sleep disorders and Functional Neurology, University Hospitals of Lyon, Member of the ERN EpiCARE, Lyon, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Pathogénèse et contrôle des infections chroniques (PCCI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier )-Université de Montpellier (UM), Service de génétique moléculaire neurovasculaire, groupe hospitalier Saint-Louis Lariboisière-Fernand-Widal, 75010 Paris, France., Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Service de Neuropédiatrie et Handicaps, Hôpital Gatien de Clocheville, CHU Tours, Pediatric Neurology Unit, Cliniques Universitaires Saint-Luc, UCLouvain, Service de Neuropédiatrie, CHU de Bicêtre, Service de Neuropédiatrie, CHU Lille, Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de Neurochirurgie pédiatrique, Hôpital Necker-Enfants Malades, APHP, Service de Neurologie Pédiatrique, Hôpital Raymond Poincarré, AP-HP, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Pédiatrie médicale [CHU Limoges], CHU Limoges, Service de Neurologie Pédiatrique, CHU Timone Enfants, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Centre de référence « Déficiences Intellectuelles de causes rares », Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, Université de Lyon, Member of the ERN EpiCARE, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Centre de malformations vasculaires congénitales, UCL - (SLuc) Centre de référence en lésions congénitales de la moëlle épinière, UCL - (SLuc) Centre de référence pour l'épilepsie réfractaire, UCL - (SLuc) Service de neurologie pédiatrique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Institut des Neurosciences de Montpellier (INM)
Subjects: 0301 basic medicine, Adult, Male, Pediatrics, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Ataxia, Movement disorders, Adolescent, [SDV]Life Sciences [q-bio], ion channel gene defects, Hemiplegia, mental retardation, 03 medical and health sciences, Young Adult, 0302 clinical medicine, medicine, Humans, chorea, developmental disorders, 10. No inequality, Child, Dystonia, Movement Disorders, business.industry, Alternating hemiplegia of childhood, Infant, Chorea, medicine.disease, Hypotonia, nervous system diseases, 030104 developmental biology, Cross-Sectional Studies, Child, Preschool, Mutation, Female, Neurology (clinical), dystonia, medicine.symptom, Sodium-Potassium-Exchanging ATPase, business, Myoclonus, 030217 neurology & neurosurgery, Alternating hemiplegia
Abstract: ObjectiveTo assess nonparoxysmal movement disorders inATP1A3mutation-positive patients with alternating hemiplegia of childhood (AHC).MethodsTwenty-eight patients underwent neurologic examination with particular focus on movement phenomenology by a specialist in movement disorders. Video recordings were reviewed by another movement disorders specialist and data were correlated with patients' characteristics.ResultsTen patients were diagnosed with chorea, 16 with dystonia (nonparoxysmal), 4 with myoclonus, and 2 with ataxia. Nine patients had more than one movement disorder and 8 patients had none. The degree of movement disorder was moderate to severe in 12/28 patients. At inclusion, dystonic patients (n = 16) were older (p= 0.007) than nondystonic patients. Moreover, patients (n = 18) with dystonia or chorea, or both, had earlier disease onset (p= 0.042) and more severe neurologic impairment (p= 0.012), but this did not correlate with genotype. All patients presented with hypotonia, which was characterized as moderate or severe in 16/28. Patients with dystonia or chorea (n = 18) had more pronounced hypotonia (p= 0.011). Bradykinesia (n = 16) was associated with an early age at assessment (p< 0.01). Significant dysarthria was diagnosed in 11/25 cases. A history of acute neurologic deterioration and further regression of motor function, typically after a stressful event, was reported in 7 patients.ConclusionsDespite the relatively limited number of patients and the cross-sectional nature of the study, this detailed categorization of movement disorders in patients with AHC offers valuable insight into their precise characterization. Further longitudinal studies on this topic are needed.
Published: 2020

2. A large multicenter study of pediatric myotonic dystrophy type 1 for evidence-based management

Author: Hubert Journel, Sylvie Ragot-Mandry, Delphine Héron, Brigitte Chabrol, S. Peudenier, Jean-Marie Cuisset, Guillaume Bassez, Pascal Sabouraud, Catherine Sarret, Claude Cances, Mélanie Fradin, Agnès Jacquin-Piques, Julie Perrier-Boeswillald, Isabelle Desguerre, Michèle Mayer, Susana Quijano-Roy, Arnaud Isapof, Vincent Laugel, Marie De Antonio, Frédérique Audic, Nathalie Bach, Emmanuelle Lagrue, C. Espil, Rémi Bellance, Catherine Vanhulle, Armelle Magot, Hervé Testard, Julien Durigneux, Yann Péréon, Cécile Laroche-Raynaud, Romain K. Gherardi, Christine Barnerias, Céline Dogan, Véronique Manel, François Rivier, Dalil Hamroun, Ulrike Walther-Louvier, Christian Richelme, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP], Département de Pédiatrie [CHU Toulouse], CHU Toulouse [Toulouse], Service de Neurologie Pédiatrique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre de Référence des Maladies Héréditaires du Métabolisme, Service de neurométabolisme, Service de neuropédiatrie, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de génétique clinique [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Groupe de recherche clinique 'déficience intellectuelle et autisme', Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Pontchaillou [Rennes], Hôpital de Hautepierre [Strasbourg], Laboratoire d'Explorations Fonctionnelles, Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Service de neurologie pédiatriques et maladies du dévéloppement, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Atlantic Gene Therapies, Service de Pédiatrie, Rééducation et Réanimation Neurorespiratoire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP], Service de pédiatrie, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), American Memorial Hospital (Reims), Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), CHU Grenoble, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service d'histologie-Hôpital Henri Mondor, Imagerie et cerveau, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), AP-HP, Paris-CHU Necker - Enfants Malades [AP-HP], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Hôpital Sud, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Service de neuropédiatrie [Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP Hôpital Raymond Poincaré [Garches], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Pascal - Clermont Auvergne (IP), Sigma CLERMONT (Sigma CLERMONT)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Myologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), SIGMA Clermont (SIGMA Clermont)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), École Pratique des Hautes Études (EPHE), Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Foot Deformities, Male, Pediatrics, medicine.medical_specialty, Adolescent, Myotonic dystrophy, Severity of Illness Index, 03 medical and health sciences, 0302 clinical medicine, Genotype-phenotype distinction, Cataracts, Severity of illness, medicine, Humans, Myotonic Dystrophy, Registries, Child, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Evidence-Based Medicine, Muscle Weakness, business.industry, Infant, Newborn, Evidence-based management, Infant, Cardiorespiratory fitness, Arrhythmias, Cardiac, Evidence-based medicine, medicine.disease, 3. Good health, 030104 developmental biology, Multicenter study, Child, Preschool, Cohort, Autism, Female, Neurology (clinical), France, business, Respiratory Insufficiency, Trinucleotide Repeat Expansion, 030217 neurology & neurosurgery
Abstract: ObjectiveTo genotypically and phenotypically characterize a large pediatric myotonic dystrophy type 1 (DM1) cohort to provide a solid frame of data for future evidence-based health management.MethodsAmong the 2,697 patients with genetically confirmed DM1 included in the French DM-Scope registry, children were enrolled between January 2010 and February 2016 from 24 centers. Comprehensive cross-sectional analysis of most relevant qualitative and quantitative variables was performed.ResultsWe studied 314 children (52% females, with 55% congenital, 31% infantile, 14% juvenile form). The age at inclusion was inversely correlated with the CTG repeat length. The paternal transmission rate was higher than expected, especially in the congenital form (13%). A continuum of highly prevalent neurodevelopmental alterations was observed, including cognitive slowing (83%), attention deficit (64%), written language (64%), and spoken language (63%) disorders. Five percent exhibited autism spectrum disorders. Overall, musculoskeletal impairment was mild. Despite low prevalence, cardiorespiratory impairment could be life-threatening, and frequently occurred early in the first decade (25.9%). Gastrointestinal symptoms (27%) and cataracts (7%) were more frequent than expected, while endocrine or metabolic disorders were scarce.ConclusionsThe pedDM-Scope study details the main genotype and phenotype characteristics of the 3 DM1 pediatric subgroups. It highlights striking profiles that could be useful in health care management (including transition into adulthood) and health policy planning.
Published: 2019

3. Manual dexterity, but not cerebral palsy, predicts cognitive functioning after neonatal stroke

Author: Thébault, Guillaume, Martin, Sophie, Brouillet, Denis, Brunel, Lionel, Dinomais, Mickaël, Presles, Emilie, Fluss, Joel, Chabrier, Stéphane, Darteyre, Stéphane, Dégano, Céline, Delion, Matthieu, Deron, Johanna, Dray, Gérard, Drutel, Laure, Groeschel, Samuel, Hertz‐Pannier, Lucie, Husson, Béatrice, Kossorotoff, Manoelle, Lazaro, Leila, Lefranc, Jérémie, Nguyen The Tich, Sylvie, Peyric, Emeline, Ravel, Magaly, Renaud, Cyrille, Vuillerot, Carole, Dynamique des capacités humaines et des conduites de santé (EPSYLON), Université de Montpellier (UM)-Université Paul-Valéry - Montpellier 3 (UPVM)-Université Montpellier 1 (UM1), Institut national de recherches archéologiques préventives (Inrap), Laboratoire Angevin de Recherche en Ingénierie des Systèmes (LARIS), Université d'Angers (UA), Groupe de recherche sur la thrombose (GRT (EA 3065)), Université Jean Monnet [Saint-Étienne] (UJM), service de médecine physique et réadaptation pédiatrique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Bellevue-CHU de Saint-Etienne, Département de neurochirurgie [Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Laboratoire de Génie Informatique et Ingénierie de Production (LGI2P), IMT - MINES ALES (IMT - MINES ALES), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Clinique, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-hôpital Sud, CHRU de Brest - Département de Pédiatrie (CHU BREST Pédiatrie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de neurologie pédiatrique, Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Pédiatrie hospices civils de Lyon, hôpital Femme-Mère-Enfant, Université Montpellier 1 (UM1)-Université Paul-Valéry - Montpellier 3 (UM3)-Université de Montpellier (UM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Sud, Université Montpellier 1 (UM1)-Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Montpellier (UM), and CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)
Subjects: Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Population, Stroke/complications/diagnosis/physiopathology/psychology, Functional Laterality, Cerebral palsy, Brain Ischemia, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Physical medicine and rehabilitation, Cognition, Sex Factors, Developmental Neuroscience, 030225 pediatrics, Medicine, Humans, Cognitive skill, education, Child, Motor skill, Neonatal stroke, ComputingMilieux_MISCELLANEOUS, Wechsler Intelligence Scale for Children, education.field_of_study, ddc:618, business.industry, Cerebral Palsy, Hand/physiopathology, medicine.disease, Hand, Stroke, Socioeconomic Factors, Motor Skills, Pediatrics, Perinatology and Child Health, Linear Models, Female, Neurology (clinical), Cerebral Palsy/complications/diagnosis/physiopathology/psychology, business, Brain Ischemia/complications/diagnosis/physiopathology/psychology, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract: Aim To disentangle the respective impacts of manual dexterity and cerebral palsy (CP) in cognitive functioning after neonatal arterial ischaemic stroke. Method The population included 60 children (21 females, 39 males) with neonatal arterial ischaemic stroke but not epilepsy. The presence of CP was assessed clinically at the age of 7 years and 2 months (range 6y 11mo-7y 8mo) using the definition of the Surveillance of CP in Europe network. Standardized tests (Nine-Hole Peg Test and Box and Blocks Test) were used to quantify manual (finger and hand respectively) dexterity. General cognitive functioning was evaluated with the Wechsler Intelligence Scale for Children, Fourth Edition. Simple and multiple linear regression models were performed while controlling for socio-economic status, lesion side, and sex. Results Fifteen children were diagnosed with CP. In simple regression models, both manual dexterity and CP were associated with cognitive functioning (β=0.41 [p=0.002] and β=0.31 [p=0.019] respectively). However, in multiple regression models, manual dexterity was the only associated variable of cognitive functioning, whether or not a child had CP (β=0.35; p=0.007). This result was reproduced in models with other covariables (β=0.31; p=0.017). Interpretation As observed in typically developing children, manual dexterity is related to cognitive functioning in children having suffered a focal brain insult during the neonatal period. What this paper adds Manual dexterity predicts cognitive functioning after neonatal arterial ischaemic stroke. Correlations between manual dexterity and cognitive functioning occur irrespective of sex, lesion side, presence of cerebral palsy, and socio-economic status. Residual motor ability may support cognitive functioning.
Published: 2018

4. Further delineation of the MECP2 duplication syndrome phenotype in 59 French male patients, with a particular focus on morphological and neurological features

Author: Sophie Scheidecker, Françoise Devillard, Gaetan Lesca, Maryline Carneiro, Christèle Dubourg, Ganaëlle Remerand, Catherine Badens, Odile Boespflug-Tanguy, Nathalie Marle, Serge Romana, Nadia Bahi-Buisson, Jean-Paul Bonnefont, Hubert Journel, Bénédicte Duban-Bedu, Brigitte Gilbert-Dussardier, Mathilde Nizon, Nathalie Perreton, Sophie Julia, Cyril Goizet, Delphine Héron, Véronique Satre, Marguerite Miguet, Joris Andrieux, Pierre-Simon Jouk, Laurence Perrin, Renaud Touraine, Ghislaine Plessis, Dominique Martin-Coignard, Caroline Rooryck, Catherine Vincent-Delorme, Laurence Faivre, Salima El Chehadeh, Thierry Bienvenu, Jean-Luc Alessandri, Anne-Claude Tabet, Laurent Pasquier, Martine Raynaud, Réseau AChro-Puce, Marjolaine Willems, Bruno Leheup, Marianne Till, Jeanne Amiel, Jacqueline Vigneron, Nicole Philip, Valérie Kremer, Massimiliano Rossi, Boris Keren, Annick Toutain, Fabienne Prieur, Bertrand Isidor, Séverine Drunat, Marilyn Lackmy-Port-Lis, Albert David, Christel Thauvin-Robinet, Damien Sanlaville, Laetitia Lambert, Lydie Burglen, Klaus Dieterich, Catherine Sarret, Anne Moncla, Didier Lacombe, Fanny Laffargue, Kim Maincent, Marlène Rio, Clarisse Baumann, Mathilde Lefebvre, Sabine Sigaudy, Laurent Guibaud, Adeline Vigouroux, Valérie Malan, Patrick Callier, Chantal Missirian, Christophe Philippe, Christine Francannet, Anne-Laure Mosca-Boidron, Valérie Cormier-Daire, Cédric Le Caignec, Vincent des Portes, Charles Coutton, Alexandra Afenjar, Sandrine Chantot-Bastaraud, Julien Thevenon, Mylène Béri-Dexheimer, Hilde Van Esch, Bernard Echenne, Jean-Marie Cuisset, Jean-Michel Pedespan, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), FHU TRANSLAD (CHU de Dijon), Service de Génétique Médicale [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Clinique (CHU de Saint-Etienne), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Service de Génétique Clinique [CHU Rennes] (Réseau de Génétique et Génomique Médicale), Hôpitaux Universitaires du Grand Ouest, Laboratoire de Génétique Moléculaire & Génomique [CHU Rennes], CHU Pontchaillou [Rennes], Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Image Guided Clinical Neurosciences and Connectomics (IGCNC), Université d'Auvergne - Clermont-Ferrand I (UdA), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Génétique Médicale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Laboratoire de Génétique Médicale (CHU de Nancy), Centre hospitalier universitaire de Nantes (CHU Nantes), Service de neuro-pédiatrie (CHRU de Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Génétique Médicale, Hopital Jeanne de Flandre, Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de Radiologie [Hôpital Femme Mère Enfant - HCL], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de génétique clinique [CHU Necker], Département de neurologie pédiatrique [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biochimie et biologie moléculaire, Hôpital Cochin [AP-HP], Service de génétique clinique [Debré], Dynamique Cellulaire et Tissulaire- Interdisciplinarité, Modèles & Microscopies (TIMC-IMAG-DyCTiM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Maladies rares, génétique et métabolisme / Rare Diseases, Genetics and Metabolism, Institut National de la Santé et de la Recherche Médicale (INSERM)-École de sage femme - Groupe hospitalier Pellegrin - CHU de Bordeaux, Service de Génétique Médicale du CHU de Bordeaux, Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de génétique chromosomique [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire de Biologie Moléculaire (MARSEILLE - Biolo Moléculaire), Assistance Publique - Hôpitaux de Marseille (APHM), CIC 1407, Hospices Civils de Lyon (HCL), Service de neurologie pédiatrique [CHU de Bordeaux], CHU de Bordeaux Pellegrin [Bordeaux], Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Centre de Génétique Chromosomique [Hôpital Saint Vincent de Paul], GHICL-Hôpital Saint Vincent de Paul, Service de Neuropédiatrie [CHU Necker - Enfants Malades], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Laboratoire de génétique médicale et cytogénétique [Le Mans], Centre Hospitalier Le Mans (CH Le Mans), Service de Génétique [HCL Groupement Hospitalier Est], Groupement hospitalier Lyon-Est, Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Génétique Moléculaire [CHU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Laboratoire de Génétique Chromosomique et Moléculaire [CHU Dijon], Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université Bretagne Loire (UBL), Laboratoire de Cytogénétique Constitutionnelle [Hospices civils de Lyon], Service de Neurologie Pédiatrique [CHU Lyon], Service Génétique Médicale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Centre for Human Genetics, University Hospitals Leuven [Leuven], Institut des Sciences cognitives Marc Jeannerod - Laboratoire sur le langage, le cerveau et la cognition (L2C2), École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre de référence des déficiences intellectuelles de causes rares (Hospices Civils de Lyon), Hospices civils de Lyon (HCL), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Laboratoire de génétique moléculaire et génomique médicale [CHU Rennes], Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Dynamiques Cellulaire et Tissulaire - Interdisciplinarité, Modélisation & Microscopie (TIMC-IMAG-DyCTiM2), Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Groupement Hospitalier Lyon-Est (GHE), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, and Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)
Subjects: 0301 basic medicine, Pediatrics, medicine.medical_specialty, MECP2 duplication syndrome, MECP2gene, Scoliosis, MECP2duplication syndrome, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Gene duplication, Genetics, medicine, Spasticity, Genetics (clinical), X-linked, Vasomotor, business.industry, facial dysmorphism, medicine.disease, Gait, Hypotonia, 3. Good health, 030104 developmental biology, Xq28 duplication, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, medicine.symptom, business, 030217 neurology & neurosurgery, genetic counselling
Abstract: The Xq28 duplication involving theMECP2gene (MECP2duplication) has been mainly described in male patients with severe developmental delay (DD) associated with spasticity, stereotypic movements and recurrent infections. Nevertheless, only a few series have been published. We aimed to better describe the phenotype of this condition, with a focus on morphological and neurological features. Through a national collaborative study, we report a large French series of 59 affected males with interstitialMECP2duplication. Most of the patients (93%) shared similar facial features, which evolved with age (midface hypoplasia, narrow and prominent nasal bridge, thick lower lip, large prominent ears), thick hair, livedo of the limbs, tapered fingers, small feet and vasomotor troubles. Early hypotonia and global DD were constant, with 21% of patients unable to walk. In patients able to stand, lower limbs weakness and spasticity led to a singular standing habitus: flexion of the knees, broad-based stance with pseudo-ataxic gait. Scoliosis was frequent (53%), such as divergent strabismus (76%) and hypermetropia (54%), stereotypic movements (89%), without obvious social withdrawal and decreased pain sensitivity (78%). Most of the patients did not develop expressive language, 35% saying few words. Epilepsy was frequent (59%), with a mean onset around 7.4 years of age, and often (62%) drug-resistant. Other medical issues were frequent: constipation (78%), and recurrent infections (89%), mainly lung. We delineate the clinical phenotype ofMECP2duplication syndrome in a large series of 59 males. Pulmonary hypertension appeared as a cause of early death in these patients, advocating its screening early in life.
Published: 2018

5. Association of transcallosal motor fibres with function of both hands after unilateral neonatal arterial ischemic stroke

Author: Groeschel, Samuel, Hertz‐Pannier, Lucie, Delion, Matthieu, Loustau, Sébastien, Husson, Béatrice, Kossorotoff, Manoelle, Renaud, Cyrille, Nguyen The Tich, Sylvie, Chabrier, Stéphane, Dinomais, Mickaël, Darteyre, Stéphane, Dégano, Céline, Deron, Johanna, Dray, Gérard, Drutel, Laure, Lazaro, Leila, Lefranc, Jérémie, Peyric, Emeline, Presles, Emilie, Ravel, Magaly, Thébault, Guillaume, Vuillerot, Carole, Department of Child Neurology, University Hospital Tübingen, Tübingen, Germany, Unité de recherche en NeuroImagerie Applicative Clinique et Translationnelle (UNIACT), Service NEUROSPIN (NEUROSPIN), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Département de neurochirurgie [Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Laboratoire d'Analyse, Topologie, Probabilités (LATP), Université Paul Cézanne - Aix-Marseille 3-Université de Provence - Aix-Marseille 1-Centre National de la Recherche Scientifique (CNRS), Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Groupe de recherche sur la thrombose (GRT (EA 3065)), Université Jean Monnet [Saint-Étienne] (UJM), Service de neurologie pédiatrique, service de médecine physique et réadaptation pédiatrique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Bellevue-CHU de Saint-Etienne, Laboratoire Angevin de Recherche en Ingénierie des Systèmes (LARIS), Université d'Angers (UA), PRES Université Nantes Angers Le Mans (UNAM), Department of Pediatrics, French Polynesia Hospital, Laboratoire de Génie Informatique et Ingénierie de Production (LGI2P), IMT - MINES ALES (IMT - MINES ALES), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Service de pédiatrie, Le CHCB, Centre Hospitalier de la Côte Basque, CHRU de Brest - Département de Pédiatrie (CHU BREST Pédiatrie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Dynamique des capacités humaines et des conduites de santé (EPSYLON), Université Montpellier 1 (UM1)-Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Montpellier (UM), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), Laboratoire Angevin de Recherche en Mathématiques (LAREMA), Université d'Angers (UA)-Centre National de la Recherche Scientifique (CNRS), Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), CHU Lille, AVCnn study group: Stéphane Darteyre, Céline Dégano, Johanna Deron, Gérard Dray, Laure Drutel, Manoëlle Kossorotoff, Leila Lazaro, Jérémie Lefranc, Emeline Peyric, Emilie Presles, Magaly Ravel, Guillaume Thébault, Carole Vuillerot, Gerard, Marie-Françoise, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université Montpellier 1 (UM1)-Université Paul-Valéry - Montpellier 3 (UM3)-Université de Montpellier (UM), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), and ANR-11-LABX-0020,LEBESGUE,Centre de Mathématiques Henri Lebesgue : fondements, interactions, applications et Formation(2011)
Subjects: Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Pyramidal Tracts, Lesion volume, Motor Activity, Corpus callosum, Functional Laterality, Brain Ischemia, Corpus Callosum, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, Developmental Neuroscience, 030225 pediatrics, medicine.artery, medicine, Humans, Association (psychology), Child, medicine.diagnostic_test, Motor Cortex, Magnetic resonance imaging, Anatomy, Organ Size, Hand, Arterial Ischemic Stroke, Magnetic Resonance Imaging, [SDV] Life Sciences [q-bio], Stroke, Diffusion Tensor Imaging, Pediatrics, Perinatology and Child Health, Corticospinal tract, Middle cerebral artery, Female, Neurology (clinical), Psychology, 030217 neurology & neurosurgery, Diffusion MRI
Abstract: International audience; AIM: The objective of this study was to investigate the involvement of the motor fibres of the corpus callosum after unilateral neonatal arterial ischemic stroke (NAIS) of the middle cerebral artery territory and the relationship to both ipsilesional and contralesional hand function.METHOD: Using high-resolution structural magnetic resonance imaging (MRI), functional MRI, and magnetic resonance diffusion-tractography, we compared the midsagittal area of the motor part of the corpus callosum (defined by the fibres connecting the precentral gyri) between 33 7-year-old children after unilateral NAIS and 31 typically developing 7-year-old children. Hand motor performance was assessed by the box and blocks test.RESULTS: Children after NAIS showed on average significantly smaller motor corpus callosum area compared to typically developing children (p|t|)=0.034) and ipsilesional hand motor performance (Pr(>|t|)=0.006) after controlling for lesion volume and sex. In a post-hoc analysis the additional contribution of corticospinal tract damage was evaluated.INTERPRETATION: Compared to typically developing children, children after NAIS exhibited a smaller motor part of their corpus callosum associated with reduced contralesional but also ipsilesional manual dexterity. These results indicate that the affection of transcallosal motor fibres in unilateral NAIS might be of functional relevance and an important part of the involved structural network that should be elucidated in further studies.TRIAL REGISTRATION: ClinicalTrials.gov NCT02511249.© 2017 Mac Keith Press.
Published: 2017

6. Autosomal-Recessive Mutations in AP3B2, Adaptor-Related Protein Complex 3 Beta 2 Subunit, Cause an Early-Onset Epileptic Encephalopathy with Optic Atrophy

Author: Catherine Nowak, Kamiar Mireskandari, Masano Amamoto, Jean-Baptiste Rivière, Amber Begtrup, Thibaud Jouan, Laurence Faivre, Aline Saunier, Nicolas Chatron, Noriko Miyake, Mitsuhiro Kato, Dorothée Ville, Jessica Douglas, Stéphane Auvin, Bertrand Isidor, Guylène Lemeur, Stylianos E. Antonarakis, Naomichi Matsumoto, Mathieu Milh, Philippe Jonveaux, Hanan Hamamy, Neal Sondheimer, Mirna Assoum, Paolo Milani, Mitsuko Nakashima, Amira Masri, Gaetan Lesca, Julien Thevenon, Yannis Duffourd, Laurence Perrin, Caroline Paris, Christel Thauvin-Robinet, Christophe Philippe, Periklis Makrythanasis, Génétique des Anomalies du Développement ( GAD ), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne ( UB ), Nutrition-Génétique et Exposition aux Risques Environnementaux ( NGERE ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lorraine ( UL ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), Service de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP), University of Geneva, Division of Clinical and Metabolic Genetics [Toronto], The Hospital for sick children [Toronto] ( SickKids ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Boston Children's Hospital, Centre de recherche en neurosciences de Lyon ( CRNL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Lyon, Service de Génétique Médicale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), GeneDx, Service de Neurologie Pédiatrique [CHU Lyon], Hôpital Femme Mère Enfant [CHU - HCL] ( HFME ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Service de Neurologie Pédiatrique, HFME, Bron, France, Service d'ophtalmologie [Nantes], Hôtel-Dieu, Service de pédiatrie et neurologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Génétique Médicale et Génomique Fonctionnelle ( GMGF ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Pediatric Emergency Centre, Kitakyushu Municipal Yahata Hospital, Yokohama City University School of Medecine ( YCUSM ), University School of Medecine, University of Amman, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Regional Council of Burgundy Dijon University Hospital Association Française du Syndrome de Rett, Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre hospitalier universitaire de Nantes (CHU Nantes), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The Hospital for sick children [Toronto] (SickKids), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), GeneDx [Gaithersburg, MD, USA], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Yokohama City University School of Medecine (YCUSM), Yokohama University School of Medecine, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, Microcephaly, Developmental Disabilities, Postnatal microcephaly, copper-metabolism, Epilepsy, 0302 clinical medicine, expansion, hermansky-pudlak-syndrome, ddc:576.5, Age of Onset, Child, disorders, Genetics (clinical), seizures, Genetics, MEDNIK syndrome, Syndrome, 3. Good health, Pedigree, intellectual disability, Child, Preschool, mednik syndrome, Female, Developmental regression, Adaptor Protein Complex 3, Genes, Recessive, Biology, AP3B1, 03 medical and health sciences, Atrophy, Report, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, medicine, Humans, Adaptor Protein Complex beta Subunits, mouse, disease, ap-4 deficiency, Infant, Newborn, Infant, medicine.disease, Optic Atrophy, 030104 developmental biology, Mutation, Hermansky–Pudlak syndrome, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Early-onset epileptic encephalopathy (EOEE) represents a heterogeneous group of severe disorders characterized by seizures, interictal epileptiform activity with a disorganized electroencephalography background, developmental regression or retardation, and onset before 1 year of age. Among a cohort of 57 individuals with epileptic encephalopathy, we ascertained two unrelated affected individuals with EOEE associated with developmental impairment and autosomal-recessive variants in AP3B2 by means of whole-exome sequencing. The targeted sequencing of AP3B2 in 86 unrelated individuals with EOEE led to the identification of an additional family. We gathered five additional families with eight affected individuals through the Matchmaker Exchange initiative by matching autosomal- recessive mutations in AP3B2. Reverse phenotyping of 12 affected individuals from eight families revealed a homogeneous EOEE phenotype characterized by severe developmental delay, poor visual contact with optic atrophy, and postnatal microcephaly. No spasticity, albinism, or hematological symptoms were reported. AP3B2 encodes the neuron-specific subunit of the AP-3 complex. Autosomal-recessive variations of AP3B1, the ubiquitous isoform, cause Hermansky-Pudlak syndrome type 2. The only isoform for the delta subunit of the AP-3 complex is encoded by AP3D1. Autosomal-recessive mutations in AP3D1 cause a severe disorder cumulating the symptoms of the AP3B1 and AP3B2 defects.
Published: 2016

7. Epilepsy in young Tsc1+/− mice exhibits age-dependent expression that mimics that of human tuberous sclerosis complex

Author: Gilles Huberfeld, Jean-Michel Pedespan, Svetlana Gataullina, Françoise Watrin, Marie-Laure Moutard, Nadia Bahi-Buisson, Dorothée Ville, Monika Eisermann, Anne de Saint Martin, Fabrice Wendling, Silvia Napuri, Audrey Riquet, Olivier Dulac, Anna Kaminska, Catherine Chiron, Eric Lemaire, Rima Nabbout, Epilepsies de l'Enfant et Plasticité Cérébrale (U1129), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurophysiologie Clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U901), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Explorations Fonctionnelles Neurologiques, CHU Pontchaillou [Rennes]-hôpital Sud, Service de neurologie pédiatrique [CHU Necker], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre de Reference Epilepsies Rares-CHU Necker - Enfants Malades [AP-HP], Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), French League Against Epilepsy, Association Thermalliance, Rothschild Foundation, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Epilepsies de l'Enfant et Plasticité Cérébrale ( U1129 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris Descartes - Paris 5 ( UPD5 ), Laboratoire Traitement du Signal et de l'Image ( LTSI ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut de neurobiologie de la Méditerranée ( INMED ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Pontchaillou [Rennes]-Hôpital Sud, Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Centre de Reference Epilepsies Rares-CHU Necker - Enfants Malades [AP-HP], NeuroSpin, Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Institut d'imagerie biomédicale (I²BM), Département de neurophysiologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre de Reference Epilepsies Rares-CHU Necker - Enfants Malades [AP-HP], and CHU Pitié-Salpêtrière [APHP]
Subjects: 0301 basic medicine, Male, Pathology, Spikes, Electroencephalography, Somatosensory system, Tuberous Sclerosis Complex 1 Protein, Tuberous sclerosis, Epilepsy, Mice, 0302 clinical medicine, Tuberous Sclerosis, [ SDV.IB ] Life Sciences [q-bio]/Bioengineering, Child, medicine.diagnostic_test, Age Factors, Epileptic spasms, medicine.anatomical_structure, Neurology, Child, Preschool, Female, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Psychology, Infants, medicine.drug, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Mice, Transgenic, Vigabatrin, 03 medical and health sciences, Seizures, medicine, Animals, Humans, Ictal, Retrospective Studies, Tumor Suppressor Proteins, Infant, medicine.disease, nervous system diseases, Mice, Inbred C57BL, Electroencephalogram, 030104 developmental biology, Gene Expression Regulation, Neurology (clinical), TSC1, Neuroscience, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: International audience; Objective - To describe the epileptic phenotype of Tsc1(+/-) mice pups in comparison with age-related seizures in human tuberous sclerosis complex (TSC). Methods - Tsc1(+/-) and control mice underwent intracranial electroencephalography (EEG) recording at postnatal ages (P)8 to P33, with linear silicon probe implanted in the somatosensory cortex of one or both hemispheres for 8-24 h. Ictal events were classified visually by independent analyzers; distinct EEG patterns were related to age and analyzed to quantify field potential characteristics and signal dynamics between hemispheres. We collected retrospectively 20 infants with prenatally diagnosed TSC and EEG before seizure onset, and analyzed the electroclinical course of epilepsy, taking into account a first-line treatment by vigabatrin. Results - Spontaneous seizures were disclosed in 55% of Tsc1(+/-) mice at P9-18. Three ictal patterns were identified: from P9 to P12 "spike clusters" consisted of recurring large spikes without clinical correlate; "spasm-like" discharges dominated from P13 to P16 consisting of high amplitude large field potential superimposed with or followed by fast activity repeated every 2-10 s for at least 20 s, accompanied by rhythmic limb contractions; from P14 to P18 a "tonic-clonic like" pattern comprised rhythmic spikes of increasing amplitude with tonic-clonic movements. Early onset "spike clusters" were mainly unilateral, whereas "spasm-like" and "tonic-clonic like" patterns were bilateral. Interhemispheric propagation was significantly faster for "tonic-clonic like" than for "spasm-like" events. In infants diagnosed prenatally with TSC, clusters of sharp waves or spikes preceded the first seizure, and vigabatrin prevented the development of seizures. Patients treated after seizure onset developed spasms or focal seizures that were pharmacoresistant in 66.7% of cases. Significance - Tsc1(+/-) mice pups exhibit an age-dependent seizure pattern sequence mimicking early human TSC epilepsy features. Spike clusters before seizure onset in TSC should be considered as a first stage of epilepsy reinforcing the concept of preventive antiepileptic therapy.
Published: 2016

8. Multimodal Outcome at 7 Years of Age after Neonatal Arterial Ischemic Stroke

Author: Stéphane Chabrier, Emeline Peyric, Laure Drutel, Johanna Deron, Manoëlle Kossorotoff, Mickaël Dinomais, Leila Lazaro, Jérémie Lefranc, Guillaume Thébault, Gérard Dray, Joel Fluss, Cyrille Renaud, Sylvie Nguyen The Tich, Stéphane Darteyre, Céline Dégano, Matthieu Delion, Samuel Groeschel, Lucie Hertz-Pannier, Béatrice Husson, Emilie Presles, Magaly Ravel, Carole Vuillerot, Dray, Gérard, CIC Saint Etienne, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Nord (Saint Etienne), Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire Angevin de Recherche en Ingénierie des Systèmes (LARIS), Université d'Angers (UA), Le CHCB, Centre Hospitalier de la Côte Basque, CHRU de Brest - Département de Pédiatrie (CHU BREST Pédiatrie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Dynamique des capacités humaines et des conduites de santé (EPSYLON), Université Paul-Valéry - Montpellier 3 (UPVM), Laboratoire de Génie Informatique et Ingénierie de Production (LGI2P), IMT - MINES ALES (IMT - MINES ALES), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Geneva University Hospital (HUG), Groupe de recherche sur la thrombose (GRT (EA 3065)), Université Jean Monnet - Saint-Étienne (UJM), Accident Vasculaire Cérébral du nouveau-né (AVCnn, [Neonatal Stroke]) Study Group: Stéphane Darteyre, Céline Dégano, Matthieu Delion, Samuel Groeschel, Lucie Hertz-Pannier, Béatrice Husson, Emilie Presles, Magaly Ravel, Carole Vuillerot, service de médecine physique et réadaptation pédiatrique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Bellevue-CHU de Saint-Etienne, Service de neurologie pédiatrique, Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de Génétique Clinique, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Sud, Université Montpellier 1 (UM1)-Université Paul-Valéry - Montpellier 3 (UM3)-Université de Montpellier (UM), Université Jean Monnet [Saint-Étienne] (UJM), Département de neurochirurgie [Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Pédiatrie hospices civils de Lyon, hôpital Femme-Mère-Enfant, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Nord (Saint Etienne), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-hôpital Sud, Université de Montpellier (UM)-Université Paul-Valéry - Montpellier 3 (UPVM)-Université Montpellier 1 (UM1), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP]
Subjects: Male, Pediatrics, medicine.medical_specialty, Developmental Disabilities, Cerebral palsy, Cohort Studies, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Borderline intellectual functioning, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, 030225 pediatrics, Humans, Medicine, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Preschool, Child, Stroke, ComputingMilieux_MISCELLANEOUS, Wechsler Intelligence Scale for Children, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, ddc:618, Epilepsy/epidemiology/etiology, business.industry, Infant, Newborn, Infant, Newborn, medicine.disease, Arterial Ischemic Stroke, 3. Good health, Institutional repository, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Developmental Disabilities/epidemiology/etiology, Child, Preschool, Pediatrics, Perinatology and Child Health, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Stroke/complications, Cohort study
Abstract: Objectives To evaluate the epileptic, academic, and developmental status at age 7 years in a large population of term-born children who sustained neonatal arterial ischemic stroke (NAIS), and to assess the co-occurrence of these outcomes. Study design A cohort study including 100 term newborns with NAIS was designed. Two infants died during the neonatal period, 13 families were lost to follow-up, and 5 families declined to participate in this evaluation. Thus, 80 families completed the 7-year clinical assessment. Epileptic status, schooling, motor abilities, global intellectual functioning, spoken language, and parental opinions were recorded. Principal component analysis was applied. Results Rates of impaired language, cerebral palsy, low academic skills, active epilepsy, and global intellectual deficiency were 49%, 32%, 28%, 11%, and 8%, respectively. All were highly correlated. Eventually, 59% of children were affected by at least 1 of the aforementioned conditions. In 30% of cases, the viewpoints of health practitioners and parents did not match. Conclusion The prevalence of severe disabilities at 7 years after NAIS is low, but most children exhibit some impairment in developmental profile. Trial registration ClinicalTrials.gov ( NCT02511249 ), Programme Hospitalier de Recherche Clinique Regional (0308052), Programme Hospitalier de Recherche Clinique Interregional (1008026), and EudraCT (2010-A00329-30).
Published: 2016

9. Mutations and Deletions in PCDH19 Account for Various Familial or Isolated Epilepsies in Females

Author: Eric LeGuern, François Rivier, Brigitte Gilbert-Dussardier, Denys Chaigne, Delphine Bouteiller, Karine Poirier, Agathe Roubertie, Anne Dusser, Sandra Whalen, Marie Bru, Dominique Steschenko, Oriane Trouillard, Isabelle Gourfinkel-An, Stéphanie Baulac, Alexis Arzimanoglou, Agnès Gautier, Dorota Hoffman-Zacharska, Christel Depienne, Anna Kaminska, Hélène Maurey, Cyril Mignot, Gaetan Lesca, Annie Lannuzel, Marilyn Lackmy-Port-Lis, Rima Nabbout, Patrick Berquin, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Pôle d'Epileptologie, AP-HP, Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Service de Neuropédiatrie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de neuropédiatrie, CHU Hôpital Nord Amiens, Département de Neuropédiatrie, CHU Necker - Enfants Malades [AP-HP], Clinique Sainte-Odile, Strasbourg, Unité de Neurologie Pédiatrique, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Serice de Neuropédiatrie, Institute of Mother and Child Department of Medical Genetics, Department of neurology, CHU Pointe-à-Pitre/Abymes [Guadeloupe], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Service de neurologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Hôpital Mère-Enfant, CHU de Nantes, Service de Genetique medicale, Centre hospitalier universitaire de Poitiers (CHU Poitiers), CHU Hôpital, CHU Trousseau [APHP], Pavillon E, Laboratoire de Genetique, Unité d'Epileptologie Pédiatrique, Service de Neurologie Pédiatrique et des Maladies Métaboliques, AP-HP, Hôpital Robert Debré, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Amiens-Picardie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière ( CRICM ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, and Centre hospitalier universitaire de Poitiers ( CHU Poitiers )
Subjects: Adult, Male, PCDH19, Adolescent, Febrile seizures, Protocadherin, Mutation in Brief, Biology, medicine.disease_cause, 03 medical and health sciences, Exon, Epilepsy, Young Adult, 0302 clinical medicine, Genetics, medicine, Humans, Family history, Child, Genetics (clinical), X chromosome, cognitive function, 030304 developmental biology, 0303 health sciences, Mutation, Polymorphism, Genetic, Point mutation, Life Sciences, Infant, Exons, Middle Aged, medicine.disease, Cadherins, Protocadherins, Pedigree, Child, Preschool, Female, microdeletion, Generalized epilepsy with febrile seizures plus, 030217 neurology & neurosurgery, Gene Deletion
Abstract: International audience; Mutations in PCDH19, encoding protocadherin 19 on chromosome X, cause familial epilepsy and mental retardation limited to females or Dravet-like syndrome. Heterozygous females are affected while hemizygous males are spared, this unusual mode of inheritance being probably due to a mechanism called cellular interference. To extend the mutational and clinical spectra associated with PCDH19, we screened 150 unrelated patients (113 females) with febrile and afebrile seizures for mutations or rearrangements in the gene. Fifteen novel point mutations were identified in 15 female patients (6 sporadic and 9 familial cases). In addition, qPCR revealed two whole gene deletions and one partial deletion in 3 sporadic female patients. Clinical features were highly variable but included almost constantly a high sensitivity to fever and clusters of brief seizures. Interestingly, cognitive functions were normal in several family members of 2 families: the familial condition in family 1 was suggestive of Generalized Epilepsy with Febrile Seizures Plus (GEFS+) whereas all three affected females had partial cryptogenic epilepsy. These results show that mutations in PCDH19 are a relatively frequent cause of epilepsy in females and should be considered even in absence of family history and/or mental retardation.
Published: 2011

10. De novo mutations in HCN1 cause early infantile epileptic encephalopathy

Author: Nava, Caroline, Dalle, Carine, Rastetter, Agnès, Striano, Pasquale, de Kovel, Carolien G F, Nabbout, Rima, Cancès, Claude, Ville, Dorothée, Brilstra, Eva H, Gobbi, Giuseppe, Raffo, Emmanuel, Bouteiller, Delphine, Marie, Yannick, Trouillard, Oriane, Robbiano, Angela, Keren, Boris, Agher, Dahbia, Roze, Emmanuel, Lesage, Suzanne, Nicolas, Aude, Brice, Alexis, Baulac, Michel, Vogt, Cornelia, El Hajj, Nady, Schneider, Eberhard, Suls, Arvid, Weckhuysen, Sarah, Gormley, Padhraig, Lehesjoki, Anna-Elina, De Jonghe, Peter, Helbig, Ingo, Baulac, Stéphanie, Zara, Federico, Koeleman, Bobby P C, Haaf, Thomas, LeGuern, Eric, Depienne, Christel, Møller, Rikke Steensbjerre, Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Giannina Gaslini Institute, University Medical Center [Utrecht], Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Epilepsies de l'Enfant et Plasticité Cérébrale (U1129), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie Pédiatrique [Toulouse], CHU Toulouse [Toulouse], Service de Neurologie Pédiatrique [CHU Lyon], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), IRCCS Istituto delle Scienze Neurologiche di Bologna [Bologna, Italy], Ospedale Bellaria [Bologna, Italy], Développement, Adaptation et Handicap. Régulations cardio-respiratoires et de la motricité. (DevAH), Université de Lorraine (UL), Service de Neurologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Institüt für Humangenetik [Würzburg], Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Neurogenetics Group, Institute Born-Bunge, University of Antwerp (UA), The Wellcome Trust Sanger Institute [Cambridge], Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, University of Helsinki, University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Développement, Adaptation et Handicap. Régulations cardio-respiratoires et de la motricité (DevAH), EuroEPINOMICS RES Consortium, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service Neurologie Pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Julius-Maximilians-Universität Würzburg (JMU), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, and Helsingin yliopisto = Helsingfors universitet = University of Helsinki
Subjects: Male, MESH: Sequence Analysis, DNA, Patch-Clamp Techniques, Potassium Channels, MESH: Spasms, Infantile, MESH: Sequence Homology, Amino Acid, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Mutant, DNA Mutational Analysis, Sequence Homology, MESH: Cricetinae, Aicardi Syndrome, Amino Acid Sequence, Animals, CHO Cells, Child, Preschool, Cohort Studies, Cricetinae, Cricetulus, Female, Humans, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, Infant, Molecular Sequence Data, Mutation, Missense, Pedigree, Sequence Analysis, DNA, Sequence Homology, Amino Acid, Spasms, Infantile, Point Mutation, Genetics, MESH: Amino Acid Sequence, Bioinformatics, Infantile, Spasms, Epilepsy, 0302 clinical medicine, MESH: Cricetulus, Missense mutation, MESH: Animals, MESH: DNA Mutational Analysis, Child, MESH: Cohort Studies, Exome sequencing, 0303 health sciences, MESH: Potassium Channels, de novo mutation, epileptic encephalopathies, MESH: Infant, 3. Good health, Amino Acid, Sequence Analysis, MESH: Pedigree, Biology, 03 medical and health sciences, Dravet syndrome, MESH: CHO Cells, MESH: Patch-Clamp Techniques, medicine, Homomeric, MESH: Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, MESH: Aicardi Syndrome, Preschool, Gene, 030304 developmental biology, MESH: Point Mutation, MESH: Mutation, Missense, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, MESH: Humans, MESH: Molecular Sequence Data, Point mutation, MESH: Child, Preschool, DNA, medicine.disease, MESH: Male, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Human medicine, Missense, MESH: Female, 030217 neurology & neurosurgery
Abstract: International audience; Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels contribute to cationic Ih current in neurons and regulate the excitability of neuronal networks. Studies in rat models have shown that the Hcn1 gene has a key role in epilepsy, but clinical evidence implicating HCN1 mutations in human epilepsy is lacking. We carried out exome sequencing for parent-offspring trios with fever-sensitive, intractable epileptic encephalopathy, leading to the discovery of two de novo missense HCN1 mutations. Screening of follow-up cohorts comprising 157 cases in total identified 4 additional amino acid substitutions. Patch-clamp recordings of Ih currents in cells expressing wild-type or mutant human HCN1 channels showed that the mutations had striking but divergent effects on homomeric channels. Individuals with mutations had clinical features resembling those of Dravet syndrome with progression toward atypical absences, intellectual disability and autistic traits. These findings provide clear evidence that de novo HCN1 point mutations cause a recognizable early-onset epileptic encephalopathy in humans.
Published: 2014

11. Creatine and guanidinoacetate reference values in a French population

Author: Gilles Simard, Gajja S. Salomons, Olivier Douay, Marc Tardieu, François Rivier, Nicole Porchet, Marion Gérard, Gaelle Pitelet, David Cheillan, Jean-Marie Cuisset, François Cartault, Joseph Vamecq, Karine Mention-Mulliez, Delphine Héron, Alice Goldenberg, Vincent des Portes, Richard Delorme, Soumeya Bekri, Brigitte Chabrol, L. Lion-François, Vassili Valayannopoulos, JM Pinard, Jean-François Benoist, Allel Chabli, Gilbert Briand, Kumaran Deiva, Fabienne Prieur, Christine Vianey-Saban, Dries Dobbelaere, Alexandra Afenjar, Marie Joncquel-Chevalier Curt, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Laboratoire d'Hormonologie, Métabolisme-Nutrition & Oncologie (HMNO), Département de Biochimie et Biologie Moléculaire-Centre de Biologie et Pathologie (CBP) Pierre-Marie Degand-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Mass Spectrometry Application Laboratory, Université de Lille, Droit et Santé, Metabolic Unit, Department of Clinical Chemistry-VU University Medical Center [Amsterdam], Hôpital Jeanne de Flandre [Lille], Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Jeanne de Flandres-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de référence des maladies héréditaires du métabolisme de l'enfant et de l'adulte, Centre Hospitalier Universitaire de Lille (CHU de Lille), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Laboratoire de Biochimie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de neurologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP], Stress Oxydant et Pathologies Métaboliques (SOPAM), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neuropédiatrie, Hôpital Bicêtre, Génétique Médicale et Génomique Fonctionnelle (GMGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Unité Fonctionnelle de Génétique Clinique [CHU Pitié Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier], Service de Neurologie Pédiatrique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre de Référence des Maladies Héréditaires du Métabolisme, Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne, Service de génétique, Centre hospitalier Félix-Guyon [Saint-Denis, La Réunion], Hôpital l'Archet, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Laboratoire de biochimie générale [Rouen], Normandie Université (NU)-Centre hospitalier universitaire de Rouen, Université de Lorraine (UL), Service Psychiatrie de l'Enfant et de l'Adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Clinical chemistry, and NCA - Brain mechanisms in health and disease
Subjects: Male, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Choreoathetosis, Physiology, Urine, Biochemistry, chemistry.chemical_compound, Epilepsy, Plasma, 0302 clinical medicine, Endocrinology, Reference Values, Intellectual disability, Child, Dystonia, Aged, 80 and over, 0303 health sciences, education.field_of_study, Age Factors, Middle Aged, 3. Good health, Child, Preschool, Creatinine, Female, France, medicine.symptom, Adult, medicine.medical_specialty, Ataxia, Adolescent, Population, Glycine, Creatine, White People, 03 medical and health sciences, Young Adult, Sex Factors, Internal medicine, Genetics, medicine, Humans, education, Molecular Biology, Amino Acid Metabolism, Inborn Errors, 030304 developmental biology, Aged, Guanidinoacetate, business.industry, Infant, Newborn, Laboratory values, Infant, medicine.disease, chemistry, Case-Control Studies, business, 030217 neurology & neurosurgery
Abstract: International audience; Creatine and guanidinoacetate are biomarkers of creatine metabolism. Their assays in body fluids may be used for detecting patients with primary creatine deficiency disorders (PCDD), a class of inherited diseases. Their laboratory values in blood and urine may vary with age, requiring that reference normal values are given within the age range. Despite the long known role of creatine for muscle physiology, muscle signs are not necessarily the major complaint expressed by PCDD patients. These disorders drastically affect brain function inducing, in patients, intellectual disability, autistic behavior and other neurological signs (delays in speech and language, epilepsy, ataxia, dystonia and choreoathetosis), being a common feature the drop in brain creatine content. For this reason, screening of PCDD patients has been repeatedly carried out in populations with neurological signs. This report is aimed at providing reference laboratory values and related age ranges found for a large scale population of patients with neurological signs (more than 6 thousand patients) previously serving as a background population for screening French patients with PCDD. These reference laboratory values and age ranges compare rather favorably with literature values for healthy populations. Some differences are also observed, and female participants are discriminated from male participants as regards to urine but not blood values including creatine on creatinine ratio and guanidinoacetate on creatinine ratio values. Such gender differences were previously observed in healthy populations; they might be explained by literature differential effects of testosterone and estrogen in adolescents and adults, and by estrogen effects in prepubertal age on SLC6A8 function. Finally, though they were acquired on a population with neurological signs, the present data might reasonably serve as reference laboratory values in any future medical study exploring abnormalities of creatine metabolism and transport.
Published: 2013

12. A prospective behavioral and imaging study exploring the impact on long-term memory of radiotherapy delivered for a brain tumor in childhood and adolescence

Author: Jérémie Pariente, B. Lemesle, Anne Ducassou, Déborah Méligne, Dominique Barbolosi, Helene Gros-Dagnac, Lisa Pollidoro, Eloïse Baudou, Germain Arribarat, Jérémy Danna, Mathilde Cazaux, Patrice Péran, F. Tensaouti, Delphine Larrieu-Ciron, Anne Laprie, Yves Chaix, Anne-Isabelle Bertozzi, Annick Sevely, Marion Gambart, Jean-Pierre Desirat, Xavier Muracciole, Margaux Roques, Jessica Tallet, Toulouse Neuro Imaging Center (ToNIC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Service de Neurologie Pédiatrique [Toulouse], CHU Toulouse [Toulouse], CHU Toulouse, Departement de Neurologie, Département d'Oncologie Médicale [CHU Toulouse] (IUCT Oncopole - Institut Universitaire du Cancer), Centre hospitalier universitaire de Toulouse - CHU Toulouse-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Simulation and Modeling of Adaptive Response for Therapeutics in Cancer (SMARTc), Centre de Recherche en Cancérologie de Marseille (CRCM), Laboratoire de Neurosciences Cognitives [Marseille] (LNC), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Pediatrics, resting-state functional magnetic resonance imaging, R895-920, NTCP, Procedural memory, SRTT, Medical physics. Medical radiology. Nuclear medicine, PFT, WISC, 0302 clinical medicine, Posterior fossa brain tumor, IQ, intellectual quotient, NTCP, normal tissue complication probability, normal tissue complication probability, intellectual quotient, serial reaction time task, Wechsler Adult Intelligence Scale, DFA, discriminating factor analysis, Semantic memory, Episodic memory, 3DT1, T1-weighted imaging, RC254-282, Spectroscopy, posterior fossa tumor, Long-term memory, CMS, pseudocontinuous arterial spin labeling, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cognition, Executive functions, diffusion tensor imaging, 3. Good health, Oncology, DTI, 030220 oncology & carcinogenesis, TCP, rs-fMRI, resting-state functional magnetic resonance imaging, medicine.medical_specialty, WAIS, Wechsler Adult Intelligence Scale, PFT, posterior fossa tumor, Brain tumor, WAIS, pCASL, [SDV.CAN]Life Sciences [q-bio]/Cancer, MEM-III, Article, 03 medical and health sciences, Magnetic resonance imaging, Memory, medicine, Wechsler Memory Scale, Radiology, Nuclear Medicine and imaging, Wechsler Intelligence Scale for Children, Children's Memory Scale, SRTT, serial reaction time task, TCP, tumor control probability, Radiotherapy, Working memory, business.industry, discriminating factor analysis, CMS, Children's Memory Scale, medicine.disease, T1-weighted imaging, tumor control probability, DFA, nervous system, IQ, MEM-III, Wechsler Memory Scale, DTI, diffusion tensor imaging, business, 3DT1, 030217 neurology & neurosurgery, rs-fMRI, pCASL, pseudocontinuous arterial spin labeling, WISC, Wechsler Intelligence Scale for Children
Abstract: Highlights • Common long-term memory defects after pediatric brain tumor affect school achievement • The hippocampi, the cerebellum and cerebellar-cortical networks play a role in several memory systems. • This study will provide long-term neuropsychological data about four different memory systems. • We will investigate the correlations between neuropsychological, neuroimaging and radiotherapy dose data. • Imaging will be structural (3DT1), microstructural (DTI), functional (rs-fMRI), vascular (ASL) and metabolic (spectroscopy)., Background Posterior fossa tumors represent two thirds of brain tumors in children. Although progress in treatment has improved survival rates over the past few years, long-term memory impairments in survivors are frequent and have an impact on academic achievement. The hippocampi, cerebellum and cerebellar-cortical networks play a role in several memory systems. They are affected not only by the location of the tumor itself and its surgical removal, but also by the supratentorial effects of complementary treatments, particularly radiotherapy. The IMPALA study will investigate the impact of irradiation doses on brain structures involved in memory, especially the hippocampi and cerebellum. Methods/design In this single-center prospective behavioral and neuro-imaging study, 90 participants will be enrolled in three groups. The first two groups will include patients who underwent surgery for a posterior fossa brain tumor in childhood, who are considered to be cured, and who completed treatment at least 5 years earlier, either with radiotherapy (aggressive brain tumor; Group 1) or without (low-grade brain tumor; Group 2). Group 3 will include control participants matched with Group 1 for age, sex, and handedness. All participants will perform an extensive battery of neuropsychological tests, including an assessment of the main memory systems, and undergo multimodal 3 T MRI. The irradiation dose to the different brain structures involved in memory will be collected from the initial radiotherapy dosimetry. Discussion This study will provide long-term neuropsychological data about four different memory systems (working memory, episodic memory, semantic memory, and procedural memory) and the cognitive functions (attention, language, executive functions) that can interfere with them, in order to better characterize memory deficits among the survivors of brain tumors. We will investigate the correlations between neuropsychological and neuroimaging data on the structural (3DT1), microstructural (DTI), functional (rs-fMRI), vascular (ASL) and metabolic (spectroscopy) impact of the tumor and irradiation dose. This study will thus inform the setting of dose constraints to spare regions linked to the development of cognitive and memory functions. Trial registration ClinicalTrials.gov: NCT04324450, registered March 27, 2020, updated January 25th, 2021. Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/NCT04324450.
Published: 2022

13. Behavior and interaction imaging at 9 months of age predict autism/intellectual disability in high-risk infants with West syndrome

Author: Marluce Leitgel Gille, Laurence Robel, Mohamed Afshar, Mariana Guergova-Kuras, David Cohen, Giuseppe Palestra, Hugues Pellerin, Rima Nabbout, Mohamed Chetouani, Bernard Golse, Isabelle Desguerre, Catherine Saint-Georges, Lisa Ouss, Kevin Bailly, Psychiatrie de l'enfant et de l'adolescent [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut des Systèmes Intelligents et de Robotique (ISIR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Psychiatrie de l'Enfant et de l'Adolescent [CHU Pitié-Salpêtrière] (SPEA), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Ariana Pharmaceuticals (ARIANA), Ariana Pharmaceuticals, Perception, Interaction, Robotique sociales (PIROS), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: medicine.medical_specialty, Autism Spectrum Disorder, [SDV]Life Sciences [q-bio], Audiology, Predictive markers, Hand movements, Article, lcsh:RC321-571, 03 medical and health sciences, Cellular and Molecular Neuroscience, Typically developing, 0302 clinical medicine, Intellectual Disability, Intellectual disability, Medicine, Humans, Speech, 0501 psychology and cognitive sciences, Autistic Disorder, Child, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, High risk infants, business.industry, 05 social sciences, Infant, West Syndrome, Autism spectrum disorders, medicine.disease, Psychiatry and Mental health, Autism spectrum disorder, Autism, business, Spasms, Infantile, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 050104 developmental & child psychology
Abstract: Automated behavior analysis are promising tools to overcome current assessment limitations in psychiatry. At 9 months of age, we recorded 32 infants with West syndrome (WS) and 19 typically developing (TD) controls during a standardized mother–infant interaction. We computed infant hand movements (HM), speech turn taking of both partners (vocalization, pause, silences, overlap) and motherese. Then, we assessed whether multimodal social signals and interactional synchrony at 9 months could predict outcomes (autism spectrum disorder (ASD) and intellectual disability (ID)) of infants with WS at 4 years. At follow-up, 10 infants developed ASD/ID (WS+). The best machine learning reached 76.47% accuracy classifying WS vs. TD and 81.25% accuracy classifying WS+ vs. WS−. The 10 best features to distinguish WS+ and WS− included a combination of infant vocalizations and HM features combined with synchrony vocalization features. These data indicate that behavioral and interaction imaging was able to predict ASD/ID in high-risk children with WS.
Published: 2020

14. Neonatal presentation of genetic epilepsies: Early differentiation from acute provoked seizures

Author: Adam L. Numis, Valeria Morabito, Hannah C. Glass, Tristan T. Sands, Susana Ferrao Santos, Damien Lederer, Marie-Coralie Cornet, Maria Roberta Cilio, Donna M. Ferriero, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de neurologie, UCL - (SLuc) Service de neurologie pédiatrique, UCL - (SLuc) Centre de référence pour l'épilepsie réfractaire, and UCL - (SLuc) Centre des maladies neuro-cutanées congénitales
Subjects: 0301 basic medicine, tonic, Pediatrics, Potassium Channels, Electroencephalography, Potassium Channels, Sodium-Activated, Neurodegenerative, Epilepsy, 0302 clinical medicine, Child, Stroke, Pediatric, medicine.diagnostic_test, BRAT1, Brain, Neurology, Hypoxia-Ischemia, Brain, Neurological, video-EEG, Sodium-Activated, Adult, medicine.medical_specialty, semiology, Clinical Sciences, Nerve Tissue Proteins, Neonatal onset, 03 medical and health sciences, Seizures, Intensive care, Hypoxia-Ischemia, medicine, Genetics, Tonic (music), Humans, Retrospective Studies, Neurology & Neurosurgery, business.industry, Infant, Newborn, Neurosciences, Infant, medicine.disease, Newborn, neonates, Brain Disorders, 030104 developmental biology, Good Health and Well Being, Neurology (clinical), business, 030217 neurology & neurosurgery, PRRT2
Abstract: Author(s): Cornet, Marie-Coralie; Morabito, Valeria; Lederer, Damien; Glass, Hannah C; Ferrao Santos, Susana; Numis, Adam L; Ferriero, Donna M; Sands, Tristan T; Cilio, Maria Roberta | Abstract: ObjectiveAlthough most seizures in neonates are due to acute brain injury, some represent the first sign of neonatal onset genetic epilepsies. Delay in recognition and lack of expert assessment of neonates with epilepsy may result in worse developmental outcomes. As in older children and adults, seizure semiology in neonates is an essential determinant in diagnosis. We aimed to establish whether seizure type at presentation in neonates can suggest a genetic etiology.MethodsWe retrospectively analyzed the clinical and electroencephalographic (EEG) characteristics of seizures in neonates admitted in two Level IV neonatal intensive care units, diagnosed with genetic epilepsy, for whom a video-EEG recording at presentation was available for review, and compared them on a 1:2 ratio with neonates with seizures due to stroke or hypoxic-ischemic encephalopathy.ResultsTwenty neonates with genetic epilepsy were identified and compared to 40 neonates with acute provoked seizures. Genetic epilepsies were associated with pathogenic variants in KCNQ2 (nn=n12), KCNQ3 (nn=n2), SCN2A (nn=n2), KCNT1 (nn=n1), PRRT2 (nn=n1), and BRAT1 (nn=n2). All neonates with genetic epilepsy had seizures with clinical correlates that were either tonic (18/20) or myoclonic (2/20). In contrast, 17 of 40 (42%) neonates with acute provoked seizures had electrographic only seizures, and the majority of the remainder had clonic seizures. Time to first seizure was longer in neonates with genetic epilepsies (median = 60nh of life) compared to neonates with acute provoked seizures (median = 15nh of life, pnln.001). Sodium channel-blocking antiseizure medications were effective in 13 of 14 (92%) neonates with tonic seizures who were trialed at onset or during the course of the epilepsy.SignificanceSeizure semiology is an easily accessible sign of genetic epilepsies in neonates. Early identification of the seizure type can prompt appropriate workup and treatment. Tonic seizures are associated with channelopathies and are often controlled by sodium channel-blocking antiseizure medications.
Published: 2021

15. Improving early diagnosis of rare diseases using Natural Language Processing in unstructured medical records: an illustration from Dravet syndrome

Author: Mathieu Kuchenbuch, Antoine Neuraz, Rima Nabbout, Tommaso Lo Barco, Nicolas Garcelon, Gestionnaire, HAL Sorbonne Université 5, Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Neuraz, Antoine, Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Università degli studi di Verona = University of Verona (UNIVR), Service d'informatique médicale et biostatistiques [CHU Necker], This work was supported by State funding from the Agence Nationale de la Recherche under 'Investissements d’Avenir' program (ANR-10-IAHU-01) and the 'Fondation Bettencourt Schueller' (RN)., École Pratique des Hautes Études (EPHE), Health data- and model- driven Knowledge Acquisition (HeKA), Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], First year of life, Epilepsies, Myoclonic, Epilepsies, computer.software_genre, Logistic regression, Medical Records, 03 medical and health sciences, 0302 clinical medicine, Rare Diseases, Dravet syndrome, Medicine, Humans, Pharmacology (medical), [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Child, Preschool, Data mining, Genetics (clinical), Early diagnosis, Natural Language Processing, Child, Preschool, Early Diagnosis, business.industry, Medical record, Research, Unified Medical Language System, General Medicine, medicine.disease, 3. Good health, Natural history, 030104 developmental biology, Cohort, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Artificial intelligence, business, Myoclonic, computer, 030217 neurology & neurosurgery, Natural language processing, Computer technology
Abstract: Background The growing use of Electronic Health Records (EHRs) is promoting the application of data mining in health-care. A promising use of big data in this field is to develop models to support early diagnosis and to establish natural history. Dravet Syndrome (DS) is a rare developmental and epileptic encephalopathy that commonly initiates in the first year of life with febrile seizures (FS). Age at diagnosis is often delayed after 2 years, as it is difficult to differentiate DS at onset from FS. We aimed to explore if some clinical terms (concepts) are significantly more used in the electronic narrative medical reports of individuals with DS before the age of 2 years compared to those of individuals with FS. These concepts would allow an earlier detection of patients with DS resulting in an earlier orientation toward expert centers that can provide early diagnosis and care. Methods Data were collected from the Necker Enfants Malades Hospital using a document-based data warehouse, Dr Warehouse, which employs Natural Language Processing, a computer technology consisting in processing written information. Using Unified Medical Language System Meta-thesaurus, phenotype concepts can be recognized in medical reports. We selected individuals with DS (DS Cohort) and individuals with FS (FS Cohort) with confirmed diagnosis after the age of 4 years. A phenome-wide analysis was performed evaluating the statistical associations between the phenotypes of DS and FS, based on concepts found in the reports produced before 2 years and using a series of logistic regressions. Results We found significative higher representation of concepts related to seizures’ phenotypes distinguishing DS from FS in the first phases, namely the major recurrence of complex febrile convulsions (long-lasting and/or with focal signs) and other seizure-types. Some typical early onset non-seizure concepts also emerged, in relation to neurodevelopment and gait disorders. Conclusions Narrative medical reports of individuals younger than 2 years with FS contain specific concepts linked to DS diagnosis, which can be automatically detected by software exploiting NLP. This approach could represent an innovative and sustainable methodology to decrease time of diagnosis of DS and could be transposed to other rare diseases.
Published: 2021

16. The Epilepsy Genetics Initiative: Systematic reanalysis of diagnostic exomes increases yield

Author: Ingrid Scheffer, Colleen Campbell, Samuel Berkovic, Laura Jansen, Susannah Cornes, Brenda Porter, Kristen Park, Gianpiero Cavalleri, Nicholas Stong, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de neurologie pédiatrique
Subjects: 0301 basic medicine, Adult, Male, Parents, Delayed Diagnosis, Adolescent, data sharing, whole exome sequencing, 03 medical and health sciences, Epilepsy, Young Adult, 0302 clinical medicine, Data sequences, Seizures, Databases, Genetic, Exome Sequencing, Medicine, Humans, Exome, Medical diagnosis, Child, Exome sequencing, seizures, Retrospective Studies, Genetics, Family Health, business.industry, Information Dissemination, Siblings, Whole exome sequencing, Infant, Pathogenicity, medicine.disease, 030104 developmental biology, Neurology, Child, Preschool, Mutation, Full‐length Original Research, Data sharing, Female, Neurology (clinical), Genetic diagnosis, business, 030217 neurology & neurosurgery, Gene Discovery
Abstract: Summary Objective The Epilepsy Genetics Initiative (EGI) was formed in 2014 to create a centrally managed database of clinically generated exome sequence data. EGI performs systematic research‐based reanalysis to identify new molecular diagnoses that were not possible at the time of initial sequencing and to aid in novel gene discovery. Herein we report on the efficacy of this approach 3 years after inception. Methods One hundred sixty‐six individuals with epilepsy who underwent diagnostic whole exome sequencing (WES) were enrolled, including 139 who had not received a genetic diagnosis. Sequence data were transferred to the EGI and periodically reevaluated on a research basis. Results Eight new diagnoses were made as a result of updated annotations or the discovery of novel epilepsy genes after the initial diagnostic analysis was performed. In five additional cases, we provided new evidence to support or contradict the likelihood of variant pathogenicity reported by the laboratory. One novel epilepsy gene was discovered through dual interrogation of research and clinically generated WES. Significance EGI's diagnosis rate of 5.8% represents a considerable increase in diagnostic yield and demonstrates the value of periodic reinterrogation of whole exome data. The initiative's contributions to gene discovery underscore the importance of data sharing and the value of collaborative enterprises.
Published: 2019

17. Chudley-McCullough Syndrome

Author: Anna Jansen, Dana Dumitriu, Marie-Cécile Nassogne, Chloe A Stutterd, Katrien Stouffs, Paul J. Lockhart, Richard J. Leventer, Aglaë Blauen, Naima Deggouj, Clinical sciences, Medical Genetics, Reproduction and Genetics, Physiotherapy, Human Physiology and Anatomy, Pediatrics, Public Health Sciences, Mental Health and Wellbeing research group, Neurogenetics, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie pédiatrique, UCL - (SLuc) Service d'oto-rhino-laryngologie, and UCL - (SLuc) Service de radiologie
Subjects: Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, cerebellar hypoplasia, Adolescent, Hearing loss, Cerebellar dysplasia, Hearing Loss, Sensorineural, Deafness, Diagnosis, Differential, 03 medical and health sciences, 0302 clinical medicine, Polymicrogyria, otorhinolaryngologic diseases, Humans, Medicine, Genetics(clinical), polymicrogyria, GPSM2, Child, Agenesis of the corpus callosum, Cerebellar hypoplasia, ventriculomegaly, frontal dysplasia, business.industry, Brain, medicine.disease, Magnetic Resonance Imaging, Arachnoid Cysts, Epileptic spasms, 030104 developmental biology, Pediatrics, Perinatology and Child Health, Speech delay, Female, Neurology (clinical), Agenesis of Corpus Callosum, medicine.symptom, corpus callosum dysgenesis, business, 030217 neurology & neurosurgery, Ventriculomegaly, reproductive medicine
Abstract: Chudley-McCullough syndrome, a rare autosomal recessive disorder due to pathogenic variants in the GPSM2 (G-protein signaling modulator 2) gene, is characterized by early-onset sensorineural deafness and a typical combination of brain malformations, including ventriculomegaly, (partial) agenesis of the corpus callosum, cerebellar dysplasia, arachnoid cysts, frontal subcortical heterotopia, and midline polymicrogyria. When hearing loss is managed early, most patients have minor or no impairment of motor and cognitive development, despite the presence of brain malformations. We report 2 cases of Chudley-McCullough syndrome, one presenting with congenital deafness and normal development except for speech delay and one presenting prenatally with ventriculomegaly and an atypical postnatal course characterized by epileptic spasms, deafness, and moderate intellectual disability. These highlight the challenges faced by clinicians when predicting prognosis based on pre- or postnatal imaging of brain malformations. We have also reviewed the phenotype and genotype of previous published cases to better understand Chudley-McCullough syndrome.
Published: 2021

18. MINPP1 prevents intracellular accumulation of the chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia

Author: Nathalie Rabasse, Catherine Fossoud, Nadia Bahi-Buisson, Miranda S. C. Wilson, Elsa Lorino, Celine Banal, Meral Topçu, Gaele Pitelet, Eric Bieth, Christine Bole-Feysot, Nami Altin, Vincent Cantagrel, Arnold Munnich, Marie-Therese Vasilache-Dangles, Fabienne Giuliano, Lydie Burglen, Adolfo Saiardi, Valentina Stanley, Nathalie Lefort, Giulia Barcia, Pierre David, Karthyayani Rajamani, Daniel Medina-Cano, Patrick Nitschke, Joseph G. Gleeson, Maha S. Zaki, Laurence Colleaux, Nathalie Boddaert, Fatma Mujgan Sonmez, Damir Musaev, Ekin Ucuncu, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University College of London [London] (UCL), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Antibes - Juan-les-Pins, CHU Toulouse [Toulouse], Hacettepe University = Hacettepe Üniversitesi, Karadeniz Technical University (KTU), Rady Children's Hospital, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Gestionnaire, Hal Sorbonne Université
Subjects: Male, 0301 basic medicine, Cytoplasm, [SDV]Life Sciences [q-bio], Cellular differentiation, General Physics and Astronomy, Gene Knockout Techniques, chemistry.chemical_compound, 0302 clinical medicine, Homeostasis, Inositol, Phosphorylation, Child, Chelating Agents, Mice, Knockout, Multidisciplinary, Cell Death, Chemistry, Stem Cells, Neurodevelopmental disorders, Cell Differentiation, Cell biology, [SDV] Life Sciences [q-bio], Child, Preschool, Second messenger system, Female, Intracellular, Cell physiology, Programmed cell death, Phytic Acid, Science, Pontocerebellar hypoplasia, Stem-cell differentiation, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Cerebellar Diseases, medicine, Animals, Humans, HEK 293 cells, Infant, General Chemistry, medicine.disease, Phosphoric Monoester Hydrolases, Mice, Inbred C57BL, HEK293 Cells, 030104 developmental biology, Mutation, Transcriptome, 030217 neurology & neurosurgery
Abstract: Inositol polyphosphates are vital metabolic and secondary messengers, involved in diverse cellular functions. Therefore, tight regulation of inositol polyphosphate metabolism is essential for proper cell physiology. Here, we describe an early-onset neurodegenerative syndrome caused by loss-of-function mutations in the multiple inositol-polyphosphate phosphatase 1 gene (MINPP1). Patients are found to have a distinct type of Pontocerebellar Hypoplasia with typical basal ganglia involvement on neuroimaging. We find that patient-derived and genome edited MINPP1−/− induced stem cells exhibit an inefficient neuronal differentiation combined with an increased cell death. MINPP1 deficiency results in an intracellular imbalance of the inositol polyphosphate metabolism. This metabolic defect is characterized by an accumulation of highly phosphorylated inositols, mostly inositol hexakisphosphate (IP6), detected in HEK293 cells, fibroblasts, iPSCs and differentiating neurons lacking MINPP1. In mutant cells, higher IP6 level is expected to be associated with an increased chelation of intracellular cations, such as iron or calcium, resulting in decreased levels of available ions. These data suggest the involvement of IP6-mediated chelation on Pontocerebellar Hypoplasia disease pathology and thereby highlight the critical role of MINPP1 in the regulation of human brain development and homeostasis., Tight regulation of inositol polyphosphate metabolism is essential for proper cell physiology. Here, the authors describe an early-onset neurodegenerative syndrome caused by loss-of-function mutations in the MINPP1 gene, characterised by intracellular imbalance of inositol polyphosphate metabolism.
Published: 2020

19. Catatonia in a patient with Aicardi-Goutières syndrome efficiently treated with immunoadsorption

Author: Flore Rozenberg, Richard Delorme, Pierre Ellul, Odile Boespflug-Tanguy, Vincent Bondet, Yanick J. Crow, Theresa Kwon, Darragh Duffy, Isabelle Melki, Monique Elmaleh-Bergès, Séverine Drunat, Anaël Ayrolles, Florence Renaldo, Service Psychiatrie de l'Enfant et de l'Adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Service de neurologie pédiatrique et maladies métaboliques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Centre de référence des leucodystrophies et leucoencéphalopathies de cause rare [AP-HP Hôpital Robert-Debré] (LEUKOFRANCE), Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de radiologie pédiatrique [AP-HP Hôpital Robert Debré], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Néphrologie pédiatrique [Hôpital Robert Debré, Paris], Service de Virologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of neurogenetics and neuroinflammation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, Centre de référence des rhumatismes inflammatoires et maladies autoimmunes systémiques rares de l'enfant [Paris] (RAISE), Département d'Immunologie, hématologie et rhumatologie pédiatriques [Hôpital Necker-Enfants malades - APHP], CHU Necker - Enfants Malades [AP-HP], We acknowledge the contribution of the General Paediatrics, Infectious Disease and Internal Medicine Department, the Child and Adolescent Psychiatry Department, the Child Neurology Department, the Pediatric Nephrology Department and the Genetics Department of Robert Debre Hospital. We thank the patient and his family members for allowing us to report the findings of his case., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: Pathology, medicine.medical_specialty, Catatonia, Alpha interferon, Interstitial lung disease, Aicardi-Goutières syndrome, Nervous System Malformations, 03 medical and health sciences, Autoimmune Diseases of the Nervous System, 0302 clinical medicine, medicine, Humans, Immunoadsorption, Biological Psychiatry, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, business.industry, Interferon-alpha, medicine.disease, 3. Good health, Psychiatry and Mental health, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Aicardi–Goutières syndrome, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], business, 030217 neurology & neurosurgery
Abstract: International audience; Letter to the Editor
Published: 2020

20. Motor Skill Training May Restore Impaired Corticospinal Tract Fibers in Children With Cerebral Palsy

Author: Anne Renders, Julie Paradis, Andrew M. Gordon, Laurence Dricot, Yannick Bleyenheuft, Daniela Ebner-Karestinos, Rodrigo Araneda, Kathleen M. Friel, Anne De Volder, Geoffroy Saussez, UCL - SSS/IONS/COSY - Systems & cognitive Neuroscience, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de médecine physique et de réadaptation motrice, and UCL - (SLuc) Service de neurologie pédiatrique
Subjects: Male, corticospinal tract, 030506 rehabilitation, medicine.medical_specialty, motor skill training, Adolescent, Pyramidal Tracts, Cerebral palsy, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, Nerve Fibers, medicine, Humans, Child, Postural Balance, Motor skill, cerebral palsy, business.industry, Cerebral Palsy, Neurological Rehabilitation, General Medicine, diffusion tensor imaging, medicine.disease, Diffusion Tensor Imaging, Outcome and Process Assessment, Health Care, Lower Extremity, Motor Skills, Practice, Psychological, Corticospinal tract, Arm, intensive training, Female, 0305 other medical science, business, human activities, 030217 neurology & neurosurgery, Diffusion MRI
Abstract: Background. In children with unilateral cerebral palsy (UCP), the fibers of the corticospinal tract (CST) emerging from the lesioned hemisphere are damaged following the initial brain injury. The extent to which the integrity of these fibers is restorable with training is unknown. Objective. To assess changes in CST integrity in children with UCP following Hand-and-Arm-Bimanual-Intensive-Therapy-Including-Lower-Extremity (HABIT-ILE) compared to a control group. Methods. Forty-four children with UCP participated in this study. Integrity of the CSTs was measured using diffusion tensor imaging before and after 2 weeks of HABIT-ILE (treatment group, n = 23) or 2 weeks apart without intensive treatment (control group, n = 18). Fractional anisotropy (FA) and mean diffusivity (MD) were the endpoints for assessing the integrity of CST. Results. As highlighted in our whole tract analysis, the FA of the CST originating from the nonlesioned and lesioned hemispheres increased significantly after therapy in the treatment group compared to the control group (group * test session interaction: P < .001 and P = .049, respectively). A decrease in MD was also observed in the CST emerging from the nonlesioned and lesioned hemispheres (group * time interaction: both P < .001). In addition, changes in manual ability correlated with changes in FA in both CSTs ( r = 0.463, P = .024; r = 0.643, P < .001) and changes in MD in CST emerging from nonlesioned hemisphere ( r = −0.662, P < .001). Conclusions. HABIT-ILE improves FA/MD in the CST and hand function of children with UCP, suggesting that CST fibers retain a capacity for functional restoration. This finding supports the application of intensive motor skill training in clinical practice for the benefit of numerous patients.
Published: 2020

21. A qualitative awake EEG score for the diagnosis of continuous spike and waves during sleep (CSWS) syndrome in self-limited focal epilepsy (SFE): A case-control study

Author: Justine Vermeiren, Roberto Santalucia, Xavier De Tiège, Audrey Van Hecke, Patrick Van Bogaert, Alec Aeby, Andrea Nebbioso, Nicolas Deconinck, and UCL - (SLuc) Service de neurologie pédiatrique
Subjects: medicine.medical_specialty, Audiology, Electroencephalography, EEG wakefulness, Self-limited focal epilepsy (SFE), Quantitative eeg, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, medicine, Epilepsy with centro-temporal spikes (ECTS), Humans, Wakefulness, Retrospective Studies, Reproducibility, Receiver operating characteristic, medicine.diagnostic_test, business.industry, Continuous spike and waves during sleep (CSWS), Case-control study, Reproducibility of Results, General Medicine, Sciences bio-médicales et agricoles, medicine.disease, Cognitive regression, Neurology, Case-Control Studies, Neurology (clinical), Electrical status epilepticus during sleep (ESES), Epilepsies, Partial, business, Sleep, 030217 neurology & neurosurgery, Kappa, EEG score
Abstract: 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.
Published: 2020

22. Expanding the Spectrum of Neurological Manifestations in Cutis Laxa, Autosomal Recessive, Type IIIA

Author: Cyril Goizet, Fanny Morice-Picard, Annachiara De Sandre-Giovannoli, Sébastien Cabasson, Nathalie Aladjidi, Chloé Angelini, Cindy Colson, Caroline Espil-Taris, Jean-Michel Pedespan, Marie Thibaud, Pierre Bessou, Marie Husson, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie pédiatrique [CHU de Bordeaux], CHU de Bordeaux Pellegrin [Bordeaux], CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Référence National des Cytopénies Auto-immunes de l'Enfant (CEREVANCE), Service de Génétique Clinique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Centre de ressources biologiques Tissus ADN Cellules [Hôpital de la Timone - APHM] (CRB TAC), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)
Subjects: 0301 basic medicine, Male, Pathology, medicine.medical_specialty, genetic structures, education, Wrinkled skin, cutis laxa, 030105 genetics & heredity, 03 medical and health sciences, Consanguinity, 0302 clinical medicine, medicine, Humans, Neurological findings, vascular tortuosity, ALDH18A1, Heterogeneous group, business.industry, Infant, General Medicine, Aldehyde Dehydrogenase, medicine.disease, eye diseases, 3. Good health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Severe phenotype, Pediatrics, Perinatology and Child Health, Neurology (clinical), sense organs, business, human activities, neurological findings, 030217 neurology & neurosurgery, Cutis laxa
Abstract: Cutis laxa is a heterogeneous group of diseases, characterized by abundant and wrinkled skin and a variable degree of intellectual disability. Cutis laxa, autosomal recessive, type IIIA and autosomal dominant 3 syndromes are caused by autosomal recessive or de novo pathogenic variants in ALDH18A1. Autosomal recessive variants are known to lead to the most severe neurological phenotype, and very few patients have been described.We describe a 13-month-old patient with cutis laxa, autosomal recessive, type IIIA, with an extremely severe phenotype, including novel neurological findings. This description enlarges the neurological spectrum associated to cutis laxa, autosomal recessive, type IIIA, and provides an additional description of this syndrome.
Published: 2020

23. Age and sex prevalence estimate of Joubert syndrome in Italy

Author: Nuovo, Sara, Bacigalupo, Ilaria, Ginevrino, Monia, Battini, Roberta, Bertini, Enrico, Borgatti, Renato, Casella, Antonella, Micalizzi, Alessia, Nardella, Marta, Romaniello, Romina, Serpieri, Valentina, Zanni, Ginevra, Valente, Enza Maria, Vanacore, Nicola, JS Italian Study Group, Patrizia, Accorsi, Enrico, Alfei, Elena, Andreucci, Gianluigi, Ardissino, Emanuela, Avola, Rita, Barone, Francesco, Benedicenti, Stefania, Bigoni, Loredana, Boccone, Bonati, Maria T., Stefania, Bova, Marilena, Briguglio, Silvana, Briuglia, Olga, Calabrese, Cantalupo, Gaetano, Gianluca, Caridi, Monica, Cazzagon, Celle, Maria E., Cilio, Maria R., Giangennaro, Coppola, Adele, D’Amico, Stefano, D’Arrigo, Daniele De Brasi, Maria Fulvia de Leva, Ennio Del Giudice, Marilena Carmela Di Giacomo, Maria Lucia Di Sabato, Bruno, Dallapiccola, Raffaella, Devescovi, Maria Cristina Digilio, Ilaria, Donati, Donati, Maria A., Dotti, Maria T., Francesco, Emma, Antonella, Fabretto, Elisa, Fazzi, Alessandra, Ferlini, Alessandro, Ferraris, Giovanni Battista Ferrero, Anna, Ficcadenti, Simona, Fiori, Rita, Fischetto, Elena, Freri, Livia, Garavelli, Mattia, Gentile, Lucio, Giordano, Donatella, Greco, Claudia, Izzi, Vincenzo, Leuzzi, Elisabetta, Lucarelli, Silvia, Majore, Mancardi, Maria M., Francesca, Mari, Giuseppina, Marra, Laura, Mazzanti, Daniela, Melis, Emanuele, Micaglio, Marisol, Mirabelli-Badenier, Isabella, Moroni, Nardo, Nardocci, Margherita, Nosadini, Simona, Orcesi, Giovanni, Pagani, Chiara, Pantaleoni, Francesco Papadia Papadia, Pasquale, Parisi, Maria Grazia Patricelli, Cinzia, Peruzzi, Alice, Pessagno, Maria, Piccione, Antonella, Pini, Tiziana, Pisano, Livia, Pisciotta, Marzia, Pollazzon, Francesca, Rivieri, Alfonso, Romano, Corrado, Romano, Leonardo, Salviati, Carmelo Damiano Salpietro, Margherita, Santucci, Emanuela, Scarano, Barbara, Scelsa, Alberto, Sensi, Marco, Seri, Sabrina, Signorini, Margherita, Silengo, Simonati, Alessandro, Fabio, Sirchia, Luigina, Spaccini, Franco, Stanzial, Gilda, Stringini, Eva, Trevisson, Antonella, Trivelli, Vera, Uliana, Graziella, Uziel, Gessica, Vasco, Marina, Vascotto, Giuseppina, Vitiello, Federica, Zibordi, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de neurologie pédiatrique
Subjects: IQR=interquartile range, 0301 basic medicine, Proband, Male, JS=Joubert syndrome, Prevalence, CI=confidence interval, CI = confidence interval, 0302 clinical medicine, Cerebellum, Epidemiology, Databases, Genetic, JS = Joubert syndrome, Medicine, Eye Abnormalities, Young adult, Age of Onset, Child, education.field_of_study, Age Factors, High-Throughput Nucleotide Sequencing, Kidney Diseases, Cystic, Middle Aged, Italy, Child, Preschool, Joubert syndrome, Italy, Cohort, Kidney Diseases, Female, MTS = molar tooth sign, Abnormalities, Multiple, NGS=next-generation sequencing, Adult, medicine.medical_specialty, Adolescent, IQR = interquartile range, NGS = next-generation sequencing, Population, Retina, Databases, Cystic, 03 medical and health sciences, Young Adult, Sex Factors, Genetic, Joubert syndrome, Humans, Abnormalities, Multiple, Infant, Preschool, CI=confidence interval, IQR=interquartile range, JS=Joubert syndrome, MTS=molar tooth sign, NGS=next-generation sequencing, education, business.industry, MTS=molar tooth sign, Confidence interval, 030104 developmental biology, Neurology (clinical), Age of onset, business, 030217 neurology & neurosurgery, Demography
Abstract: ObjectiveTo estimate the prevalence of Joubert syndrome (JS) in Italy applying standards of descriptive epidemiology and to provide a molecular characterization of the described patient cohort.MethodsWe enrolled all patients with a neuroradiologically confirmed diagnosis of JS who resided in Italy in 2018 and calculated age and sex prevalence, assuming a Poisson distribution. We also investigated the correlation between proband chronological age and age at diagnosis and performed next-generation sequencing (NGS) analysis on probands' DNA when available.ResultsWe identified 284 patients with JS: the overall, female- and male-specific population-based prevalence rates were 0.47 (95% confidence interval [CI] 0.41–0.53), 0.41 (95% CI 0.32–0.49), and 0.53 (95% CI 0.45–0.61) per 100,000 population, respectively. When we considered only patients in the age range from 0 to 19 years, the corresponding population-based prevalence rates rose to 1.7 (95% CI 1.49–1.97), 1.62 (95% CI 1.31–1.99), and 1.80 (95% CI 1.49–2.18) per 100,000 population. NGS analysis allowed identifying the genetic cause in 131 of 219 screened probands. Age at diagnosis was available for 223 probands, with a mean of 6.67 ± 8.10 years, and showed a statistically significant linear relationship with chronological age (r2 = 0.79; p < 0.001).ConclusionsWe estimated for the first time the age and sex prevalence of JS in Italy and investigated the patients’ genetic profile. The obtained population-based prevalence rate was ≈10 times higher than that available in literature for children population.
Published: 2020

24. CDK5RAP2 primary microcephaly is associated with hypothalamic, retinal and cochlear developmental defects

Author: Anita Rauch, Nathalie Pouvreau, Séverine Drunat, Yves Alembik, Anais Ernault, Liza Vera, Hala Nasser, Katharina Steindl, Fabien Guimiot, Pierre Gressens, Vincent El Ghouzzi, Sophie Guilmin Crepon, Delphine Héron, Nathalie Kubis, Alain Verloes, Natacha Teissier, Marie Laure Moutard, Sandrine Passemard, Florentia Kaguelidou, Alexandra Afenjar, Paolo Milani, Marcella Zollino, Pascaline Letard, Martha Momtchilova, Monique Elmaleh-Bergès, University of Zurich, Passemard, Sandrine, Service d'imagerie pédiatrique, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital universitaire Robert-Debré [Paris], Hôpital Robert Debré, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Department of Medical Genetics, Hôpitaux Universitaires de Strasbourg, Service de Neurologie Pédiatrique, HFME, Bron, France, Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), Unité fonctionnelle de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Istituto di Genetica Medica, Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Institute of Medical Genetics, University of Zürich [Zürich] (UZH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), and Universität Zürich [Zürich] = University of Zurich (UZH)
Subjects: Microcephaly, Pathology, medicine.medical_specialty, 2716 Genetics (clinical), 10039 Institute of Medical Genetics, [SDV]Life Sciences [q-bio], CDK5RAP2, intellectual disability, MCPH, primary microcephaly, retinal alteration, sensorineural hearing loss, 610 Medicine & health, Settore MED/03 - GENETICA MEDICA, Microphthalmia, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Holoprosencephaly, 1311 Genetics, Genetics, medicine, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genetics (clinical), Cochlea, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Retinal, medicine.disease, chemistry, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Brain size, 570 Life sciences, biology, Sensorineural hearing loss, business, 030217 neurology & neurosurgery
Abstract: BackgroundPrimary hereditary microcephaly (MCPH) comprises a large group of autosomal recessive disorders mainly affecting cortical development and resulting in a congenital impairment of brain growth. Despite the identification of >25 causal genes so far, it remains a challenge to distinguish between different MCPH forms at the clinical level.Methods7 patients with newly identified mutations in CDK5RAP2 (MCPH3) were investigated by performing prospective, extensive and systematic clinical, MRI, psychomotor, neurosensory and cognitive examinations under similar conditions.ResultsAll patients displayed neurosensory defects in addition to microcephaly. Small cochlea with incomplete partition type II was found in all cases and was associated with progressive deafness in 4 of them. Furthermore, the CDK5RAP2 protein was specifically identified in the developing cochlea from human fetal tissues. Microphthalmia was also present in all patients along with retinal pigmentation changes and lipofuscin deposits. Finally, hypothalamic anomalies consisting of interhypothalamic adhesions, a congenital midline defect usually associated with holoprosencephaly, was detected in 5 cases.ConclusionThis is the first report indicating that CDK5RAP2 not only governs brain size but also plays a role in ocular and cochlear development and is necessary for hypothalamic nuclear separation at the midline. Our data indicate that CDK5RAP2 should be considered as a potential gene associated with deafness and forme fruste of holoprosencephaly. These children should be given neurosensory follow-up to prevent additional comorbidities and allow them reaching their full educational potential.Trial registration numberNCT01565005.
Published: 2020

25. Epileptogenicity in tuberous sclerosis complex: A stereoelectroencephalographic study

Author: Julien Jung, Andrew Neal, A. Arzimanoglou, Marc Guénot, Fabrice Bartolomei, Sylvain Rheims, Karine Ostrowsky-Coste, Jean Isnard, Louis Maillard, Renaud Touraine, Alexandra Montavont, Philippe Kahane, Stanislas Lagarde, Hélène Catenoix, Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d’épileptologie clinique, des troubles du sommeil et de neurologie fonctionnelle chez l’enfant, Centre de référence des Épilepsies Rares et Centre Européen EpiCARE, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon, Lyon, France, Institut de Neurosciences des Systèmes (INS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Service de neurophysiologie clinique [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Recherche en Automatique de Nancy (CRAN), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Service de neurologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne-Hôpital Nord - Saint-Etienne, Department of Epileptology, CHU Grenoble-Hôpital Michallon, Unité d'Epileptologie Pédiatrique, Service de Neurologie Pédiatrique et des Maladies Métaboliques, AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neurosurgery, Hospices Civils de Lyon (HCL), Service de Neurologie Fonctionnelle et d'Épileptologie, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Dynamique des Reseaux Neuronaux, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), and AP-HP, Hôpital Robert Debré
Subjects: 0301 basic medicine, Adult, Male, Drug Resistant Epilepsy, Neurosurgery, Epileptogenic Zone, Fluid-attenuated inversion recovery, Electroencephalography, Pediatrics, Stereo-EEG, 03 medical and health sciences, Tuberous sclerosis, Epilepsy, 0302 clinical medicine, Child Development, Tuberous Sclerosis, Cortex (anatomy), Seizure Disorders, Medicine, Humans, Epilepsy surgery, Ictal, Child, Retrospective Studies, Brain Diseases, medicine.diagnostic_test, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, fungi, Infant, food and beverages, Anatomy, Pediatric Epilepsy Surgery, Cortical dysplasia, Middle Aged, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Neurology, Child, Preschool, Tuberous Sclerosis Complex, Female, Neurology (clinical), Nervous System Diseases, business, 030217 neurology & neurosurgery
Abstract: International audience; Objective: In tuberous sclerosis complex (TSC)‐associated drug‐resistant epilepsy, the optimal invasive electroencephalographic (EEG) and operative approach remains unclear. We examined the role of stereo‐EEG in TSC and used stereo‐EEG data to investigate tuber and surrounding cortex epileptogenicity.Methods: We analyzed 18 patients with TSC who underwent stereo‐EEG (seven adults). One hundred ten seizures were analyzed with the epileptogenicity index (EI). In 13 patients with adequate tuber sampling, five anatomical regions of interest (ROIs) were defined: dominant tuber (tuber with highest median EI), perituber cortex, secondary tuber (tuber with second highest median EI), nearby cortex (normal‐appearing cortex in the same lobe as dominant tuber), and distant cortex (in other lobes). At the seizure level, epileptogenicity of ROIs was examined by comparing the highest EI recorded within each anatomical region. At the patient level, epileptogenic zone (EZ) organization was separated into focal tuber (EZ confined to dominant tuber) and complex (all other patterns).Results: The most epileptogenic ROI was the dominant tuber, with higher EI than perituber cortex, secondary tuber, nearby cortex, and distant cortex (P < .001). A focal tuber EZ organization was identified in seven patients. This group had 80% Engel IA postsurgical outcome and distinct dominant tuber characteristics: continuous interictal discharges (IEDs; 100%), fluid‐attenuated inversion recovery (FLAIR) hypointense center (86%), center‐to‐rim EI gradient, and stimulation‐induced seizures (71%). In contrast, six patients had a complex EZ organization, characterized by nearby cortex as the most epileptogenic region and 40% Engel IA outcome. At the intratuber level, the combination of FLAIR hypointense center, continuous IEDs, and stimulation‐induced seizures offered 98% specificity for a focal tuber EZ organization.Significance: Tubers with focal EZ organization have a striking similarity to type II focal cortical dysplasia. The presence of distinct EZ organizations has significant implications for EZ hypothesis generation, invasive EEG approach, and resection strategy.
Published: 2020

26. The ClinGen Epilepsy Gene Curation Expert Panel—Bridging the divide between clinical domain knowledge and formal gene curation criteria

Author: Rebecca K. Siegert, Carrie Anne Barry, Kristen Park, Maria Roberta Cilio, Bekim Sadikovic, Ghayda M. Mirzaa, David A. Dyment, Ingo Helbig, Annapurna Poduri, Tristan T. Sands, Karl Martin Klein, Courtney Thaxton, Jacy L. Wagnon, Erin Rooney Riggs, Erika Axeen, Pasquale Striano, Tanya Bardakjian, Katherine L. Helbig, Heather C Mefford, Elizabeth Butler, Khalida Liaquat, Andrew R. Grant, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de neurologie pédiatrique
Subjects: ClinGen/Clinical Genome Resource, 0301 basic medicine, Disease, Computational biology, Biology, Article, gene–disease association, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, clinical validity, Genetics, medicine, Humans, Genetic Testing, epilepsy, epileptic encephalopathy, Gene, Genetics (clinical), Genetic testing, Disease entity, medicine.diagnostic_test, medicine.disease, Phenotype, 030104 developmental biology, Gene selection, Seizure Disorders, Mutation, Gene-disease association, Domain knowledge, 030217 neurology & neurosurgery
Abstract: The field of epilepsy genetics is advancing rapidly and epilepsy is emerging as a frequent indication for diagnostic genetic testing. Within the larger ClinGen framework, the ClinGen Epilepsy Gene Curation Expert Panel is tasked with connecting two increasingly separate fields: the domain of traditional clinical epileptology, with its own established language and classification criteria, and the rapidly evolving area of diagnostic genetic testing that adheres to formal criteria for gene and variant curation. We identify critical components unique to the epilepsy gene curation effort, including: (1) precise phenotype definitions within existing disease and phenotype ontologies; (2) consideration of when epilepsy should be curated as a distinct disease entity; (3) strategies for gene selection; and (4) emerging rules for evaluating functional models for seizure disorders. Given that de novo variants play a prominent role in many of the epilepsies, sufficient genetic evidence is often awarded early in the curation process. Therefore, the emphasis of gene curation is frequently shifted towards an iterative precuration process to better capture phenotypic associations. We demonstrate that within the spectrum of neurodevelopmental disorders, gene curation for epilepsy-associated genes is feasible and suggest epilepsy-specific conventions, laying the groundwork for a curation process of all major epilepsy-associated genes.
Published: 2018

27. De novo mutation screening in childhood-onset cerebellar atrophy identifies gain-of-function mutations in the CACNA1G calcium channel gene

Author: Giulia Barcia, Laurence Hubert, Emily Fassi, Julien Thevenon, Laurence Faivre, Philippe Lory, Daniel Medina-Cano, Pierre Blanc, Nathalie Boddaert, Nami Altin, Karine Siquier-Pernet, Marlène Rio, Céline Vidal, Jean Chemin, Sylvain Hanein, Holly H. Zimmerman, Marwan Shinawi, Patrick Nitschke, Vincent Cantagrel, Cécile Fourage, Nadia Bahi-Buisson, Christine Bole-Feysot, Jeanne Amiel, Ali Ahmad, Arnold Munnich, Michael Nicouleau, Stanislas Lyonnet, Laurence Colleaux, Isabelle Desguerre, Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Plateforme de génomique [SFR Necker], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Plate Forme Paris Descartes de Bioinformatique (BIP-D), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de neurologie pédiatrique [CHU Necker], Neuroimagerie en psychiatrie (U1000), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Radiologie et imagerie médicale [CHU Necker], Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, ANR-16-CE12-0005,SCD-Mec,Mécanismes développementaux des anomalies structurelles cérébelleuses(2016), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Male, 0301 basic medicine, Microcephaly, [SDV]Life Sciences [q-bio], Developmental Disabilities, medicine.disease_cause, Deep cerebellar nuclei, Cohort Studies, Calcium Channels, T-Type, Purkinje Cells, Epilepsy, 0302 clinical medicine, Cerebellum, Child, Exome sequencing, Mutation, Brain, Phenotype, Pedigree, Child, Preschool, Gain of Function Mutation, CACNA1G, Female, Cerebellar atrophy, medicine.symptom, voltage-gated calcium channel, Adult, medicine.medical_specialty, Adolescent, Cerebellar Ataxia, Biology, 03 medical and health sciences, cerebellar atrophy, Cerebellar Diseases, Intellectual Disability, Internal medicine, medicine, Humans, [SDV.GEN]Life Sciences [q-bio]/Genetics, Cerebellar ataxia, medicine.disease, de novo mutation, 030104 developmental biology, Endocrinology, Calcium, Calcium Channels, Neurology (clinical), Atrophy, Cav3.1, 030217 neurology & neurosurgery
Abstract: IF 10.848; International audience; Cerebellar atrophy is a key neuroradiological finding usually associated with cerebellar ataxia and cognitive development defect in children. Unlike the adult forms, early onset cerebellar atrophies are classically described as mostly autosomal recessive conditions and the exact contribution of de novo mutations to this phenotype has not been assessed. In contrast, recent studies pinpoint the high prevalence of pathogenic de novo mutations in other developmental disorders such as intellectual disability, autism spectrum disorders and epilepsy. Here, we investigated a cohort of 47 patients with early onset cerebellar atrophy and/or hypoplasia using a custom gene panel as well as whole exome sequencing. De novo mutations were identified in 35% of patients while 27% had mutations inherited in an autosomal recessive manner. Understanding if these de novo events act through a loss or a gain of function effect is critical for treatment considerations. To gain a better insight into the disease mechanisms causing these cerebellar defects, we focused on CACNA1G, a gene not yet associated with the early-onset form. This gene encodes the Cav3.1 subunit of T-type calcium channels highly expressed in Purkinje neurons and deep cerebellar nuclei. We identified four patients with de novo CACNA1G mutations. They all display severe motor and cognitive impairment, cerebellar atrophy as well as variable features such as facial dysmorphisms, digital anomalies, microcephaly and epilepsy. Three subjects share a recurrent c.2881G>A/p.Ala961Thr variant while the fourth patient has the c.4591A>G/p.Met1531Val variant. Both mutations drastically impaired channel inactivation properties with significantly slower kinetics (∼5 times) and negatively shifted potential for half-inactivation (>10 mV). In addition, these two mutations increase neuronal firing in a cerebellar nuclear neuron model and promote a larger window current fully inhibited by TTA-P2, a selective T-type channel blocker. This study highlights the prevalence of de novo mutations in early-onset cerebellar atrophy and demonstrates that A961T and M1531V are gain of function mutations. Moreover, it reveals that aberrant activity of Cav3.1 channels can markedly alter brain development and suggests that this condition could be amenable to treatment.
Published: 2018

28. Treatment outcome of creatine transporter deficiency: international retrospective cohort study

Author: Lionel Van Maldergem, Theodora U. J. Bruun, Dwight D. Koeberl, Sarah Sidky, Saadet Mercimek-Andrews, Gajja S. Salomons, Katrin Õunap, Marie-Cécile Nassogne, Francoise-Guillaume Debray, Andreas Schulze, Anabela O. Bandeira, Jennifer L. Goldstein, Siobhan O’Sullivan, Can Ficicioglu, Diogo Luísa, Kairit Joost, Laboratory Genetic Metabolic Diseases, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie pédiatrique, Laboratory Medicine, AGEM - Endocrinology, metabolism and nutrition, AGEM - Inborn errors of metabolism, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, and Amsterdam Reproduction & Development (AR&D)
Subjects: 0301 basic medicine, Male, Neurology, Arginine, Intellectual disability, Creatine treatment, Biochemistry, chemistry.chemical_compound, Epilepsy, 0302 clinical medicine, Genotype, Medicine, Global developmental delay, Child, Phenotype, Treatment Outcome, Child, Preschool, Creatinine, Female, Adult, medicine.medical_specialty, Adolescent, Creatine transporter deficiency, Glycine, Arginine and glycine treatment, macromolecular substances, SLC6A8, Creatine, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, Seizures, Internal medicine, Intellectual Disability, Humans, business.industry, Infant, Membrane Transport Proteins, Retrospective cohort study, medicine.disease, 030104 developmental biology, chemistry, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: To evaluate the outcome of current treatment for creatine transporter (CRTR) deficiency, we developed a clinical severity score and initiated an international treatment registry. An online questionnaire was completed by physicians following patients with CRTR deficiency on a treatment, including creatine and/or arginine, and/or glycine. Clinical severity score included 1) global developmental delay/intellectual disability; 2) seizures; 3) behavioural disorder. Phenotype scored 1–3 = mild; 4–6 = moderate; and 7–9 = severe. We applied the clinical severity score pre- and on-treatment. Seventeen patients, 14 males and 3 females, from 16 families were included. Four patients had severe, 6 patients had moderate, and 7 patients had a mild phenotype. The phenotype ranged from mild to severe in patients diagnosed at or before 2 years of age or older than 6 years of age. The phenotype ranged from mild to severe in patients with mildly elevated urine creatine to creatinine ratio. Fourteen patients were on the combined creatine, arginine and glycine therapy. On the combined treatment with creatine, arginine and glycine, none of the males showed either deterioration or improvements in their clinical severity score, whereas two females showed improvements in the clinical severity score. Creatine monotherapy resulted in deterioration of the clinical severity score in one male. There seems to be no correlation between phenotype and degree of elevation in urine creatine to creatinine ratio, genotype, or age at diagnosis. Combined creatine, arginine and glycine therapy might have stopped disease progression in males and improved phenotype in females.
Published: 2018

29. A key role of the prefrontal cortex in the maintenance of chronic tinnitus: An fMRI study using a Stroop task

Author: Rodrigo Araneda, Laurence Dricot, Monique Decat, Naima Deggouj, Laurent Renier, Anne De Volder, Daniela Ebner-Karestinos, UCL - SSS/IONS/COSY - Systems & cognitive Neuroscience, UCL - (SLuc) Service d'oto-rhino-laryngologie, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie pédiatrique, and UCL - (SLuc) Centre de référence pour l'épilepsie réfractaire
Subjects: 0301 basic medicine, Male, Brain activity and meditation, 1.2 Psychological and socioeconomic processes, lcsh:RC346-429, Tinnitus, Executive Function, 0302 clinical medicine, Psychology, 2.1 Biological and endogenous factors, Aetiology, Prefrontal cortex, Brain Mapping, medicine.diagnostic_test, fMRI, Regular Article, Middle Aged, Executive functions, Magnetic Resonance Imaging, medicine.anatomical_structure, Neurology, Neurological, lcsh:R858-859.7, Female, Mental health, Consumer neuroscience, psychological phenomena and processes, Adult, Cognitive Neuroscience, 1.1 Normal biological development and functioning, Ventromedial prefrontal cortex, Prefrontal Cortex, lcsh:Computer applications to medicine. Medical informatics, behavioral disciplines and activities, 03 medical and health sciences, Young Adult, Clinical Research, Underpinning research, medicine, otorhinolaryngologic diseases, Humans, Radiology, Nuclear Medicine and imaging, lcsh:Neurology. Diseases of the nervous system, Neurosciences, Recognition, Psychology, Brain Disorders, Dorsolateral prefrontal cortex, Recognition, 030104 developmental biology, tinnitus, Stroop Test, Neurology (clinical), Functional magnetic resonance imaging, Neuroscience, 030217 neurology & neurosurgery, Stroop effect
Abstract: Introduction Since we recently showed in behavioural tasks that the top-down cognitive control was specifically altered in tinnitus sufferers, here we wanted to establish the link between this impaired executive function and brain alterations in the frontal cortex in tinnitus patients. Method Using functional magnetic resonance imaging (fMRI), we monitored the brain activity changes in sixteen tinnitus patients (TP) and their control subjects (CS) while they were performing a spatial Stroop task, both in audition and vision. Results We observed that TP differed from CS in their functional recruitment of the dorsolateral prefrontal cortex (dlPFC, BA46), the cingulate gyrus and the ventromedial prefrontal cortex (vmPFC, BA10). This recruitment was higher during interference conditions in tinnitus participants than in controls, whatever the sensory modality. Furthermore, the brain activity level in the right dlPFC and vmPFC correlated with the performance in the Stroop task in TP. Conclusion Due to the direct link between poor executive functions and prefrontal cortex alterations in TP, we postulate that a lack of inhibitory modulation following an impaired top-down cognitive control may maintain tinnitus by hampering habituation mechanisms. This deficit in executive functions caused by prefrontal cortex alterations would be a key-factor in the generation and persistence of tinnitus., Highlights • Tinnitus patients show a selective impairment of their top-down cognitive control. • Tinnitus patients show altered activity in the prefrontal cortex. • The cognitive control deficit contributes to explain the maintaining of tinnitus. • This finding opens new perspectives for successful rehabilitation of tinnitus.
Published: 2018

30. Childhood hearing loss is a key feature of CAPOS syndrome: A case report

Author: Naima Deggouj, Elsa Wiame, Antonella Boschi, Marie-Cécile Nassogne, Stéphanie Paquay, Romolo Daniele De Siati, Yves Sznajer, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique, UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de neurologie pédiatrique, UCL - (SLuc) Service d'ophtalmologie, UCL - (SLuc) Service d'oto-rhino-laryngologie, and UCL - (SLuc) Centre de génétique médicale UCL
Subjects: 0301 basic medicine, medicine.medical_specialty, Pes cavus, Areflexia, Cerebellar Ataxia, Foot Deformities, Congenital, Hearing loss, Hearing Loss, Sensorineural, Neurological disorder, Audiology, Auditory neuropathy, Diagnosis, Differential, CAPOS, 03 medical and health sciences, 0302 clinical medicine, Atrophy, ATP1A3, otorhinolaryngologic diseases, medicine, Humans, Optic atrophy, Child, Reflex, Abnormal, Cerebellar ataxia, business.industry, Hearing Tests, General Medicine, medicine.disease, Optic Atrophy, 030104 developmental biology, Otorhinolaryngology, Mutation, Pediatrics, Perinatology and Child Health, Female, Ataxia, Sensorineural hearing loss, Sodium-Potassium-Exchanging ATPase, medicine.symptom, Differential diagnosis, business, 030217 neurology & neurosurgery
Abstract: CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) is a rare neurological disorder, recently associated with the c.2452G > A hotspot mutation in the ATP1A3 gene, with sensorineural hearing loss as a prominent feature. We herein report on a girl who has experienced hearing loss for three years following an initial encephalitic episode when aged 15 months old. CAPOS was diagnosed only when she was six years old by targeted testing whilst she displayed optic atrophy, cerebellar signs and areflexia. CAPOS syndrome should be considered in the differential diagnosis of acquired childhood deafness, prompting clinicians to search for associated neurological features.
Published: 2018

31. Inhibition of IFNα secretion in cells from patients with juvenile dermatomyositis under TBK1 inhibitor treatment revealed by single-molecular assay technology

Author: Cyril Gitiaux, Brigitte Bader Meunier, Pierre Quartier, Isabelle Melki, Mathieu P Rodero, Christine Bodemer, Yanick J. Crow, Vincent Bondet, Patrick Nusbaum, Nassima Bekaddour, Darragh Duffy, Jean-Philippe Herbeuval, Arnaud Hubas, Isabelle Desguerre, Service de neurologie pédiatrique [CHU Necker], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Modélisation et Immunologie pour la Thérapie (CBMIT), Université Paris Descartes - Paris 5 (UPD5), CHU Cochin [AP-HP], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Rheumatism and autoimmune diseases (RAISE), Mother and Children University Hospital, AP-HP Hôpital universitaire Robert-Debré [Paris], CHU Necker - Enfants Malades [AP-HP], Centre de Référence National des Maladies Génétiques à Expression Cutanée (MAGEC), Service de Dermatologie, University of Edinburgh, Immunologie cellulaire et tissulaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR113-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by by the Agence National de la Recherche sur le SIDA et les Hépatites ANRS (AAP 2017–166 to J.-P.H. and N.B.), SATT idfinnov (Grant No. 303 to J.-P.H.) and Agence National de Recherche ANR (CE17001002 to Y.J.C. and D.D.)., D.D. and Y.J.C acknowledge Immunoqure for provision of mAbs for Simoa assays, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Cochin [AP-HP], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), ANR-16-CE17-0010,IFNX,Investigation des interferonopathies type I humaine(2016), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Centre de référence des rhumatismes inflammatoires et maladies autoimmunes systémiques rares de l'enfant [Paris] (RAISE), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Male, Adolescent, [SDV]Life Sciences [q-bio], Enzyme-Linked Immunosorbent Assay, Pharmacology, Protein Serine-Threonine Kinases, Sensitivity and Specificity, Severity of Illness Index, Dermatomyositis, Cohort Studies, Young Adult, 03 medical and health sciences, 0302 clinical medicine, TANK-binding kinase 1, Rheumatology, medicine, Humans, Secretion, Pharmacology (medical), Juvenile dermatomyositis, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, business.industry, Interferon-alpha, medicine.disease, Single Molecule Imaging, 3. Good health, Protein Transport, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, business, 030217 neurology & neurosurgery, 030215 immunology
Abstract: International audience; Letter to the Editor
Published: 2019

32. Synthetic pharmaceutical grade cannabidiol for treatment of refractory infantile spasms: A multicenter phase-2 study

Author: Shaun A. Hussain, Neha Parikh, Dennis J. Dlugos, M. Roberta Cilio, Raman Sankar, Alex Oh, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de neurologie pédiatrique
Subjects: Male, medicine.medical_specialty, Drug Resistant Epilepsy, Clobazam, Phases of clinical research, Vigabatrin, Cohort Studies, 03 medical and health sciences, Behavioral Neuroscience, 0302 clinical medicine, Refractory, Internal medicine, Outcome Assessment, Health Care, medicine, Cannabidiol, Humans, 030212 general & internal medicine, Cannabis, Hypsarrhythmia, business.industry, Infant, West syndrome, medicine.disease, Epileptic spasms, Neurology, Child, Preschool, Cohort, Anticonvulsants, Female, Neurology (clinical), medicine.symptom, business, Spasms, Infantile, 030217 neurology & neurosurgery, medicine.drug
Abstract: Purpose Limited data suggest that cannabidiol (CBD) may be effective for treatment of refractory infantile spasms (IS). This study was designed to more rigorously evaluate the efficacy and safety of synthetic CBD in the treatment of IS. Methods Children six to 36 months of age with IS that failed treatment with both adrenocorticotropic hormone (ACTH) and vigabatrin (VGB) were eligible for enrollment. Children receiving clobazam were excluded. After baseline overnight video-electroencephalography (vEEG) to confirm diagnosis and ascertain hypsarrhythmia, patients were treated with synthetic CBD oral solution (20 mg/kg/day). Overnight video-EEG was repeated after 14 days, and both baseline and repeat video-EEGs were completely de-identified and reviewed in a pairwise fashion by an independent, blinded pediatric electroencephalographer. The primary efficacy endpoint was freedom from spasms and hypsarrhythmia on day 14. Results Nine patients were enrolled, comprising an older (median age = 23 months) cohort with long-standing IS (median duration = 13 months) and numerous prior treatment failures (median = 6). One patient responded to therapy and eight patients exhibited neither clinical nor electrographic response. Conclusions The immediate but temporary response in a single patient suggests that CBD oral solution is not particularly effective in highly refractory cases, but may, nevertheless, be effective in younger patients with shorter durations of IS. Further study, examining both short- and long-term outcomes, is warranted to further evaluate the efficacy and safety of CBD oral solution in the treatment of IS.
Published: 2019

33. Impact of Physical Exercise on Symptoms of Depression and Anxiety in Pre-adolescents: A Pilot Randomized Trial

Author: Arnaud Philippot, Alexandre Meerschaut, Laura Danneaux, Gauthier Smal, Yannick Bleyenheuft, Anne G. De Volder, UCL - SSS/IONS/COSY - Systems & cognitive Neuroscience, UCL - Louvain Bionics, UCL - SSH/IPSY - Psychological Sciences Research Institute, UCL - (SLuc) Service de neurologie pédiatrique, and UCL - (SLuc) Centre de référence pour l'épilepsie réfractaire
Subjects: medicine.medical_specialty, lcsh:BF1-990, Pre adolescents, Primary education, Physical exercise, move and feel good clinical trial, 050105 experimental psychology, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, medicine, Psychology, Trait anxiety, 0501 psychology and cognitive sciences, exercise medicine, General Psychology, Depression (differential diagnoses), youth, students, 05 social sciences, anxiety, Clinical Trial, Exercise programme, lcsh:Psychology, depression, Physical therapy, Anxiety, medicine.symptom, 030217 neurology & neurosurgery
Abstract: AIM: The intensity of the most appropriate exercise to use in depressed youth is unclear due to differences in methodology and the lack of evidence documenting the effect of physical activity in children. Therefore, the authors of this study attempted to document the effectiveness of different training intensities to reduce symptoms of depression and anxiety in pre-teens. METHODS: The study included twenty-seven, randomly selected pre-adolescents (aged between 9-11 years of age) all of whom had Primary education. The participants were enrolled and, over a 5-week period, were subject to either intensive or low-to-moderate exercise programs four times a week. Psychological self-reports, as well as physical examinations, were conducted before and after such programs in blinded assessments. Psychological effects were considered the primary outcome, whilst physical condition was secondary. RESULTS: Four subjects were lost and twenty-three were analyzed. General linear model with 2 criteria revealed significant changes (p = 0.05) in trait anxiety symptoms over time in the low-to-moderate intensity group (LMIG). Within group changes followed a significant decrease in levels of anxiety (38.82 ± 2.20 to 33.36 ± 2.83, p = 0.004) and depression (10.36 ± 2.83 to 6.73 ± 1.88, p = 0.006) related symptoms amongst those in the LMIG. INTERPRETATION: This study indicated that depression and anxiety symptoms were reduced amongst a non-clinical sample of Primary educated pre-adolescents when they were subject to a low-to-moderate exercise program. The program focused on associating movement with pleasure, encouraged positive and non-competitive interactions between participants. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT02970825, autumn 2016, updated May 7, 2018 (https://clinicaltrials.gov/ct2/show/NCT02970825).
Published: 2019

34. Expanding the phenotypic spectrum of Allan–Herndon–Dudley syndrome in patients with SLC 16A2 mutations

Author: Remerand, Ganaelle, Boespflug‐Tanguy, Odile, Tonduti, Davide, Touraine, Renaud, Rodriguez, Diana, Curie, Aurore, Perreton, Nathalie, Des Portes, Vincent, Sarret, Catherine, Afenjar, Alexandra, Burglen, Lydie, Castellotti, Barbara, Cuntz, Danielle, Desguerre, Isabelle, Doummar, Diane, Estienne, Margherita, Freri, Elena, Heron, Delphine, Moutard, Marie‐Laure, Novara, Francesca, Orcesi, Simona, Saletti, Veronica, Zibordi, Federica, Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Clinique Chromosomique et Moléculaire, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Affections de la Myeline et des Canaux Ioniques Musculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Sciences cognitives Marc Jeannerod - Laboratoire sur le langage, le cerveau et la cognition (L2C2), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), CIC CHU Lyon (inserm), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire sur le langage, le cerveau et la cognition (L2C2), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service: neuropédiatrie pathologie du développement, Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cytogenetics, Fondation 'Neurological Institute C. Mondino ', Fondazione IRCCS Istituto Neurologico 'Carlo Besta', CHU Saint-Etienne-Hôpital Nord - Saint-Etienne, École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and SIGMA Clermont (SIGMA Clermont)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])
Subjects: 030506 rehabilitation, Pediatrics, medicine.medical_specialty, Muscle Hypotonia, [SDV]Life Sciences [q-bio], Choreoathetosis, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Developmental Neuroscience, Intellectual disability, medicine, Kyphoscoliosis, ComputingMilieux_MISCELLANEOUS, Dystonia, Allan–Herndon–Dudley syndrome, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, medicine.disease, Hypotonia, 3. Good health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Pediatrics, Perinatology and Child Health, Neurology (clinical), medicine.symptom, 0305 other medical science, business, 030217 neurology & neurosurgery
Abstract: The aim of the study was to redefine the phenotype of Allan-Herndon-Dudley syndrome (AHDS), which is caused by mutations in the SLC16A2 gene that encodes the brain transporter of thyroid hormones. Clinical phenotypes, brain imaging, thyroid hormone profiles, and genetic data were compared to the existing literature. Twenty-four males aged 11 months to 29 years had a mutation in SLC16A2, including 12 novel mutations and five previously described mutations. Sixteen patients presented with profound developmental delay, three had severe intellectual disability with poor language and walking with an aid, four had moderate intellectual disability with language and walking abilities, and one had mild intellectual disability with hypotonia. Overall, eight had learned to walk, all had hypotonia, 17 had spasticity, 18 had dystonia, 12 had choreoathetosis, 19 had hypomyelination, and 10 had brain atrophy. Kyphoscoliosis (n=12), seizures (n=7), and pneumopathies (n=5) were the most severe complications. This study extends the phenotypic spectrum of AHDS to a mild intellectual disability with hypotonia. Developmental delay, hypotonia, hypomyelination, and thyroid hormone profile help to diagnose patients. Clinical course depends on initial severity, with stable acquisition after infancy; this may be adversely affected by neuro-orthopaedic, pulmonary, and epileptic complications. WHAT THIS PAPER ADDS: Mild intellectual disability is associated with SLC16A2 mutations. A thyroid hormone profile with a free T3 /T4 ratio higher than 0.75 can help diagnose patients. Patients with SLC16A2 mutations present a broad spectrum of neurological phenotypes that are also observed in other hypomyelinating disorders. Axial hypotonia is a consistent feature of Allan-Herndon-Dudley syndrome and leads to specific complications.
Published: 2019

35. Newly diagnosed and growing subependymal giant cell astrocytoma in adults with tuberous sclerosis complex: results from the international TOSCA study

Author: Jansen, Anna C., Belousova, Elena, Benedik, Mirjana P., Carter, Tom, Cottin, Vincent, Curatolo, Paolo, d'Amato, Lisa, d'Augeres, Guillaume Beaure, Vries, Petrus J., Ferreira, Jose C., Feucht, Martha, Fladrowski, Carla, Hertzberg, Christoph, Jozwiak, Sergiusz, Lawson, John A., Macaya, Alfons, Marques, Ruben, Nabbout, Rima, O'Callaghan, Finbar, Qin, Jiong, Sander, Valentin, Sauter, Matthias, Shah, Seema, Takahashi, Yukitoshi, Touraine, Renaud, Youroukos, Sotiris, Zonnenberg, Bernard, Fattal-Valevski, Aviva, Papathanasopoulos, Panagiotis, Papavasiliou, Antigone Syrigou, Giannakodimos, Stylianos, Gatzonis, Stylianos, Pavlou, Evangelos, Tzoufi, Meropi, Vergeer, A. M. H., Dhooghe, Marc, Verhelst, Helene, Roelens, Filip, Nassogne, Marie Cecile, Defresne, Pierre, de Waele, Liesbeth, Leroy, Patricia, Demonceau, Nathalie, Legros, Benjamin, van Bogaert, Patrick, Ceulemans, Berten, Dom, Lina, Castelnau, Pierre, Martin, Anne de Saint, Riquet, Audrey, Milh, Mathieu, Cances, Claude, Pedespan, Jean-Michel, Ville, Dorothée, Roubertie, Agathe, Auvin, Stephane, Berquin, Patrick, Richelme, Christian, Allaire, Catherine, Gueden, Sophie, Tich, Sylvie Nguyen The, Godet, Bertrand, Falco Rojas, Maria Luz Ruiz, Campistol Planas, Jaume, Martinez Bermejo, Antonio, Smeyers Dura, Patricia, Roldan Aparicio, Susana, Martinez Gonzalez, Maria Jesus, Lopez Pison, Javier, Blanco Barca, Manuel Oscar, Lopez Laso, Eduardo, Alonso Luengo, Olga, Aguirre Rodriguez, Francisco Javier, Malaga Dieguez, Ignacio, Camacho Salas, Ana, Marti Carrera, Itxaso, Martinez Salcedo, Eduardo, Yoldi Petri, Maria Eugenia, Cancho Candela, Ramon, Carrilho, Ines da Conceicao, Vieira, Jose Pedro, Silva Oliveira Monteiro, Jose Paulo, Oliveira Ferreira Leao, Miguel Jorge Santos, Marceano Ribeiro Luis, Catarina Sofia, Mendonca, Carla Pires, Endziniene, Milda, Strautmanis, Jurgis, Talvik, Inga, Canevini, Maria Paola, Gambardella, Antonio, Pruna, Dario, Buono, Salvatore, Fontana, Elena, Dalla Bernardina, Bernardo, Burloiu, Carmen, Cosma, Iuliu Stefan Bacos, Vintan, Mihaela Adela, Popescu, Laura, Zitterbart, Karel, Payerova, Jaroslava, Bratsky, Ladislav, Zilinska, Zuzana, Gruber-Sedlmayr, Ursula, Baumann, Matthias, Haberlandt, Edda, Rostasy, Kevin, Pataraia, Ekaterina, Elmslie, Frances, Johnston, Clare Ann, Crawford, Pamela, Uldall, Peter, Dahlin, Maria, Uvebrant, Paul, Rask, Olof, Bjoernvold, Marit, Brodtkorb, Eylert, Sloerdahl, Andreas, Solhoff, Ragnar, Jaatun, Martine Sofie Gilje, Mandera, Marek, Radzikowska, Elzbieta Janina, Wysocki, Mariusz, Fischereder, Michael, Kurlemann, Gerhard, Wilken, Bernd, Wiemer-Kruel, Adelheid, Budde, Klemens, Marquard, Klaus, Knuf, Markus, Hahn, Andreas, Hartmann, Hans, Merkenschlager, Andreas, Trollmann, Regina, [Jansen AC] Pediatric Neurology Unit, Department of Pediatrics, UZ Brussel VUB, Brussels, Belgium. [Belousova E] Research and Clinical Institute of Pediatrics, Pirogov Russian National Research Medical University, Moscow, Russia. [Benedik MP] Child Neurology Department, SPS Pediatriêna Klinika, Ljubljana, Slovenia. [Carter T] Tuberous Sclerosis Association, Nottingham, United Kingdom. [Cottin V] Hôpital Louis Pradel, Claude Bernard University Lyon 1, Lyon, France. [Curatolo P] Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University Hospital, Rome, Italy. [Macaya A] Neurologia pediàtrica, Hospital Universitari Vall d’Hebron, Barcelona, Spain, Departament de Salut, Moscow Regional Research Clinical Institute (MONICA), Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Infections Virales et Pathologie Comparée - UMR 754 (IVPC), Institut National de la Recherche Agronomique (INRA)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Association Sclérose Tubéreuse de Bourneville (Gradignan), Universitat Autònoma de Barcelona (UAB), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de Génétique Clinique Chromosomique et Moléculaire, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), University Medical Center [Utrecht], Department of Neurology, University Hospital Patras, University Hospitals Leuven [Leuven], CHU de Liège, Laboratoire Angevin de Recherche en Ingénierie des Systèmes (LARIS), Université d'Angers (UA), University of Antwerp (UA), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), UMR 1253 IBrain Imagerie & Cerveau Equipe 3 'Imagerie, Biomarqueurs & Thérapie' (IBT), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôpitaux Universitaires de Strasbourg (HUS), Service de Neuro-pédiatrie[Lille], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service de neurologie pédiatrique [CHU de Bordeaux], CHU de Bordeaux Pellegrin [Bordeaux], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital universitaire Robert-Debré [Paris], Groupe de Recherche sur l'Analyse Multimodale de la Fonction Cérébrale - UMR INSERM_S 1105 (GRAMFC), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pédiatrie, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de Neurologie [Chateaulin], Centre Toul-arC'hoat, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Service de Neurologie [CHU Limoges], CHU Limoges, Lithuanian University of Health Sciences [Kaunas, Lithuania], Regional Epilepsy Center, Reggio Calabria, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Witten/Herdecke University, St. George's Hospital, Danish Epilepsy Centre, Denmark and Aarhus University, Aarhus, Department of Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus Copernicus University [Toruń], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], The International TOSCA Study, De Waele, L, and Neurogenetics
Subjects: 0301 basic medicine, Pediatrics, Neurology, [SDV]Life Sciences [q-bio], Nervous System Diseases::Nervous System Diseases::Nervous System Diseases::Neurodegenerative Diseases::Heredodegenerative Disorders, Nervous System::Tuberous Sclerosis [DISEASES], tuberous sclerosis complex, 030105 genetics & heredity, registry, SEGA, lcsh:RC346-429, RECOMMENDATIONS, Tuberous sclerosis, 0302 clinical medicine, Medicine and Health Sciences, Original Research, Esclerosi tuberosa, TUMORS, 3. Good health, mTOR, medicine.symptom, Life Sciences & Biomedicine, Astrocitomes, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Persons::Age Groups::Adult [NAMED GROUPS], Clinical Neurology, Newly diagnosed, Asymptomatic, 03 medical and health sciences, medicine, MANAGEMENT, Adults, In patient, lcsh:Neurology. Diseases of the nervous system, TOSCA, personas::Grupos de Edad::adulto [DENOMINACIONES DE GRUPOS], Science & Technology, Subependymal giant cell astrocytoma, business.industry, Neurosciences, enfermedades del sistema nervioso::enfermedades del sistema nervioso::enfermedades del sistema nervioso::enfermedades neurodegenerativas::trastornos heredodegenerativos del sistema nervioso::esclerosis tuberosa [ENFERMEDADES], neoplasias::neoplasias por tipo histológico::neoplasias de células germinales y embrionarias::tumores neuroectodérmicos::neoplasias neuroepiteliales::glioma::astrocitoma [ENFERMEDADES], medicine.disease, Clinical neurology, nervous system diseases, Neoplasms::Neoplasms by Histologic Type::Neoplasms, Germ Cell and Embryonal::Neuroectodermal Tumors::Neoplasms, Neuroepithelial::Glioma::Astrocytoma [DISEASES], REGISTRY, Neurosciences & Neurology, Neurology (clinical), TSC2, business, 030217 neurology & neurosurgery
Abstract: SEGA; TOSCA; Tuberous sclerosis complex SEGA; TOSCA; Complex d’esclerosi tuberosa SEGA; TOSCA; Complejo de esclerosis tuberosa The onset and growth of subependymal giant cell astrocytoma (SEGA) in tuberous sclerosis complex (TSC) typically occurs in childhood. There is minimal information on SEGA evolution in adults with TSC. Of 2,211 patients enrolled in TOSCA, 220 of the 803 adults (27.4%) ever had a SEGA. Of 186 patients with SEGA still ongoing in adulthood, 153 (82.3%) remained asymptomatic, and 33 (17.7%) were reported to ever have developed symptoms related to SEGA growth. SEGA growth since the previous scan was reported in 39 of the 186 adults (21%) with ongoing SEGA. All but one patient with growing SEGA had mutations in TSC2. Fourteen adults (2.4%) were newly diagnosed with SEGA during follow-up, and majority had mutations in TSC2. Our findings suggest that surveillance for new or growing SEGA is warranted also in adulthood, particularly in patients with mutations in TSC2. The study was funded by Novartis Pharma AG.
Published: 2019

36. Clinical Characteristics of Subependymal Giant Cell Astrocytoma in Tuberous Sclerosis Complex

Author: Karas, Antonina, Jiang, yuwu, Zou, Liping, Xu, Kaifeng, Zhang, yushi, Luan, Guoming, Zhang, yuqin, Wang, yi, Jin, Meiling, ye, Dingwei, Liao, Weiping, Zhou, Liemin, Liu, Jie, Liao, Jianxiang, yan, Bo, Deng, yanchun, Jiang, Li, Liu, Zhisheng, Huang, Shaoping, Li, Hua, Kim, Kijoong, Chen, Pei-Lung, Lee, Hsiu-Fen, Tsai, Jeng-Dau, Chi, Ching-Shiang, Huang, Chao-Ching, Riney, Kate, yates, Deborah, Kwan, Patrick, Likasitwattanakul, Surachai, Nabangchang, Charcrin, Chomtho, Lunliya Thampratankul Krisnachai, Katanyuwong, Kamornwan, Sriudomkajorn, Somjit, Wilmshurst, Jo, Segel, Reeval, Gilboa, Tal, Tzadok, Michal, Fattal-Valevski, Aviva, Papathanasopoulos, Panagiotis, Papavasiliou, Antigone Syrigou, Giannakodimos, Stylianos, Gatz, Stylianos, Pavlou, Evangelos, Tzoufi, Meropi, Vergeer, A. M. H., Dhooghe, Marc, Verhelst, Helene, Roelens, Filip, Nassogne, Marie Cecile, Defresne, Pierre, de Waele, Liesbeth, Leroy, Patricia, Demonceau, Nathalie, Legros, Benjamin, van Bogaert, Patrick, Ceulemans, Berten, Dom, Lina, Castelnau, Pierre, Martin, Anne de St, Riquet, Audrey, Milh, Mathieu, Cances, Claude, Pedespan, Jean-Michel, Ville, Dorothee, Roubertie, Agathe, Auvin, Stephane, Berquin, Patrick, Richelme, Christian, Allaire, Catherine, Gueden, Sophie, Tich, Sylvie Nguyen The, Godet, Bertrand, Rojas, Maria Luz Ruiz Falco, Planas, Jaume Campistol, Bermejo, Antonio Martinez, Dura, Patricia Smeyers, Aparicio, Susana Roldan, Gonzalez, Maria Jesus Martinez, Pison, Javier Lopez, Barca, Manuel Oscar Blanco, Laso, Eduardo Lopez, Luengo, Olga Alonso, Rodriguez, Francisco Javier Aguirre, Dieguez, Ignacio Malaga, Salas, Ana Camacho, Carrera, Itxaso Marti, Salcedo, Eduardo Martinez, Petri, Maria Eugenia yoldi, Candela, Ramon Cancho, Carrilho, Ines da Conceicao, Vieira, Jose Pedro, Monteiro, Jose Paulo da Silva Oliveira, Leao, Miguel Jorge Santos de Oliveira Ferreira, Luis, Catarina Sofia Marceano Ribeiro, Mendonca, Carla Pires, Endziniene, Milda, Strautmanis, Jurgis, Talvik, Inga, Canevini, Maria Paola, Gambardella, Antonio, Pruna, Dario, Buono, Salvatore, Fontana, Elena, Dalla Bernardina, Bernardo, Burloiu, Carmen, Cosma, Iuliu Stefan Bacos, Vintan, Mihaela Adela, Popescu, Laura, Zitterbart, Karel, Payerova, Jaroslava, Bratsky, Ladislav, Zilinska, Zuzana, Gruber-Sedlmayr, Ursula, Baumann, Matthias, Haberland, Edda, Rostasy, Kevin, Pataraia, Ekaterina, Elmslie, Frances, Johnston, Clare Ann, Crawford, Pamela, Uldall, Peter, Uvebrant, Paul, Rask, Olof, Bjoernvold, Marit, Brodtkorb, Eylert, Sloerdahl, Andreas, Solhoff, Ragnar, Jaatun, Martine Sofie Gilje, Mandera, Marek, Radzikowska, Elzbieta Janina, Wysocki, Mariusz, Fischereder, Michael, Kurlemann, Gerhard, Wilken, Bernd, Wiemer-Kruel, Adelheid, Budde, Klemens, Marquard, Klaus, Knuf, Markus, Hahn, Andreas, Hartmann, Hans, Merkenschlager, Andreas, Trollmann, Regina, Jansen, Anna C., Belousova, Elena, Benedik, Mirjana P., Carter, Tom, Cottin, Vincent, Curatolo, Paolo, Dahlin, Maria, d'Amato, Lisa, d'Augeres, Guillaume Beaure, Vries, Petrus J., Ferreira, Jose C., Feucht, Martha, Fladrowski, Carla, Hertzberg, Christoph, Jozwiak, Sergiusz, Lawson, John A., Macaya, Alfons, Marques, Ruben, Nabbout, Rima, O'Callaghan, Finbar, Qin, Jiong, Sander, Valentin, Sauter, Matthias, Shah, Seema, Takahashi, yukitoshi, Touraine, Renaud, youroukos, Sotiris, Zonnenberg, Bernard, Kingswood, John C., Shinohara, Nobuo, Horie, Shigeo, Kubota, Masaya, Tohyama, Jun, Imai, Katsumi, Kaneda, Mari, Kaneko, Hideo, Uchida, yasushi, Kirino, Tomoko, Endo, Shoichi, Inoue, yoshikazu, Uruno, Katsuhisa, Serdaroglu, Ayse, yapici, Zuhal, Anlar, Banu, Altunbasak, Sakir, Lvova, Olga, Belyaev, Oleg Valeryevich, Agranovich, Oleg, Levitina, Elena Vladislavovna, Maksimova, yulia Vladimirovna, Johns Hopkins University (JHU), Fudan University [Shanghai], EED, University of California [Los Angeles] (UCLA), University of California-University of California, Chimie pour la Reconnaissance et l’Etude d’Assemblages Biologiques (CREAB), SYstèmes Moléculaires et nanoMatériaux pour l’Energie et la Santé (SYMMES), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Département Interfaces pour l'énergie, la Santé et l'Environnement (DIESE), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), College of Computing (GATECH), Georgia Institute of Technology [Atlanta], Institute for Human Genetics, Safra Children's Hospital, Department of Neurology, University Hospital Patras, University Hospitals Leuven [Leuven], CHU de Liège, Laboratoire Angevin de Recherche en Ingénierie des Systèmes (LARIS), Université d'Angers (UA), University of Antwerp (UA), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de Neuro-pédiatrie[Lille], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Pédiatrie [CHU Toulouse], CHU Toulouse [Toulouse], Service de neurologie pédiatrique [CHU de Bordeaux], CHU de Bordeaux Pellegrin [Bordeaux], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Groupe de Recherche sur l'Analyse Multimodale de la Fonction Cérébrale - UMR INSERM_S 1105 (GRAMFC), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pédiatrie, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de Neurologie [Chateaulin], Centre Toul-arC'hoat, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Service de Neurologie [CHU Limoges], CHU Limoges, Lithuanian University of Health Sciences [Kaunas, Lithuania], Regional Epilepsy Center, Reggio Calabria, Innsbruck Medical University [Austria] (IMU), Witten/Herdecke University, St. George's Hospital, Danish Epilepsy Centre, Denmark and Aarhus University, Aarhus, Department of Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus Copernicus University [Toruń], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Moscow Regional Research Clinical Institute (MONICA), Infections Virales et Pathologie Comparée - UMR 754 (IVPC), Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Universitat Autònoma de Barcelona (UAB), CHU Necker - Enfants Malades [AP-HP], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne-Hôpital Nord - Saint-Etienne, Department of Clinical Genetics, Physiotherapy, Human Physiology and Anatomy, Pediatrics, Public Health Sciences, Mental Health and Wellbeing research group, Neurogenetics, De Waele, L, University of California (UC)-University of California (UC), UMR 1253 IBrain Imagerie & Cerveau Equipe 3 'Imagerie, Biomarqueurs & Thérapie' (IBT), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Institut National de la Recherche Agronomique (INRA)-École Pratique des Hautes Études (EPHE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), [Jansen AC] Pediatric Neurology Unit, Department of Pediatrics, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium. [Belousova E] Research and Clinical Institute of Pediatrics, Pirogov Russian National Research Medical University, Moscow, Russia. [Benedik MP] Child Neurology Department, SPS Pediatriêna Klinika, Ljubljana, Slovenia. [Carter T] Tuberous Sclerosis Association, Nottingham, United Kingdom. [Cottin V] Hôpital Louis Pradel, Claude Bernard University Lyon 1, Lyon, France. [Curatolo P] Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University Hospital, Rome, Italy. [Macaya A] Neurologia pediàtrica, Hospital Universitari Vall d’Hebron, Barcelona, Spain., and Vall d'Hebron Barcelona Hospital Campus
Subjects: Quinases, Pediatrics, enzimas y coenzimas::enzimas::transferasas::fosfotransferasas::fosfotransferasas (grupo alcohol aceptor)::proteína cinasas::proteína-serina-treonina cinasas::TOR serina-treonina cinasas [COMPUESTOS QUÍMICOS Y DROGAS], Angiomyolipoma, Neurology, [SDV]Life Sciences [q-bio], CHILDREN, tuberous sclerosis complex, registry, Neoplasms::Neoplasms by Histologic Type::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Glandular and Epithelial::Neoplasms, Neuroepithelial::Glioma::Neoplasms::Neoplasms by Histologic Type::Astrocytoma [DISEASES], SEGA, RECOMMENDATIONS, DISEASE, lcsh:RC346-429, Tuberous sclerosis, DOUBLE-BLIND, 0302 clinical medicine, EVEROLIMUS, neoplasias::hamartoma::esclerosis tuberosa [ENFERMEDADES], Medicine and Health Sciences, 030212 general & internal medicine, Original Research, Intracranial pressure, Esclerosi tuberosa, 3. Good health, medicine.anatomical_structure, mTOR, Astrocitomes, Life Sciences & Biomedicine, medicine.drug, medicine.medical_specialty, Clinical Neurology, DIAGNOSIS, 03 medical and health sciences, medicine, MANAGEMENT, TOSCA, lcsh:Neurology. Diseases of the nervous system, Everolimus, Science & Technology, Subependymal giant cell astrocytoma, business.industry, ANGIOMYOLIPOMA, neoplasias::neoplasias por tipo histológico::neoplasias::neoplasias por tipo histológico::neoplasias glandulares y epiteliales::neoplasias neuroepiteliales::glioma::neoplasias::neoplasias por tipo histológico::astrocitoma [ENFERMEDADES], Neurosciences, medicine.disease, SEVERITY, Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Serine-Threonine Kinases::TOR Serine-Threonine Kinases [CHEMICALS AND DRUGS], Neurology (clinical), TSC1, Neurosciences & Neurology, TSC2, business, 030217 neurology & neurosurgery, Neoplasms::Hamartoma::Tuberous Sclerosis [DISEASES]
Abstract: SEGA; TOSCA; Tuberous sclerosis complex SEGA; TOSCA; Complejo de esclerosis tuberosa SEGA; TOSCA; Complex d'esclerosi tuberosa Background: This study evaluated the characteristics of subependymal giant cell astrocytoma (SEGA) in patients with tuberous sclerosis complex (TSC) entered into the TuberOus SClerosis registry to increase disease Awareness (TOSCA). Methods: The study was conducted at 170 sites across 31 countries. Data from patients of any age with a documented clinical visit for TSC in the 12 months preceding enrollment or those newly diagnosed with TSC were entered. Results: SEGA were reported in 554 of 2,216 patients (25%). Median age at diagnosis of SEGA was 8 years (range, 18 years. SEGA were symptomatic in 42.1% of patients. Symptoms included increased seizure frequency (15.8%), behavioural disturbance (11.9%), and regression/loss of cognitive skills (9.9%), in addition to those typically associated with increased intracranial pressure. SEGA were significantly more frequent in patients with TSC2 compared to TSC1 variants (33.7 vs. 13.2 %, p < 0.0001). Main treatment modalities included surgery (59.6%) and mammalian target of rapamycin (mTOR) inhibitors (49%). Conclusions: Although SEGA diagnosis and growth typically occurs during childhood, SEGA can occur and grow in both infants and adults. The study was funded by Novartis Pharma AG. Novartis has contributed to the study design, data analysis, and the decision to publish. Novartis authors reviewed the draft for submission.
Published: 2019

37. Response to cannabidiol in epilepsy of infancy with migrating focal seizures associated with KCNT1 mutations: An open-label, prospective, interventional study

Author: Kelsey Poisson, Chon Lee, Maria Roberta Cilio, Matthew Wong, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de neurologie pédiatrique
Subjects: Male, Pediatrics, medicine.medical_specialty, Adolescent, Nerve Tissue Proteins, Potassium Channels, Sodium-Activated, law.invention, Treatment resistant epilepsy, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Dravet syndrome, Randomized controlled trial, law, Seizures, 030225 pediatrics, medicine, Cannabidiol, Humans, Prospective Studies, Epilepsy of infancy with migrating focal seizures, Seizure frequency, business.industry, Epileptic encephalopathy, Infant, General Medicine, medicine.disease, Child, Preschool, Pediatrics, Perinatology and Child Health, Mutation, Anticonvulsants, Female, Neurology (clinical), Open label, business, Epileptic Syndromes, Spasms, Infantile, 030217 neurology & neurosurgery, medicine.drug
Abstract: Epilepsy of Infancy with Migrating Focal Seizures (EIMFS) is a rare, developmental and epileptic encephalopathy most commonly associated with mutations in KCNT1, a potassium channel. Polymorphous migrating focal seizures begin within 6 months of life and are pharmacoresistant to standard anticonvulsants. Additional therapies are needed to decrease seizure frequency and subsequent developmental deterioration associated with EIMFS. Cannabidiol (CBD) has recently arisen in public interest due to its potential in treatment-resistant epilepsies as demonstrated in randomized controlled trials for Dravet Syndrome and Lennox-Gastaut Syndrome. Here we evaluate the response of three patients, all diagnosed with EIMFS secondary to KCNT1 mutations, to pharmaceutical grade CBD. Two patients showed no benefit and have since voluntarily stopped CBD. One patient showed no overall reduction in seizure frequency, however showed a notable reduction in seizure intensity with possible developmental progression. Further studies are needed to assess the potential benefit of CBD in treatment-resistant epilepsies such as EIMFS, with a focus on early identification and intervention.
Published: 2019

38. Homozygous GRN mutations: unexpected phenotypes and new insights into pathological and molecular mechanisms: New insights in homozygous GRN mutations

Author: Antoinette Gelot, Alexis Brice, Agnès Camuzat, Benoit Rucheton, Laureen Chat, Dario Saracino, Frédérique Fluchère, Johannes Alexander Lobrinus, Fabienne Clot, Sylvie Forlani, Peter Myers, Alexandra Durr, Ludmila Jornea, Isabelle Le Ber, Vincent Huin, Foudil Lamari, Mathieu Barbier, Armand Bottani, Catherine Caillaud, Stéphane Auvin, Charles Duyckaerts, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Technocentre Renault [Guyancourt], RENAULT, Génétique médicale, Hôpitaux Universitaires de Genève (HUG), University of Geneva [Switzerland], Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Biochimie Métabolique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Université de Bordeaux (UB), Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie pédiatrique et maladies métaboliques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Polytech'Paris-UPMC, Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire de Neuropathologie Raymond Escourolle, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Geneva University Hospital (HUG), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital de la Timone [CHU - APHM] (TIMONE), Aix Marseille Université (AMU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université de Paris (UP), Medical Office [Geneva, Switzerland], Service de pathologie [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neuropathologie [CHU Pitié Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Cité (UPCité), Sorbonne Université, Institut du Cerveau et de la Moelle épinière (ICM), AP-HP, INSERM, CNRS, University Hospital Pitié - Salpêtrière, Paris, France, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP]
Subjects: Male, MESH: Epilepsy / genetics, MESH: Neuronal Ceroid-Lipofuscinoses / diagnostic imaging, MESH: TDP-43 Proteinopathies / physiopathology, MESH: RNA Splicing / genetics, ddc:616.07, 0302 clinical medicine, MESH: Child, MESH: Cerebellar Ataxia / genetics, ddc:576.5, Age of Onset, Child, ComputingMilieux_MISCELLANEOUS, Mutation, MESH: Middle Aged, 3. Good health, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Neuronal ceroid lipofuscinosis, MESH: Parkinsonian Disorders / genetics, MESH: Cognitive Dysfunction / genetics, MESH: Young Adult, Frontotemporal Dementia, GRN, Retinitis Pigmentosa, MESH: Progranulins / metabolism, MESH: Rare Diseases, MESH: Frontotemporal Dementia / genetics, Cerebellar Ataxia, MESH: Age of Onset, RNA Splicing, 03 medical and health sciences, Parkinsonian Disorders, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Retinitis pigmentosa, Humans, Cognitive Dysfunction, MESH: Adolescent, MESH: Humans, Epilepsy, MESH: Adult, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, MESH: TDP-43 Proteinopathies / diagnostic imaging, 030104 developmental biology, FOS: Biological sciences, Neurology (clinical), MESH: Frontotemporal Dementia / physiopathology, MESH: Female, 030217 neurology & neurosurgery, 0301 basic medicine, TDP-43, medicine.disease_cause, Progranulins, MESH: Heterozygote, Genetics, Homozygote, Frontotemporal lobar degeneration, Middle Aged, MESH: Neuronal Ceroid-Lipofuscinoses / physiopathology, frontotemporal lobar degeneration, Neurons and Cognition (q-bio.NC), MESH: Parkinsonian Disorders / diagnostic imaging, MESH: TDP-43 Proteinopathies / genetics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, medicine.symptom, MESH: Neuronal Ceroid-Lipofuscinoses / genetics, Frontotemporal dementia, MESH: Homozygote, Adult, Progranulin, Heterozygote, MESH: Mutation, Adolescent, MESH: Parkinsonian Disorders / physiopathology, Biology, MESH: Frontotemporal Dementia / diagnostic imaging, Young Adult, Rare Diseases, Neuronal Ceroid-Lipofuscinoses, MESH: Retinitis Pigmentosa / genetics, medicine, Dementia, Quantitative Biology - Genomics, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Genomics (q-bio.GN), Cerebellar ataxia, MESH: Progranulins / genetics, Biomolecules (q-bio.BM), MESH: Male, Quantitative Biology - Biomolecules, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Quantitative Biology - Neurons and Cognition, TDP-43 Proteinopathies, Age of onset, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Homozygous mutations in the progranulin gene (GRN) are associated with neuronal ceroid lipofuscinosis 11 (CLN11), a rare lysosomal-storage disorder characterized by cerebellar ataxia, seizures, retinitis pigmentosa, and cognitive disorders, usually beginning between 13 and 25 years of age. This is a rare condition, previously reported in only four families. In contrast, heterozygous GRN mutations are a major cause of frontotemporal dementia associated with neuronal cytoplasmic TDP-43 inclusions. We identified homozygous GRN mutations in six new patients. The phenotypic spectrum is much broader than previously reported, with two remarkably distinct presentations, depending on the age of onset. A childhood/juvenile form is characterized by classical CLN11 symptoms at an early age at onset. Unexpectedly, other homozygous patients presented a distinct delayed phenotype of frontotemporal dementia and parkinsonism after 50 years; none had epilepsy or cerebellar ataxia. Another major finding of this study is that all GRN mutations may not have the same impact on progranulin protein synthesis. A hypomorphic effect of some mutations is supported by the presence of residual levels of plasma progranulin and low levels of normal transcript detected in one case with a homozygous splice-site mutation and late onset frontotemporal dementia. This is a new critical finding that must be considered in therapeutic trials based on replacement strategies. The first neuropathological study in a homozygous carrier provides new insights into the pathological mechanisms of the disease. Hallmarks of neuronal ceroid lipofuscinosis were present. The absence of TDP-43 cytoplasmic inclusions markedly differs from observations of heterozygous mutations, suggesting a pathological shift between lysosomal and TDP-43 pathologies depending on the mono or bi-allelic status. An intriguing observation was the loss of normal TDP-43 staining in the nucleus of some neurons, which could be the first stage of the TDP-43 pathological process preceding the formation of typical cytoplasmic inclusions. Finally, this study has important implications for genetic counselling and molecular diagnosis. Semi-dominant inheritance of GRN mutations implies that specific genetic counselling should be delivered to children and parents of CLN11 patients, as they are heterozygous carriers with a high risk of developing dementia. More broadly, this study illustrates the fact that genetic variants can lead to different phenotypes according to their mono- or bi-allelic state, which is a challenge for genetic diagnosis.
Published: 2019

39. Decreased plasma L-arginine levels in organic acidurias (MMA and PA) and decreased plasma branched-chain amino acid levels in urea cycle disorders as a potential cause of growth retardation: Options for treatment

Author: Roland Posset, Javier Blasco-Alonso, Daniela Karall, Frits A. Wijburg, Marie-Cécile Nassogne, L. Rubert, Monique Williams, C. De Laet, A.M. Jelsig, Aline Cano, Stephanie Grunewald, Tomas Honzik, Kimberly A. Chapman, Carlo Dionisi-Vici, E. Cortes I. Saladelafont, N. Lüsebrink, François Eyskens, Ans T. van der Ploeg, Friederike Hörster, Femke Molema, A. Wisniewska, P. de Lonlay, Stefan Kölker, E. Leao-Teles, Roshni Vara, Etienne Sokal, Brigitte Chabrol, Ivo Barić, V. Legros, Andrew P. Morris, Anil Jalan, Manuel Schiff, L. De Meirleir, A. B. Burlina, Johannes Häberle, Florian Gleich, F. Arnaudo, Persephone Augoustides-Savvopoulou, Calin Deleanu, Marshall L. Summar, K. Mention, D. Gil-Ortega, Ni-Chung Lee, Sandra Alves, Martin Lindner, Inmaculada Vives-Piñera, Annet M. Bosch, Allan M. Lund, Dimitris Rizopoulos, A. Garcia Cazorla, Luis Peña-Quintana, Diego Martinelli, Sabine Scholl-Bürgi, Paula Avram, A. Sarajlija, Wuh-Liang Hwu, Dries Dobbelaere, Matthias R. Baumgartner, Jiří Zeman, Peter Freisinger, Shirou Matsumoto, N. Thompson, Yin-Hsiu Chien, Anupam Chakrapani, Jolanta Sykut-Cegielska, M. Djordjevic, Peter Burgard, Paediatric Metabolic Diseases, AGEM - Inborn errors of metabolism, ARD - Amsterdam Reproduction and Development, Pediatrics, Epidemiology, Pediatric surgery, Amsterdam Reproduction & Development (AR&D), Amsterdam Gastroenterology Endocrinology Metabolism, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie pédiatrique, and E-IMD
Subjects: 0301 basic medicine, Male, Propionic Acidemia, Arginine, Endocrinology, Diabetes and Metabolism, Methylmalonic acidemia, L-arginine, 030105 genetics & heredity, Biochemistry, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Longitudinal Studies, Registries, Propionic acidemia, Child, Urea Cycle Disorders, Inborn, Body height, Branched-chain amino acids, Dietary and supplemental treatment, Organic acidurias, Urea cycle disorders, Ornithine transcarbamylase deficiency, Growth Disorders, Argininosuccinate lyase, Diabetes and Metabolism, Europe, Urea cycle, Child, Preschool, Female, Leucine, medicine.medical_specialty, Adolescent, Branched-chain amino acid, 03 medical and health sciences, Internal medicine, medicine, Genetics, Humans, Molecular Biology, Amino Acid Metabolism, Inborn Errors, business.industry, medicine.disease, Diet, chemistry, Human medicine, business, 030217 neurology & neurosurgery, Amino Acids, Branched-Chain
Abstract: Background and aim Patients with methylmalonic acidemia (MMA) and propionic acidemia (PA) and urea cycle disorders (UCD), treated with a protein restricted diet, are prone to growth failure. To obtain optimal growth and thereby efficacious protein incorporation, a diet containing the essential and functional amino acids for growth is necessary. Optimal growth will result in improved protein tolerance and possibly a decrease in the number of decompensations. It thus needs to be determined if amino acid deficiencies are associated with the growth retardation in these patient groups. We studied the correlations between plasma L-arginine levels, plasma branched chain amino acids (BCAA: L-isoleucine, L-leucine and L-valine) levels (amino acids known to influence growth), and height in MMA/PA and UCD patients. Methods We analyzed data from longitudinal visits made in stable metabolic periods by patients registered at the European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD, Chafea no. 2010 12 01). Results In total, 263 MMA/PA and 311 UCD patients were included, all aged below 18 years of age. In patients with MMA and PA, height z-score was positively associated with patients' natural-protein-to-energy prescription ratio and their plasma L-valine and L-arginine levels, while negatively associated with the amount of synthetic protein prescription and their age at visit. In all UCDs combined, height z-score was positively associated with the natural-protein-to-energy prescription ratio. In those with carbamylphosphate synthetase 1 deficiency (CPS1-D), those with male ornithine transcarbamylase deficiency (OTC-D), and those in the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome subgroup, height z-score was positively associated with patients' plasma L-leucine levels. In those with argininosuccinate synthetase deficiency (ASS-D) and argininosuccinate lyase deficiency (ASL-D), height was positively associated with patients' plasma L-valine levels. Conclusion Plasma L-arginine and L-valine levels in MMA/PA patients and plasma L-leucine and L-valine levels in UCD patients, as well as the protein-to-energy prescription ratio in both groups were positively associated with height. Optimization of these plasma amino acid levels is essential to support normal growth and increase protein tolerance in these disorders. Consequently this could improve the protein-to-energy intake ratio.
Published: 2019

40. Neonatal Developmental and Epileptic Encephalopathies

Author: Charbel El Kosseifi, Marie-Coralie Cornet, Maria Roberta Cilio, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - SSS/IONS/COSY - Systems & cognitive Neuroscience, and UCL - (SLuc) Service de neurologie pédiatrique
Subjects: Epilepsy, Neonatal intensive care unit, medicine.diagnostic_test, business.industry, Encephalopathy, Infant, Newborn, Brain, Infant, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Neuroimaging, 030225 pediatrics, Pediatrics, Perinatology and Child Health, medicine, Humans, STXBP1, Neurology (clinical), Early myoclonic encephalopathy, business, Neuroscience, Eeg monitoring, 030217 neurology & neurosurgery, Genetic testing
Abstract: The new concept of developmental and epileptic encephalopathy is based on the understanding that many genetic epilepsies are associated with developmental impairment as a direct consequence of the genetic mutation, in addition to the effect of the frequent epileptic activity on brain development. As an example, in infants with KCNQ2 or STXBP1 encephalopathy, seizures may be controlled early after onset or cease spontaneously after a few years, but the developmental consequences tend to remain profound. The term "developmental and epileptic encephalopathy" expresses the concept that the genetic defect may be responsible for both the epilepsy and adverse development which is crucial to understanding the disease process for both families and clinicians. The increased use of EEG monitoring, neuroimaging, and metabolic and genetic testing in the Neonatal Intensive Care Unit has greatly improved our understanding of neonatal-onset epilepsies as seen with the syndromes Ohtahara and Early Myoclonic Encephalopathy outlined in the 1970s into distinct etiology-specific electroclinical phenotypes.
Published: 2019

41. Pharmacokinetics and Tolerability of Multiple Doses of Pharmaceutical-Grade Synthetic Cannabidiol in Pediatric Patients with Treatment-Resistant Epilepsy

Author: Steven Sparagana, Neha Parikh, Dennis J. Dlugos, Steven Phillips, Isra Saeed, Maria Roberta Cilio, J. Ben Renfroe, Jin Yu, Colin M. Roberts, D. Alexander Oh, James W. Wheless, Ian Miller, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de neurologie pédiatrique
Subjects: Drug Resistant Epilepsy, medicine.medical_specialty, Clobazam, Adolescent, Administration, Oral, Gastroenterology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Internal medicine, medicine, Cannabidiol, Humans, Pharmacology (medical), Original Research Article, Dosing, Child, Adverse effect, Dose-Response Relationship, Drug, business.industry, Infant, 030227 psychiatry, Psychiatry and Mental health, Regimen, Treatment Outcome, Tolerability, Child, Preschool, Concomitant, Anticonvulsants, Drug Therapy, Combination, Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug
Abstract: Background Prior studies have evaluated the use of various constituents of cannabis for their anti-seizure effects. Specifically, cannabidiol, a non-psychoactive component of cannabis, has been investigated for treatment-resistant epilepsy, but more information is needed particularly on its use in a pediatric population. Objective The objective of this study was to evaluate the pharmacokinetics and safety of a synthetic pharmaceutical-grade cannabidiol oral solution in pediatric patients with treatment-resistant epilepsy. Methods In this open-label study, pediatric patients (aged 1 to ≤ 17 years) with treatment-resistant epilepsy received cannabidiol oral solution administered as add-on to their current antiepileptic drug regimen. Patients received a single dose (5, 10, or 20 mg/kg) on day 1 and twice-daily dosing on days 4 through 10 (10-mg/kg [cohort 1], 20-mg/kg [cohort 2], or 40-mg/kg [cohort 3] total daily dose). Serial blood samples were collected on day 1 before dosing and up to 72 h post-dose, and on day 10 before dosing and up to 24 h post-dose. Blood samples to assess trough concentrations of cannabidiol were collected on day 6 (for patients aged 12 to ≤ 17 years), day 8 (for patients aged 2 to ≤ 17 years), and day 9 (for patients aged 6 to ≤ 17 years). Results Overall, 61 patients across three cohorts received one of three doses of cannabidiol oral solution (mean age, 7.6 years). The age composition was similar in the three cohorts. There was a trend for increased cannabidiol exposure with increased cannabidiol oral solution dosing, but overall exposure varied. Approximately 2–6 days of twice-daily dosing provided steady-state concentrations of cannabidiol. A bi-directional drug interaction occurred with cannabidiol and clobazam. Concomitant administration of clobazam with 40 mg/kg/day of cannabidiol oral solution resulted in a 2.5-fold increase in mean cannabidiol exposure. Mean plasma clobazam concentrations were 1.7- and 2.2-fold greater in patients receiving clobazam concomitantly with 40 mg/kg/day of cannabidiol oral solution compared with 10 mg/kg/day and 20 mg/kg/day. Mean plasma norclobazam values were 1.3- and 1.9-fold higher for patients taking clobazam plus 40 mg/kg/day of cannabidiol oral solution compared with the 10-mg/kg/day and 20-mg/kg/day groups. All doses were generally well tolerated, and common adverse events that occurred at > 10% were somnolence (21.3%), anemia (18.0%), and diarrhea (16.4%). Conclusions Inter-individual variability in systemic cannabidiol exposure after pediatric patient treatment with cannabidiol oral solution was observed but decreased with multiple doses. Short-term administration was generally safe and well tolerated. Trial Registration ClinicalTrials.gov (NCT02324673). Electronic supplementary material The online version of this article (10.1007/s40263-019-00624-4) contains supplementary material, which is available to authorized users.
Published: 2019

42. Evolutionarily conserved susceptibility of the mitochondrial respiratory chain to SDHI pesticides and its consequence on the impact of SDHIs on human cultured cells

Author: Pierre Rustin, Agathe Kahn, Judith Favier, Paule Bénit, Pierre Gressens, D Chretien, Sylvie Bortoli, Anne Paule Gimenez-Roqueplo, Laurence Huc, Malgorzata Rak, Manuel Schiff, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Contaminants & Stress Cellulaire (ToxAlim-COMICS), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Service de neurologie pédiatrique et maladies métaboliques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), No specific funding was initially provided for this work. After the work realization, PB and PR received a specific support grant from the French Association POLLINIS (https://www.pollinis.org/). General expenses were covered by grants from AAJI (Association pour l’Aide aux Jeunes Infirmes & aux Personnes Handicapées), AFAF (Association Française de l’Ataxie de Friedreich), Association OLY (Ouvrir Les Yeux), ANR MITOXDRUGS (ANR-16-CE18-0010)., ANR-16-CE18-0010,MITOXDRUGS,Toxicité mitochondriale des médicaments et stéatose hépatique. Généralisation de la relation causale pour le développement de nouveaux tests prédictifs.(2016), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Rustin, Pierre, Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Bodescot, Myriam, and Toxicité mitochondriale des médicaments et stéatose hépatique. Généralisation de la relation causale pour le développement de nouveaux tests prédictifs. - - MITOXDRUGS2016 - ANR-16-CE18-0010 - AAPG2016 - VALID
Subjects: 0301 basic medicine, Glutamine, Respiratory chain, Mitochondrion, Toxicology, Biochemistry, Antioxidants, Database and Informatics Methods, 0302 clinical medicine, Animal Cells, Medicine and Health Sciences, Glycolysis, Annelids, Amino Acids, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Energy-Producing Organelles, Cells, Cultured, Connective Tissue Cells, Multidisciplinary, biology, Organic Compounds, Succinate dehydrogenase, Monosaccharides, Acidic Amino Acids, Quinones, Eukaryota, Neurodegenerative Diseases, Bees, Mitochondria, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Insects, Succinate Dehydrogenase, Chemistry, Mitochondrial respiratory chain, [SDV.TOX.TVM] Life Sciences [q-bio]/Toxicology/Vegetal toxicology and mycotoxicology, Connective Tissue, Physical Sciences, Mitochondrial Membranes, Medicine, Cellular Structures and Organelles, Cellular Types, Anatomy, Honey Bees, Sequence Analysis, Research Article, Arthropoda, Bioinformatics, Science, Carbohydrates, Médecine humaine et pathologie, [SDV.TOX.TVM]Life Sciences [q-bio]/Toxicology/Vegetal toxicology and mycotoxicology, Oxidative phosphorylation, Bioenergetics, Research and Analysis Methods, Electron Transport, Fungal Proteins, 03 medical and health sciences, Drug Resistance, Fungal, Animals, Earthworms, Humans, Oligochaeta, Pesticides, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Toxicologie, Organic Chemistry, Chemical Compounds, Organisms, Fungi, Biology and Life Sciences, Proteins, Cell Biology, Fibroblasts, Invertebrates, Hymenoptera, Biological Tissue, Glucose, 030104 developmental biology, Cell culture, biology.protein, Human health and pathology, Sequence Alignment, 030217 neurology & neurosurgery
Abstract: International audience; Succinate dehydrogenase (SDH) inhibitors (SDHIs) are used worldwide to limit the proliferation of molds on plants and plant products. However, as SDH, also known as respiratory chain (RC) complex II, is a universal component of mitochondria from living organisms, highly conserved through evolution, the specificity of these inhibitors toward fungi warrants investigation. We first establish that the human, honeybee, earthworm and fungal SDHs are all sensitive to the eight SDHIs tested, albeit with varying IC50 values, generally in the micromolar range. In addition to SDH, we observed that five of the SDHIs, mostly from the latest generation, inhibit the activity of RC complex III. Finally, we show that the provision of glucose ad libitum in the cell culture medium, while simultaneously providing sufficient ATP and reducing power for antioxidant enzymes through glycolysis, allows the growth of RC-deficient cells, fully masking the deleterious effect of SDHIs. As a result, when glutamine is the major carbon source, the presence of SDHIs leads to time-dependent cell death. This process is significantly accelerated in fibroblasts derived from patients with neurological or neurodegenerative diseases due to RC impairment (encephalopathy originating from a partial SDH defect) and/or hypersensitivity to oxidative insults (Friedreich ataxia, familial Alzheimer's disease).
Published: 2019

43. Augmented Reticular Thalamic Bursting and Seizures in Scn1a-Dravet Syndrome

Author: Jeanne T. Paz, Stefanie Ritter-Makinson, Freek E. Hoebeek, Oscar H J Eelkman Rooda, Eric Bennett, Alexandra Clemente-Perez, Kazuhiro Yamakawa, Frances S. Cho, Ana Chkhaidze, Bruno Delord, Bryan Higashikubo, Marie-Coralie Cornet, Maria Roberta Cilio, Stephanie S. Holden, UCL - SSS/IONS/COSY - Systems & cognitive Neuroscience, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de pédiatrie générale, UCL - (SLuc) Service de neurologie pédiatrique, Neurosciences, and Neurosurgery
Subjects: 0301 basic medicine, Intellectual and Developmental Disabilities (IDD), Medical Physiology, Optogenetics, Neurodegenerative, Epilepsies, Scn1a, Inhibitory postsynaptic potential, General Biochemistry, Genetics and Molecular Biology, Article, SK channel, Thalamocortical oscillations, Epilepsy, Bursting, 03 medical and health sciences, Mice, 0302 clinical medicine, Dravet syndrome, Thalamus, SK current, Seizures, medicine, 2.1 Biological and endogenous factors, Animals, Humans, Aetiology, Loss function, 030304 developmental biology, 0303 health sciences, Chemistry, Animal, Nav1.1, Neurosciences, Thalamocortical circuits, medicine.disease, Reticular thalamic nucleus, Brain Disorders, 030104 developmental biology, Reticular connective tissue, Neurological, Disease Models, Biochemistry and Cell Biology, Myoclonic, Neuroscience, 030217 neurology & neurosurgery
Abstract: SUMMARY Loss of function in the Scn1a gene leads to a severe epileptic encephalopathy called Dravet syndrome (DS). Reduced excitability in cortical inhibitory neurons is thought to be the major cause of DS seizures. Here, in contrast, we show enhanced excitability in thalamic inhibitory neurons that promotes the non-convulsive seizures that are a prominent yet poorly understood feature of DS. In a mouse model of DS with a loss of function in Scn1a, reticular thalamic cells exhibited abnormally long bursts of firing caused by the downregulation of calcium-activated potassium SK channels. Our study supports a mechanism in which loss of SK activity causes the reticular thalamic neurons to become hyperexcitable and promote non-convulsive seizures in DS. We propose that reduced excitability of inhibitory neurons is not global in DS and that non-GABAergic mechanisms such as SK channels may be important targets for treatment., Graphical Abstract, In Brief In a mouse model of Dravet syndrome (DS) resulting from voltage-gated sodium channel deficiency, Ritter-Makinson et al. find that inhibitory neurons of the reticular thalamic nucleus are paradoxically hyperexcitable due to compensatory reductions in a potassium SK current. Boosting this SK current treats nonconvulsive seizures in DS mice.
Published: 2019

44. Neonatal seizures: Is there a relationship between ictal electroclinical features and etiology? A critical appraisal based on a systematic literature review

Author: Nunes, Magda L, Yozawitz, Elissa G, Zuberi, Sameer, Mizrahi, Eli M, Cilio, Maria-Roberta, Moshé, Solomon L, Plouin, Perrine, Vanhatalo, Sampsa, Pressler, Ronit M, Task Force on Neonatal Seizures, ILAE Commission on Classification & Terminology, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de neurologie pédiatrique, Department of Neurosciences, Kliinisen neurofysiologian yksikkö, and HUS Medical Imaging Center
Subjects: medicine.medical_specialty, Pediatrics, Encephalopathy, semiology, neonatal seizures, neonatal EEG, Electroencephalography, 3124 Neurology and psychiatry, Semiology, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, 030225 pediatrics, medicine, Electroclinical features, Ictal, Stroke, Fisher's exact test, medicine.diagnostic_test, business.industry, electroclinical features, 3112 Neurosciences, Publication bias, Neonatal seizures, medicine.disease, 3. Good health, Neurology, symbols, Etiology, Neurology (clinical), business, Critical Review and Invited Commentary, Neonatal EEG, 030217 neurology & neurosurgery
Abstract: Summary The aim of this study was to evaluate whether specific etiologies of neonatal seizures have distinct ictal electroclinical features. A systematic review of English articles using the PubMed database since 2004 (last update 9/26/16). Search terms included text words and Medical Subject Headings (MeSH) terms related to neonatal seizures. Eligible articles included reports of neonates with seizures with a full description of seizure semiology and electroclinical findings. Independent extraction of data was performed by 2 authors using predefined data fields, including study quality indicators. Data were collected for every individual patient described in the articles. The dataset was analyzed with the Fisher exact test. The initial search led to 8507 titles; using filters, 2910 titles and abstracts were identified, with 177 full texts selected to be read. Fifty‐seven studies were included in the analysis with 151 neonates (37.7 male and 62.9% term). Genetic etiologies (51%) and sequential seizures (41.1%) predominated in this sample and hypoxic‐ischemic encephalopathy (HIE) accounted for only 4%. The low prevalence of HIE observed was probably due to a publication bias. A significant association was found between etiology and seizure type: hemorrhage with autonomic seizures (P = 0.003), central nervous system (CNS) infection and stroke with clonic seizures (P = 0.042, P
Published: 2019

45. Autism and developmental disability caused by KCNQ3 gain-of-function variants

Author: Kavita Thakkar, François Rivier, Bitten Schönewolf-Greulich, Gaetan Lesca, Christine Francannet, Nicholas Stong, Sarah Weckhuysen, Vandana Shashi, Marjolaine Willems, Zeynep Tümer, David Goldstein, Daniel K. Arrington, Eric H. Kossoff, Anita E. Beck, Maria Virginia Soldovieri, Erin L. Heinzen, Edward C. Cooper, A. James Barkovich, Heather C Mefford, Francesco Miceli, Lynette G. Sadleir, Tristan T. Sands, Anna Lauritano, Amber Stocco, Ingrid E. Scheffer, Anne Marie Bisgaard, Ana Grijalvo Perez, Deepa S. Rajan, M. Roberta Cilio, Piera Nappi, Bénédicte Gérard, Sébastien Moutton, Maurizio Taglialatela, Antonio Vitobello, Jennifer A. Sullivan, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de neurologie pédiatrique, Sands, T. T., Miceli, F., Lesca, G., Beck, A. E., Sadleir, L. G., Arrington, D. K., Schonewolf-Greulich, B., Moutton, S., Lauritano, A., Nappi, P., Soldovieri, M. V., Scheffer, I. E., Mefford, H. C., Stong, N., Heinzen, E. L., Goldstein, D. B., Perez, A. G., Kossoff, E. H., Stocco, A., Sullivan, J. A., Shashi, V., Gerard, B., Francannet, C., Bisgaard, A. -M., Tumer, Z., Willems, M., Rivier, F., Vitobello, A., Thakkar, K., Rajan, D. S., Barkovich, A. J., Weckhuysen, S., Cooper, E. C., Taglialatela, M., Cilio, M. R., Columbia University Medical Center (CUMC), Columbia University [New York], 'Federico II' University of Naples Medical School, Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Pediatrics, University of Washington, Seattle, WA, USA., University of Otago [Dunedin, Nouvelle-Zélande], St. Luke's Children's Hospital, Department of Paediatrics and Adolescent Medicine, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Department of Neuroscience, University of Naples 'Federico II,' Naples, Italy., University of Molise, Epilepsy Research Centre, University of Melbourne, University of Washington, Columbia University Irving Medical Center (CUIMC), University of California [San Francisco] (UCSF), University of California, Johns Hopkins University School of Medicine [Baltimore], INTEGRIS Baptist Medical Center, School of Irish, Celtic Studies, Irish Folklore and Linguistics, University College Dublin [Dublin] (UCD), Duke University [Durham], Service d'hématologie et immunologie, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de Génétique Médicale, Hôtel-Dieu-CHU Clermont-Ferrand, Rigshospitalet [Copenhagen], Copenhagen University Hospital, Clinical genetic clinic, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Hospices Civils de Lyon (HCL), Centre de référence des épilepsies rares [CHU Pitié-Salpêtrière], Unité fonctionnelle d'épilepsie [CHU Pitié-Salpêtrière], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Service de Neurologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Antwerp, Antwerp, Belgium., Baylor College of Medecine, Section of Pharmacology, Università degli studi di Napoli Federico II, University of Naples 'Federico II,', University of Louvain, MORNET, Dominique, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Washington [Seattle], University of Naples Federico II = Università degli studi di Napoli Federico II, Università degli Studi del Molise = University of Molise (UNIMOL), Department of Pediatrics [Seattle], University of California [San Francisco] (UC San Francisco), University of California (UC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, University of Antwerp (UA), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Service de Neurologie [CHU Pitié-Salpêtrière], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: 0301 basic medicine, Male, Pediatrics, medicine.medical_specialty, Developmental Disabilities, [SDV]Life Sciences [q-bio], Encephalopathy, Electroencephalography, Protein Structure, Secondary, KCNQ3 Potassium Channel, 03 medical and health sciences, Epilepsy, Young Adult, 0302 clinical medicine, medicine, Humans, Global developmental delay, Amino Acid Sequence, Young adult, Autistic Disorder, Child, ComputingMilieux_MISCELLANEOUS, medicine.diagnostic_test, business.industry, Genetic Variation, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Clinical research, Neurology, Autism spectrum disorder, Child, Preschool, Gain of Function Mutation, Autism, Neurology (clinical), Human medicine, business, 030217 neurology & neurosurgery
Abstract: Objective Recent reports have described single individuals with neurodevelopmental disability (NDD) harboring heterozygous KCNQ3 de novo variants (DNVs). We sought to assess whether pathogenic variants in KCNQ3 cause NDD and to elucidate the associated phenotype and molecular mechanisms. Methods Patients with NDD and KCNQ3 DNVs were identified through an international collaboration. Phenotypes were characterized by clinical assessment, review of charts, electroencephalographic (EEG) recordings, and parental interview. Functional consequences of variants were analyzed in vitro by patch-clamp recording. Results Eleven patients were assessed. They had recurrent heterozygous DNVs in KCNQ3 affecting residues R230 (R230C, R230H, R230S) and R227 (R227Q). All patients exhibited global developmental delay within the first 2 years of life. Most (8/11, 73%) were nonverbal or had a few words only. All patients had autistic features, and autism spectrum disorder (ASD) was diagnosed in 5 of 11 (45%). EEGs performed before 10 years of age revealed frequent sleep-activated multifocal epileptiform discharges in 8 of 11 (73%). For 6 of 9 (67%) recorded between 1.5 and 6 years of age, spikes became near-continuous during sleep. Interestingly, most patients (9/11, 82%) did not have seizures, and no patient had seizures in the neonatal period. Voltage-clamp recordings of the mutant KCNQ3 channels revealed gain-of-function (GoF) effects. Interpretation Specific GoF variants in KCNQ3 cause NDD, ASD, and abundant sleep-activated spikes. This new phenotype contrasts both with self-limited neonatal epilepsy due to KCNQ3 partial loss of function, and with the neonatal or infantile onset epileptic encephalopathies due to KCNQ2 GoF. ANN NEUROL 2019;86:181-192
Published: 2019

46. Deciphering the complexity of the 4q and 10q subtelomeres by molecular combing in healthy individuals and patients with facioscapulohumeral dystrophy

Author: Vincent Tiffreau, Albert David, Jon Andoni Urtizberea, Charlene Chaix, Emmanuelle Salort-Campana, Rafaëlle Bernard, Sabrina Sacconi, Karine Nguyen, André Mégarbané, Fabien Zagnoli, Natacha Broucqsault, Jérôme D. Robin, Shahram Attarian, Frédérique Magdinier, Jean-Marie Cuisset, Véronique Manel, Laurene Gerard, Bruno Eymard, Stéphane Roche, Catherine Vovan, Mélanie Fradin, Nicolas Lévy, Christine Barnerias, Rémi Bellance, Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Marseille (APHM), Unité de Génétique Médicale, Université Saint-Joseph de Beyrouth (USJ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], MLab, Dauphine Recherches en Management (DRM), Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Service epilepsie sommeil et explorations fonctionnelles neuropédiatriques (HFME), Hospices Civils de Lyon (HCL)-Université de Lyon, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Activité Physique, Muscle, Santé (EA4488), Université de Lille, Droit et Santé, Service de Neurologie [Brest], Hôpital d'Instruction des Armées 'Clermont-Tonnerre' (HIA), Maladies Neuromusculaires de l'Enfant, Hôpital Roger Salengro [Lille], Centre de référence des maladies neuromusculaires et de la SLA, Hôpital de la Timone [CHU - APHM] (TIMONE), Roche, Stephane, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Genotype, Genetic counseling, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Locus (genetics), Biology, subtelomeres, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Homology (biology), 03 medical and health sciences, 0302 clinical medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Gene duplication, molecular combing, smchd1, Genetics, Humans, Genetic Predisposition to Disease, Genetics (clinical), Alleles, Genetic Association Studies, Chromosomes, Human, Pair 10, Haplotype, facio scapulo humeral dystrophy, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Dystrophy, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Telomere, Subtelomere, Muscular Dystrophy, Facioscapulohumeral, 3. Good health, Pedigree, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic Loci, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Chromosome Deletion, Chromosomes, Human, Pair 4, 030217 neurology & neurosurgery
Abstract: BackgroundSubtelomeres are variable regions between telomeres and chromosomal-specific regions. One of the most studied pathologies linked to subtelomeric imbalance is facioscapulohumeral dystrophy (FSHD). In most cases, this disease involves shortening of an array of D4Z4 macrosatellite elements at the 4q35 locus. The disease also segregates with a specific A-type haplotype containing a degenerated polyadenylation signal distal to the last repeat followed by a repetitive array of β-satellite elements. This classification applies to most patients with FSHD. A subset of patients called FSHD2 escapes this definition and carries a mutation in the SMCHD1 gene. We also recently described patients carrying a complex rearrangement consisting of a cis-duplication of the distal 4q35 locus identified by molecular combing.MethodsUsing this high-resolution technology, we further investigated the organisation of the 4q35 region linked to the disease and the 10q26 locus presenting with 98% of homology in controls and patients.ResultsOur analyses reveal a broad variability in size of the different elements composing these loci highlighting the complexity of these subtelomeres and the difficulty for genomic assembly. Out of the 1029 DNA samples analysed in our centre in the last 7 years, we also identified 54 cases clinically diagnosed with FSHD carrying complex genotypes. This includes mosaic patients, patients with deletions of the proximal 4q region and 23 cases with an atypical chromosome 10 pattern, infrequently found in the control population and never reported before.ConclusionOverall, this work underlines the complexity of these loci challenging the diagnosis and genetic counselling for this disease.
Published: 2018

47. Clinical and allelic heterogeneity in a pediatric cohort of 11 patients carrying MFN2 mutation

Author: Chloé Di Meglio, Brigitte Chabrol, Mathieu Milh, Caroline Ovaert, Christophe Boulay, Nicolas Lévy, Nathalie Bonello-Palot, Centre de référence maladie rare Thalassémie, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire de Génétique Moléculaire [Hôpital de la Timone - APHM], Département de génétique médicale [Hôpital de la Timone - APHM], Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Adaptations et évolution des systèmes ostéomusculaires (AESO), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN), Service de pédiatrie et neurologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de cardiologie Pédiatrique [Marseille], Hôpital de la Timone [CHU - APHM] (TIMONE), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Service de Neurologie Pédiatrique, Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), and Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, Pediatrics, Pathology, Subacute polyneuropathy, GTP Phosphohydrolases, Cohort Studies, 0302 clinical medicine, Charcot-Marie-Tooth Disease, Spastic, Family history, Child, medicine.diagnostic_test, General Medicine, Pedigree, 3. Good health, Phenotype, Child, Preschool, Female, Allelic heterogeneity, medicine.medical_specialty, Genotype, Respiratory chain deficiency, Mitochondrial Proteins, 03 medical and health sciences, Atrophy, Developmental Neuroscience, White matter lesion, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Charcot-Marie-Tooth (CMT), medicine, Humans, Optic atrophy, Genetic Testing, Allele, Alleles, Genetic testing, Muscle biopsy, business.industry, Infant, Membrane Proteins, medicine.disease, Neuropathy, 030104 developmental biology, Mitofusin 2 (MFN2), Pediatrics, Perinatology and Child Health, Histopathology, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: International audience; Introduction: The Mitofusin 2 gene (MFN2), which encodes a mitochondrial membrane protein, is known to be the first cause of autosomal dominant Charcot Marie Tooth disease type 2 (CMT2) with early onset. This gene is involved in typical CMT2A and in more atypical phenotypes as optic atrophy or spastic paraplegia. CMT2 refers to inherited axonal polyneuropathy, which associates progressive peripheral motor and sensory neuropathy, a family history consistent mainly with autosomal dominant inheritance, and normal nerve conduction velocities. Subjects: Between 1999 and 2012, the genetic diagnosis of MFN2 mutation was made in 11 children who were treated in our department for different neurological symptoms. All data including family and personal history data, results of standardized clinical and electrophysiology testing, brain magnetic resonance imaging (MRI), neuro-ophthalmic evaluation, muscle biopsy histopathology and molecular diagnosis were retrospectively analyzed. Results: Five different mutations were found in 6 unrelated families. Three of them have previously been described; the two remaining are new mutations: one of them related a new phenotype. Clinical signs appeared before the age of 6 years in more than half of the patients (54%). The motor deficit was predominant in 8 patients (72%). Two children presented an acute onset of disease that stabilized afterwards; the other children showed a more progressive deterioration that was managed symptomatically. Conclusion: This large pediatric study describes a great interfamilial and intrafamilial phenotypic variability. We recommend screening this gene in pediatric patient with chronic neurologic symptoms such as motor deficit or optic atrophy but also in acute neurologic deficiencies such as subacute polyradiculoneuritis. (C) 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Published: 2016

48. Long-Term Safety, Tolerability, and Efficacy of Cannabidiol in Children with Refractory Epilepsy: Results from an Expanded Access Program in the US

Author: Maria Roberta Cilio, Michael S. Oldham, Shahryar Rahdari, Eduardo Caminha Nunes, Nicole Tilton, Tristan T. Sands, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de neurologie pédiatrique
Subjects: Male, medicine.medical_specialty, Adolescent, Status epilepticus, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Status Epilepticus, Weight loss, Seizures, Internal medicine, Medicine, Cannabidiol, Humans, Pharmacology (medical), Prospective Studies, Adverse effect, Child, business.industry, Seizure types, Valproic Acid, Infant, medicine.disease, United States, 030227 psychiatry, Psychiatry and Mental health, Treatment Outcome, Tolerability, Expanded access, Child, Preschool, Anticonvulsants, Drug Therapy, Combination, Female, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: BACKGROUND: Purified cannabidiol is a new antiepileptic drug that has recently been approved for use in patients with Lennox-Gastaut and Dravet syndromes, but most published studies have not extended beyond 12-16 weeks. OBJECTIVE: The objective of this study was to evaluate the long-term safety, tolerability, and efficacy of cannabidiol in children with epilepsy. METHODS: Patients aged 1-17 years with refractory epilepsy were enrolled in an open-label prospective study through individual patient and expanded access programs between April 2013 and December 2014. Seizure types were video-electroencephalogram confirmed prior to enrollment. After a 28-day evaluation period, during which baseline seizure frequency was assessed, cannabidiol was given as add-on therapy at 5 mg/kg/day and titrated weekly by 5-mg/kg increments to a dose of 25 mg/kg/day. Blood tests were performed at baseline, after 1, 2, and 3 months, and every 3 months thereafter. Trough concentrations of concomitant antiepileptic drugs were measured at baseline, after 1, 2, and 3 months of therapy, and as clinically indicated afterwards. Concomitant antiepileptic drugs, ketogenic diet ratio, and vagal nerve stimulator settings remained unchanged during the baseline period and the first 3 months of treatment, unless there was a significant increase in plasma concentrations. Seizure frequency was reported daily in seizure diaries by parents or caregivers. Clinical assessments occurred after 15 days of treatment, at 1 month, at 3 months, and every 3 months thereafter. Diaries of seizure frequency and adverse events were reviewed at each visit. The primary efficacy outcome was a reduction in seizure frequency and responders were defined as those patients achieving a > 50% reduction in motor seizures. RESULTS: Twenty-six children were enrolled. Most had genetic epilepsies with daily or weekly seizures and multiple seizure types. All were refractory to prior antiepileptic drugs (range 4-11, mean 7), and were taking two antiepileptic drugs on average. Duration of therapy ranged from 4 to 53 months (mean 21 months). Adverse events were reported in 21 patients (80.8%), including reduced appetite in ten (38.4%), diarrhea in nine (34.6%), and weight loss in eight (30.7%). Four (15.4%) had changes in antiepileptic drug concentrations and three had elevated aspartate aminotransferase and alanine aminotransferase levels when cannabidiol was administered together with valproate. Serious adverse events, reported in six patients (23.1%), included status epilepticus in three, catatonia in two, and hypoalbuminemia in one. Fifteen patients (57.7%) discontinued cannabidiol for lack of efficacy, one because of status epilepticus, and one for severe weight loss. The retention rate declined rapidly in the first 6 months and more gradually thereafter. At 24 months, the number of patients continuing cannabidiol as adjunctive therapy was nine of the original 26 (34.6%). Of these patients, seven (26.9%) had a sustained > 50% reduction in motor seizures, including three (11.5%) who remain seizure free. CONCLUSION: Over a 4-year period, cannabidiol was effective in 26.9% of children with otherwise refractory epilepsy. It was well tolerated in about 20% of patients, but 80.8% had adverse events, including 23.1% with serious adverse events. Decreased appetite and diarrhea were frequent along with weight loss that became evident only later in the treatment.
Published: 2018

49. Response to antiseizure medications in neonates with acute symptomatic seizures

Author: Glass, Hannah C, Soul, Janet S, Chu, Catherine J, Massey, Shavonne L, Wusthoff, Courtney J, Chang, Taeun, Cilio, Maria Roberta, Bonifacio, Sonia L, Abend, Nicholas S, Thomas, Cameron, Lemmon, Monica, McCulloch, Charles E, Shellhaas, Renée A, Neonatal Seizure Registry study group, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de neurologie pédiatrique
Subjects: 0301 basic medicine, Male, neonatal seizures, Diseases, Neurodegenerative, Hypoxic Ischemic Encephalopathy, Infant, Newborn, Diseases, Epilepsy, antiepileptic drug, 0302 clinical medicine, AED, Medicine, hypoxic-ischemic encephalopathy, Prospective Studies, Prospective cohort study, Neonatal Seizure Registry study group, neonatal encephalopathy, Brain, Electroencephalography, respiratory system, Treatment Outcome, neurocritical care, Neurology, Anesthesia, Anticonvulsants, Female, seizure, Clinical Sciences, Encephalopathy, Loading dose, Article, 03 medical and health sciences, Seizures, Humans, Neurology & Neurosurgery, business.industry, Neonatal encephalopathy, Neurosciences, Infant, Newborn, Infant, Neurointensive care, Symptomatic seizures, electroencephalogram, Newborn, medicine.disease, Brain Disorders, Good Health and Well Being, 030104 developmental biology, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: In a prospective cohort of 534 neonates with acute symptomatic seizures, 66% had incomplete response to the initial loading dose of antiseizure medication (ASM). Treatment response did not differ by gestational age, sex, medication, or dose. The risk of incomplete response was highest for seizures due to intracranial hemorrhage and lowest for hypoxic-ischemic encephalopathy, although the difference was not significant after adjusting for high seizure burden and therapeutic hypothermia treatment. Future trial design may test ASMs in neonates with all acute symptomatic seizure etiologies and could target neonates with seizures refractory to an initial ASM.
Published: 2018

50. Molecular diagnosis of inherited peripheral neuropathies by targeted next-generation sequencing: molecular spectrum delineation

Author: Juliette Bacquet, Nathalie Martini, Emmanuelle Salort-Campana, Tanya Stojkovic, Jean-Pierre Desvignes, Annie Verschueren, Valérie Delague, Annabelle Chaussenot, Amandine Boyer, Shahram Attarian, Frédérique Audic, Nicolas Lévy, Emilien Delmont, Brigitte Chabrol, Nathalie Bonello-Palot, Laboratoire de Génétique Moléculaire [Hôpital de la Timone - APHM], Département de génétique médicale [Hôpital de la Timone - APHM], Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Institut de Myologie, Sorbonne Université (SU)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie Pédiatrique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de référence des maladies neuromusculaires et de la SLA, Hôpital de la Timone [CHU - APHM] (TIMONE), Service de génétique médicale, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Adult, Male, inherited peripheral neuropathies, Adolescent, DNA Copy Number Variations, Context (language use), Computational biology, Disease, Polymerase Chain Reaction, DNA sequencing, Cohort Studies, 03 medical and health sciences, symbols.namesake, Young Adult, 0302 clinical medicine, SH3TC2, Hereditary sensory and autonomic neuropathy, medicine, Humans, Copy-number variation, Child, ComputingMilieux_MISCELLANEOUS, Sanger sequencing, next generation sequencing, business.industry, Research, copy number variation, High-Throughput Nucleotide Sequencing, Infant, Peripheral Nervous System Diseases, Genetics and Genomics, General Medicine, Sequence Analysis, DNA, Middle Aged, medicine.disease, 3. Good health, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child, Preschool, Hereditary Diseases, Mutation, symbols, Female, business, 030217 neurology & neurosurgery
Abstract: PurposeInherited peripheral neuropathies (IPN) represent a large heterogenous group of hereditary diseases with more than 100 causative genes reported to date. In this context, targeted next-generation sequencing (NGS) offers the opportunity to screen all these genes with high efficiency in order to unravel the genetic basis of the disease. Here, we compare the diagnostic yield of targeted NGS with our previous gene by gene Sanger sequencing strategy. We also describe several novel likely pathogenic variants.Design and participantsWe have completed the targeted NGS of 81 IPN genes in a cohort of 123 unrelated patients affected with diverse forms of IPNs, mostly Charcot-Marie-Tooth disease (CMT): 23% CMT1, 52% CMT2, 9% distal hereditary motor neuropathy, 7% hereditary sensory and autonomic neuropathy and 6.5% intermediate CMT.ResultsWe have solved the molecular diagnosis in 49 of 123 patients (~40%). Among the identified variants, 26 variants were already reported in the literature. In our cohort, the most frequently mutated genes are respectively:MFN2,SH3TC2,GDAP1,NEFL,GAN,KIF5AandAARS. Panel-based NGS was more efficient in familial cases than in sporadic cases (diagnostic yield 49%vs19%, respectively). NGS-based search for copy number variations, allowed the identification of three duplications in three patients and raised the diagnostic yield to 41%. This yield is two times higher than the one obtained previously by gene Sanger sequencing screening. The impact of panel-based NGS screening is particularly important for demyelinating CMT (CMT1) subtypes, for which the success rate reached 87% (36% only for axonal CMT2).ConclusionNGS allowed to identify causal mutations in a shorter and cost-effective time. Actually, targeted NGS is a well-suited strategy for efficient molecular diagnosis of IPNs. However, NGS leads to the identification of numerous variants of unknown significance, which interpretation requires interdisciplinary collaborations between molecular geneticists, clinicians and (neuro)pathologists.
Published: 2018

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