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1. Somatotopy of cervical dystonia in motor-cerebellar networks: Evidence from resting state fMRI

Author: Marion Apoil Brissard, Cecile Gallea, Michael Rebsamen, Cecilia Bonnet, Aurélie Méneret, Clément Tarrano, Floriane Bouquet, Giuseppe Angelo Zito, Cécile Hubsch, Cécile Delorme, Sophie Sangla, Bertrand Degos, Benoît Béranger, Asya Ekmen, Marie Vidailhet, Emmanuel Roze, Yulia Worbe, and Prasanthi Jegatheesan
Subjects: Resting state fMRI, business.industry, medicine.disease, Magnetic Resonance Imaging, Basal Ganglia, Neurology, Dystonic Disorders, Cerebellum, medicine, Humans, Neurology (clinical), Cervical dystonia, Geriatrics and Gerontology, business, 610 Medicine & health, Neuroscience, Torticollis
Abstract: INTRODUCTION Cervical dystonia is the most frequent form of isolated focal dystonia. It is often associated with a dysfunction in brain networks, mostly affecting the basal ganglia, the cerebellum, and the somatosensory cortex. However, it is unclear if such a dysfunction is somato-specific to the brain areas containing the representation of the affected body part, and may thereby account for the focal expression of cervical dystonia. In this study, we investigated resting state functional connectivity in the areas within the motor cortex and the cerebellum containing affected and non-affected body representations in cervical dystonia patients. METHODS Eighteen patients affected by cervical dystonia and 21 healthy controls had resting state fMRI. The functional connectivity between the motor cortex and the cerebellum, as well as their corresponding measures of gray matter volume and cortical thickness, were compared between groups. We performed seed-based analyses, selecting the different body representation areas in the precentral gyrus as seed regions, and all cerebellar areas as target regions. RESULTS Compared to controls, patients exhibited increased functional connectivity between the bilateral trunk representation area of the motor cortex and the cerebellar vermis 6 and 7b, respectively. These functional abnormalities did not correlate with structural changes or symptom severity. CONCLUSIONS Our findings indicate that the abnormal function of the motor network is somato-specific to the areas encompassing the neck representation. Functional abnormalities in discrete relevant areas of the motor network could thus contribute to the focal expression of CD.
Published: 2022
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2. Long-term effect of apomorphine infusion in advanced Parkinson’s disease: a real-life study

Author: Nicolas Villain, Hélène Letrillart, Clara Virbel-Fleischman, Eavan McGovern, Pauline Dodet, Lise Mantisi, Emeline Berthelot, Elise Corsetti, Cécile Delorme, David Grabli, Emmanuel Roze, Elodie Hainque, Céline Louapre, Clément Tarrano, Mohamed Doulazmi, Florence Cormier-Dequaire, Yulia Worbe, Bertrand Degos, David Bendetowicz, Marie Vidailhet, Louise-Laure Mariani, Bruna Meira, Aurélie Méneret, Universidade de Lisboa = University of Lisbon (ULISBOA), Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital Pierre Zobda-Quitman [CHU de la Martinique], CHU de la Martinique [Fort de France], 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 de Pathologies du sommeil [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Gestionnaire, HAL Sorbonne Université 5, Universidade de Lisboa (ULISBOA), 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)-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 (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), Service des Pathologies du sommeil [CHU Pitié-Salpêtrière], and 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)
Subjects: Quality of life, 0301 basic medicine, medicine.medical_specialty, Parkinson's disease, Disease, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Internal medicine, medicine, Term effect, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], RC346-429, business.industry, medicine.disease, humanities, 3. Good health, Discontinuation, Apomorphine, 030104 developmental biology, Neurology, Tolerability, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology. Diseases of the nervous system, Neurology (clinical), Life study, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: Long-term effects of continuous subcutaneous apomorphine infusion (CSAI) on health-related quality of life (HRQoL) and predictors of CSAI discontinuation are poorly known. Data from consecutive advanced Parkinson’s disease patients treated in routine care were retrospectively collected over 24 months after CSAI initiation, with a focus on the 39-item Parkinson’s disease questionnaire (PDQ-39). We determined predictors of CSAI discontinuation and HRQoL improvement using multiple regression analysis. Of the 110 subjects evaluated over a 2-year period, 35% discontinued CSAI. Of those who continued treatment, HRQoL remained stable with a sustained reduction in motor fluctuations. The observed effect on dyskinesias was mild and transient. Of note, patients with preexisting impulse control disorders showed an overall good tolerability. PDQ-39 was the only baseline predictor of HRQoL improvement after 2 years of treatment. The presence of dyskinesias, poorer psychological status, shorter disease duration, male sex, and worse OFF state were predictors of discontinuation. Best candidates for CSAI are patients with: (i) poor baseline HRQoL and (ii) marked motor fluctuations.
Published: 2021

3. Renal Pathological Findings in Action Myoclonus-Renal Failure Syndrome

Author: Guy Touchard, Geoffroy Desbuissons, Jean-Michel Goujon, Isabelle Brocheriou, Corinne Isnard-Bagnis, and Aurélie Méneret
Subjects: Kidney, Mutation, Pathology, medicine.medical_specialty, medicine.diagnostic_test, business.industry, 030232 urology & nephrology, SCARB2, Disease, Progressive myoclonus epilepsy, 030204 cardiovascular system & hematology, urologic and male genital diseases, medicine.disease, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Focal segmental glomerulosclerosis, Biopsy, medicine, business, Pathological
Abstract: Action myoclonus – renal failure is a rare syndrome associated with a progressive myoclonic epilepsy and renal impairment that may lead to end-stage renal failure. It is an autosomal recessive genetic disease related to a loss-of-function mutation in SCARB2, which encodes for lysosomal integral membrane protein type 2. Renal involvement is poorly described, and we report here the first electron microscopy renal analysis after having performed a kidney biopsy in a 31-year-old Gambian patient.
Published: 2019

4. Sleep in ADCY5 -Related Dyskinesia: Prolonged Awakenings Caused by Abnormal Movements

Author: Diane Doummar, Isabelle Arnulf, Aurélie Méneret, Florence Riant, Pauline Dodet, Smaranda Leu-Semenescu, Eavan McGovern, Jean-Baptiste Maranci, Valérie Fraix, Emmanuel Roze, Mathieu Anheim, Christine Tranchant, Asya Ekmen, Marie Vidailhet, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hôpital Lariboisière-Fernand-Widal [APHP], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital de Hautepierre [Strasbourg], Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), CHU Grenoble, Institut des Neurosciences, and Université Joseph Fourier - Grenoble 1 (UJF)
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, Movement disorders, genetic structures, Nocturnal, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, mental disorders, medicine, chorea, sleep, Dystonia, ADCY5, business.industry, Chorea, Paroxysmal dyskinesia, medicine.disease, Sleep in non-human animals, dyskinesia, 030228 respiratory system, Neurology, Dyskinesia, Cardiology, dystonia, Neurology (clinical), medicine.symptom, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract: STUDY OBJECTIVES: ADCY5 mutations cause early-onset hyperkinetic movement disorders comprising diurnal and nocturnal paroxysmal dyskinesia, and patient-reported sleep fragmentation. We aimed to characterize all movements occurring during sleep and in the transition from sleep to awakening, to ascertain if there is a primary sleep disorder, or if the sleep disturbance is rather a consequence of the dyskinesia. METHODS: Using video polysomnography, we evaluated the nocturnal motor events and abnormal movements in 7 patients with ADCY5-related dyskinesia and compared their sleep measures with those of 14 age- and sex-matched healthy controls. RESULTS: We observed an increased occurrence of abnormal movements during wake periods compared to sleep in patients with ADCY5-related dyskinesia. While asleep, abnormal movements occurred more frequently during stage N2 and REM sleep, in contrast with stage N3 sleep. Abnormal movements were also more frequent during morning awakenings compared to wake periods before falling asleep. The pattern of the nocturnal abnormal movements mirrored those observed during waking hours. Compared to controls, patients with ADCY5-related dyskinesia had lower sleep efficiencies due to prolonged awakenings secondary to the abnormal movements, but no other differences in sleep measures. Notably, sleep onset latency was short and devoid of violent abnormal movements. CONCLUSIONS: In this series of patients with ADCY5-related dyskinesia, nocturnal paroxysmal dyskinesia were not associated with drowsiness or delayed sleep onset, but emerged during nighttime awakenings with subsequent delayed sleep, whereas sleep architecture was normal.
Published: 2019

5. Biallelic AOPEP Loss‐of‐Function Variants Cause Progressive Dystonia with Prominent Limb Involvement

Author: Aurélie Méneret, Manju A. Kurian, Michael C. Kruer, Alexander P. Drew, Niccolo E. Mencacci, Jean Madeleine de Sainte Agathe, Juliane Winkelmann, Lisa G. Riley, Sylvia Boesch, Saskia Biskup, Pedro Gonzalez-Alegre, Sheng Chih Jin, Janine Reunert, Sophie Reining, Kishore R. Kumar, Matthias Baumann, Riccardo Berutti, Fabienne Clot, Marie Vidailhet, Victor S.C. Fung, Thorsten Marquardt, Steven J. Lubbe, Robert Adam, Somayeh Bakhtiari, Tanya Bardakjian, Nicolas Derive, Ignacio Juan Keller Sarmiento, Michel Tchan, Michael Zech, Helmholtz Zentrum München = German Research Center for Environmental Health, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Concord Repatriation General Hospital, The University of Sydney, Garvan Institute of medical research, University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Westmead Hospital [Sydney], Royal Brisbane & Women's Hospital, University of Queensland [Brisbane], Centre for Clinical Research [Brisbane], CeGaT GmbH, Barrow Neurological Institute, University of Arizona, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Perelman School of Medicine, University of Pennsylvania, Northwestern University Feinberg School of Medicine, Institute of Child Health [London], University College of London [London] (UCL), Great Ormond Street Hospital for Children [London] (GOSH), Unité fonctionnelle de neurogénétique moléculaire et cellulaire, 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), 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), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Munich Cluster for systems neurology [Munich] (SyNergy), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU), Gestionnaire, Hal Sorbonne Université, Helmholtz-Zentrum München (HZM), Technische Universität München [München] (TUM), Garvan Institute of Medical Research [Darlinghurst, Australia], University of Pennsylvania [Philadelphia], 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], 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), Innsbruck Medical University [Austria] (IMU), and Technische Universität München [München] (TUM)-Ludwig-Maximilians-Universität München (LMU)
Subjects: Proband, Movement disorders, AOPEP, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, rare disease, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Compound heterozygosity, loss-of-function variants, Aminopeptidases, Aopep, Genomic Analysis, Loss-of-function Variants, Monogenic Dystonia, Rare Disease, Frameshift mutation, 03 medical and health sciences, 0302 clinical medicine, Loss of Function Mutation, medicine, Humans, Exome, Allele, 030304 developmental biology, Dystonia, Genetics, 0303 health sciences, Parkinsonism, Proteolytic enzymes, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, Pedigree, Phenotype, Neurology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Dystonic Disorders, genomic analysis, Mutation, Neurology (clinical), medicine.symptom, 030217 neurology & neurosurgery, monogenic dystonia
Abstract: BACKGROUND Monogenic causes of isolated dystonia are heterogeneous. Assembling cohorts of affected individuals sufficiently large to establish new gene-disease relationships can be challenging. OBJECTIVE We sought to expand the catalogue of monogenic etiologies for isolated dystonia. METHODS After the discovery of a candidate variant in a multicenter exome-sequenced cohort of affected individuals with dystonia, we queried online platforms and genomic data repositories worldwide to identify subjects with matching genotypic profiles. RESULTS Seven different biallelic loss-of-function variants in AOPEP were detected in five probands from four unrelated families with strongly overlapping phenotypes. In one proband, we observed a homozygous nonsense variant (c.1477C>T [p.Arg493*]). A second proband harbored compound heterozygous nonsense variants (c.763C>T [p.Arg255*]; c.777G>A [p.Trp259*]), whereas a third proband possessed a frameshift variant (c.696_697delAG [p.Ala234Serfs*5]) in trans with a splice-disrupting alteration (c.2041-1G>A). Two probands (siblings) from a fourth family shared compound heterozygous frameshift alleles (c.1215delT [p.Val406Cysfs*14]; c.1744delA [p.Met582Cysfs*6]). All variants were rare and expected to result in truncated proteins devoid of functionally important amino acid sequence. AOPEP, widely expressed in developing and adult human brain, encodes a zinc-dependent aminopeptidase, a member of a class of proteolytic enzymes implicated in synaptogenesis and neural maintenance. The probands presented with disabling progressive dystonia predominantly affecting upper and lower extremities, with variable involvement of craniocervical muscles. Dystonia was unaccompanied by any additional symptoms in three families, whereas the fourth family presented co-occurring late-onset parkinsonism. CONCLUSIONS Our findings suggest a likely causative role of predicted inactivating biallelic AOPEP variants in cases of autosomal recessive dystonia. Additional studies are warranted to understand the pathophysiology associated with loss-of-function variation in AOPEP. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Published: 2021

6. Isolated parkinsonism is an atypical presentation of GRN and C9orf72 gene mutations Authors

Author: Florence Cormier, Timothée Lenglet, Alexis Brice, Jean-Christophe Corvol, Fabienne Clot, Vincent Deramecourt, Karl Mondon, Dario Saracino, Stéphane Thobois, Vincent Huin, Aurélie Méneret, Emilie Beaufils, Cécile Delorme, Audrey Gabelle, Fábio Carneiro, Marie Vidailhet, Isabelle Le Ber, Mélissa Tir, Marie-Odile Habert, Daniela Andriuta, 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], 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), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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)-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), Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), UF Neurométabolique Bioclinique et Génétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), 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), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Département de neurologie [Montpellier], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Tours (UT), Service de neurologie [Amiens], CHU Amiens-Picardie, Excellence Laboratory LabEx DISTALZ, The research leading to these results received funding from the 'Investissements d'avenir' ANR-11-INBS-0011. This work was funded by the Programme Hospitalier de Recherche Clinique (PHRC) FTLD-exome (to ILB, promotion by Assistance Publique – Hôpitaux de Paris) and by PHRC Predict-PGRN (to ILB, promotion by Assistance Publique – Hôpitaux de Paris)., 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), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), 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)-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)-Centre National de la Recherche Scientifique (CNRS), Lille Neurosciences & Cognition - U 1172 (LilNCog), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Imagerie Biomédicale [Paris] (LIB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), ANR-16-IDEX-0006,MUSE,MUSE(2016), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Gestionnaire, HAL Sorbonne Université 5, Service de neurologie 1 [CHU Pitié-Salpétrière], Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Tours
Subjects: Male, 0301 basic medicine, Parkinson's disease, TDP-43, Disease, Bioinformatics, Progranulins, 0302 clinical medicine, C9orf72, Age of Onset, Family history, PSP, Parkinsonism, Parkinson Disease, FTD, Middle Aged, Pedigree, 3. Good health, Neurology, Frontotemporal Dementia, Neurons and Cognition (q-bio.NC), [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], FTLD, GRN, Frontotemporal dementia, CBS, 03 medical and health sciences, Parkinsonian Disorders, medicine, Humans, Dementia, Cognitive Dysfunction, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Aged, C9orf72 Protein, business.industry, medicine.disease, nervous system diseases, 030104 developmental biology, Quantitative Biology - Neurons and Cognition, FOS: Biological sciences, Mutation, Etiology, Neurology (clinical), Geriatrics and Gerontology, business, 030217 neurology & neurosurgery
Abstract: Introduction A phenotype of isolated parkinsonism mimicking Idiopathic Parkinson's Disease (IPD) is a rare clinical presentation of GRN and C9orf72 mutations, the major genetic causes of frontotemporal dementia (FTD). It still remains controversial if this association is fortuitous or not, and which clinical clues could reliably suggest a genetic FTD etiology in IPD patients. This study aims to describe the clinical characteristics of FTD mutation carriers presenting with IPD phenotype, provide neuropathological evidence of the mutation's causality, and specifically address their “red flags” according to current IPD criteria. Methods Seven GRN and C9orf72 carriers with isolated parkinsonism at onset, and three patients from the literature were included in this study. To allow better delineation of their phenotype, the presence of supportive, exclusion and “red flag” features from MDS criteria were analyzed for each case. Results Amongst the ten patients (5 GRN, 5 C9orf72), seven fulfilled probable IPD criteria during all the disease course, while behavioral/language or motoneuron dysfunctions occurred later in three. Disease duration was longer and dopa-responsiveness was more sustained in C9orf72 than in GRN carriers. Subtle motor features, cognitive/behavioral changes, family history of dementia/ALS were suggestive clues for a genetic diagnosis. Importantly, neuropathological examination in one patient revealed typical TDP-43-inclusions without alpha-synucleinopathy, thus demonstrating the causal link between FTD mutations, TDP-43-pathology and PD phenotype. Conclusion We showed that, altogether, family history of early-onset dementia/ALS, the presence of cognitive/behavioral dysfunction and subtle motor characteristics are atypical features frequently present in the parkinsonian presentations of GRN and C9orf72 mutations.
Published: 2020

7. Current challenges in the pathophysiology, diagnosis, and treatment of paroxysmal movement disorders

Author: Cécile Delorme, Aurélie Méneret, Emmanuel Roze, Camille Giron, David Bendetowicz, and Louise-Laure Mariani
Subjects: Pediatrics, medicine.medical_specialty, Movement disorders, Monosaccharide Transport Proteins, medicine.medical_treatment, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Chorea, otorhinolaryngologic diseases, Medicine, Humans, Pharmacology (medical), Episodic ataxia, ADCY5, Movement Disorders, business.industry, General Neuroscience, fungi, Genetic disorder, food and beverages, Paroxysmal dyskinesia, medicine.disease, 030227 psychiatry, Triheptanoin, chemistry, Mutation, Ataxia, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, PRRT2, Ketogenic diet, Carbohydrate Metabolism, Inborn Errors
Abstract: Paroxysmal movement disorders mostly comprise paroxysmal dyskinesia and episodic ataxia, and can be the consequence of a genetic disorder or symptomatic of an acquired disease.In this review, the authors focused on certain hot-topic issues in the field: the respective contribution of the cerebellum and striatum to the generation of paroxysmal dyskinesia, the importance of striatal cAMP turnover in the pathogenesis of paroxysmal dyskinesia, the treatable causes of paroxysmal movement disorders not to be missed, with a special emphasis on the treatment strategy to bypass the glucose transport defect in paroxysmal movement disorders due to GLUT1 deficiency, and functional paroxysmal movement disorders.Treatment of genetic causes of paroxysmal movement disorders is evolving towards precision medicine with targeted gene-specific therapy. Alteration of the cerebellar output and modulation of the striatal cAMP turnover offer new perspectives for experimental therapeutics, at least for paroxysmal movement disorders due to selected causes. Further characterization of cell-specific molecular pathways or network dysfunctions that are critically involved in the pathogenesis of paroxysmal movement disorders will likely result in the identification of new biomarkers and testing of innovative-targeted therapeutics.
Published: 2020

8. Systematic review of movement disorders and oculomotor abnormalities in Whipple's disease

Author: Aurélie Méneret, Anthony E. Lang, Melanie Anderson, David Grabli, Emmanuel Roze, and Julien Bally
Subjects: medicine.medical_specialty, Movement disorders, business.industry, Disease, medicine.disease, Oculomotor abnormalities, 03 medical and health sciences, 0302 clinical medicine, Neurology, Pathognomonic, medicine, 030212 general & internal medicine, Neurology (clinical), Whipple's disease, medicine.symptom, Intensive care medicine, business, Myoclonus, 030217 neurology & neurosurgery, Confusion
Abstract: Whipple's disease, affecting the CNS, can cause a wide variety of symptoms. Movement disorders are very prevalent, and some are pathognomonic of the disease. This systematic review analyzed all published cases of movement disorders because of CNS Whipple's disease, providing detailed information on clinical and associated features. We have also attempted to address sources of confusion in the literature, particularly related to differing uses of the terminology of movement disorder. This comprehensive overview of Whipple's disease-induced movement disorders aims to aid neurologists in recognizing this very rare disorder and successfully reaching a laboratory-confirmed diagnosis in order to initiate appropriate therapy. © 2018 International Parkinson and Movement Disorder Society.
Published: 2018

9. Increased diagnostic yield in complex dystonia through exome sequencing

Author: Jamel Chelly, Cécile Laroche, Aurélie Méneret, Pierre Burbaud, Emmanuelle Ollivier, Marie-Aude Spitz, Cyril Mignot, Matthieu Bereau, Laurence Lion-François, Christine Tranchant, Mathieu Anheim, Emmanuel Roze, Diane Doummar, Laura Cif, Gabrielle Rudolf, Romain Lefaucheur, Stéphanie Bannier, Thomas Wirth, Domitille Gras, Nathalie Drouot, Vincent Laugel, Patrick Nitschke, Ouhaid Lagha-Boukbiza, Boris Keren, 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], 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), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
Subjects: 0301 basic medicine, Adult, Male, Movement disorders, [SDV]Life Sciences [q-bio], Bioinformatics, GNAO1, DNA sequencing, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Exome Sequencing, medicine, Humans, Genetic Testing, Age of Onset, Exome, Exome sequencing, Aged, Dystonia, business.industry, High-Throughput Nucleotide Sequencing, Infant, medicine.disease, Reelin Protein, 030104 developmental biology, Phenotype, Neurology, Dystonic Disorders, Child, Preschool, Neurology (clinical), Geriatrics and Gerontology, medicine.symptom, Age of onset, business, 030217 neurology & neurosurgery, ADCK3
Abstract: A strategy based on targeted gene panel sequencing identifies possibly pathogenic variants in fewer than 20% of cases in early-onset and familial form of dystonia. By using Whole Exome Sequencing (WES), we aimed to identify the missing genetic causes in dystonic patients without diagnosis despite gene panel sequencing.WES was applied to DNA samples from 32 patients with early-onset or familial dystonia investigated by sequencing of a 127 movement disorders-associated gene panel. Dystonia was described according to the familial history, body distribution, evolution pattern, age of onset, associated symptoms and associated movement disorders. Rate of diagnoses was evaluated for each clinical feature.We identified causative variants for 11 patients from 9 families in CTNNB1, SUCLG1, NUS1, CNTNAP1, KCNB1, RELN, GNAO1, HIBCH, ADCK3 genes, yielding an overall diagnostic rate of 34.4%. Diagnostic yield was higher in complex dystonia compared to non-complex dystonia (66.7%-5.9%; p 0.002), especially in patients showing intellectual disability compared to the patients without intellectual disability (87.5%-16.7%; p 0.002).Our approach suggests WES as an efficient tool to improve the diagnostic yield after gene panel sequencing in dystonia. Larger study are warranted to confirm a potential genetic overlap between neurodevelopmental diseases and dystonia.
Published: 2019

10. Dystonia: genetics, phenomenology, and pathophysiology

Author: Marie Vidailhet, Emmanuel Roze, and Aurélie Méneret
Subjects: Dystonia, business.industry, Medicine, Neurology (clinical), business, medicine.disease, Neuroscience, Exome, Phenomenology (psychology), Exome sequencing
Published: 2020

11. Transition from ketogenic diet to triheptanoin in patients with GLUT1 deficiency syndrome

Author: Aurélie Méneret, Emmanuel Roze, Thierry Billette de Villemeur, Chris Ottolenghi, Fanny Mochel, Magali Barbier, Mariana Atencio, Domitille Gras, Elodie Hainque, Anne de Saint Martin, and Marie-Pierre Luton
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Deficiency syndrome, Movement disorders, Adolescent, Monosaccharide Transport Proteins, medicine.medical_treatment, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, 0302 clinical medicine, Medicine, Humans, In patient, Confusion, Fatigue, Triglycerides, Triglyceride, business.industry, Dysarthria, Paroxysmal dyskinesia, medicine.disease, Triheptanoin, Psychiatry and Mental health, Dystonia, chemistry, Surgery, Ataxia, Female, Neurology (clinical), Ketosis, medicine.symptom, business, Diet, Ketogenic, 030217 neurology & neurosurgery, Ketogenic diet, Carbohydrate Metabolism, Inborn Errors
Abstract: Glucose transporter type 1 deficiency syndrome (GLUT1-DS) causes cerebral energy deficiency due to altered transport of glucose across the blood brain barrier and into astrocytes.1 Its main phenotype combines developmental delay, permanent motor dysfunction and paroxysmal neurological manifestations.1 In addition, GLUT1-DS may solely consist of paroxysmal manifestations such as seizures or exercise-induced paroxysmal dyskinesia. Ketogenic diet is the primary treatment of GLUT1-DS with clear efficacy on seizures and non-epileptic motor manifestations,1 but it has severe constraints. Ketogenic diet failure has been occasionally reported due to poor tolerance, inefficacy or failure to achieve ketosis,2 emphasising the need for alternative therapeutic options. Triheptanoin is a triglyceride containing three 7-carbon fatty acids, which provides acetyl-coenzyme A (CoA) and propionyl-CoA, two key carbon sources for the Krebs cycle.3 Treatment with triheptanoin resulted in a dramatic and sustained reduction of non-epileptic paroxysmal events in a group of GLUT1-DS patients who were not on ketogenic diet.4 5 Here, we evaluated the long-term effect of triheptanoin in four GLUT1-DS patients with persistent paroxysmal manifestations while on ketogenic diet. We enrolled four GLUT1-DS patients (table 1) who reported persistent paroxysmal events while on ketogenic diet (trial registration number NCT02014883). Three adults and one child’s legal guardian signed a written informed consent for participation in this study sponsored by INSERM. View this table: Table 1 Baseline characteristics of GLUT1-DS patients and changes in outcome variables The study was divided into baseline, transition from ketogenic diet to triheptanoin (transition), short-term evolution (short term) and long-term follow-up (long term) with triheptanoin. A flow …
Published: 2019

12. Biallelic MYORG mutation carriers exhibit primary brain calcification with a distinct phenotype

Author: Grangeon, Lou, Charbonnier, Camille, Quenez, Olivier, Rousseau, Stéphane, Budowski, Clara, Corbillé, Anne-Gaëlle, Antoine, Jean-Christophe, Clanet, Michel, Rovelet-Lecrux, Anne, Boland, Anne, Deleuze, Jean-François, Favrole, Pascal, Verny, Christophe, Krystkowiak, Pierre, Chamard, Ludivine, Moutton, Sébastien, Goizet, Cyril, Ferec, Claude, Timsit, Serge, Schaeffer, Stéphane, Derache, Nathalie, Defer, Gilles, Durif, Franck, Sellal, François, Rouaud, Olivier, Thauvin-Robinet, Christel, Cubizolle, Stéphanie, Sauvée, Mathilde, Leblanc, Amélie, Demas, Alexis, POISSON, Alice, Tournier-Lasserve, Elisabeth, Hervé, Dominique, Chabriat, Hugues, Grolez, Guillaume, Carrière, Nicolas, Defebvre, Luc, Lebouvier, Thibaud, Witjas, Tatiana, Azulay, Jean-Philippe, Fluchère, Frédérique, Didic, Mira, Nguyen, Karine, Charif, Mahmoud, Ayrignac, Xavier, Labauge, Pierre, Lionnet, Caroline, Marelli-Tosi, Cecilia, GAUD, Simon, Rouaud, Tiphaine, Laurens, Brice, Folgoas, Emmanuelle, Isidor, Bertrand, Chiesa, Jean, Pallix-Guyot, Maud, Gaillard, Nicolas, Olivier, Nadège, Jurici, Snejana, Marey, Isabelle, Charles, Perrine, Ewenczyck, Claire, Dürr, Alexandra, Hubsch, Cécile, Méneret, Aurélie, Vidailhet, Marie, Nadjar, Yann, Le Ber, Isabelle, Grabli, David, Roze, Emmanuel, Navarro, Vincent, Mecharles-Darrigol, Sylvie, Lagarde, Julien, Sarazin, Marie, Vérin, Marc, Lefaucheur, Romain, Maltête, David, Wallon, David, Martinaud, Olivier, Guyant-Maréchal, Lucie, Richard, Anne-claire, Guillin, Olivier, Yger, Marion, Anheim, Mathieu, Renaud, Mathilde, Tranchant, Christine, Rudolf, Gabrielle, Cretin, Benjamin, Mallaret, Martial, Pariente, Jérémie, Ory-Magne, Fabienne, Frebourg, Thierry, Hannequin, Didier, Campion, Dominique, Nicolas, Gaël, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Fer à Moulin, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Neurologie, CHU Saint-Etienne-Hôpital Bellevue, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Biologie Neurovasculaire Intégrée (BNVI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Service de neurochirurgie générale et stéréotaxique fonctionnelle, Hôpital Roger Salengro-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Mémoire de Ressources et de Recherche - CMRR [Besançon] (CMRR), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), 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 génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Génétique moléculaire et génétique épidémiologique, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Neurologie [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 neurologie, Hôpital Gabriel Montpied, Hôpital pasteur [Colmar], Université Montpellier 1 (UM1)-Hôpital Guy de Chauliac-Centre Mémoire Ressources Recherche Languedoc - Roussillon, Centre Hospitalier Universitaire [Grenoble] (CHU), Hôpital d'Instruction des Armées 'Clermont-Tonnerre' (HIA), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Genetique des Maladies Vasculaires, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Gouvernance, Risque, Environnement, Développement (GRED), Université Paul-Valéry - Montpellier 3 (UM3)-Institut de Recherche pour le Développement (IRD [France-Sud])-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de neurologie et pathologie du mouvement, Hôpital Roger Salengro-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Troubles cognitifs dégénératifs et vasculaires (U1171), INSERM-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille, Neuropathies du système nerveux entérique et pathologies digestives, implication des cellules gliales entériques, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie et de neuropsychologie, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), 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), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de neurologie [Montpellier], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Université de Lorraine (UL), Service de neurologie [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Bordeaux (UB), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Centre Hospitalier Régional d'Orléans (CHR), Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-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), CHU Pitié-Salpêtrière [APHP], 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), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Fédération des Maladies du Système Nerveux, Laboratoire de neurosciences cognitives et d'imagerie cérébrale (LENA), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Efficience Déficience Motrice [Montpellier] (EDM), Université Montpellier 1 (UM1), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU), Service des Urgences Cérébro-Vasculaires [CHU Pitié-Salpêtrière]], CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Strasbourg, Département de Neurologie, CHU Strasbourg-Hopital Civil, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et nanosciences d'Alsace, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Université de Strasbourg (UNISTRA)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Université de Strasbourg (UNISTRA), Imagerie cérébrale et handicaps neurologiques, 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-Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-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)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CIC Toulouse, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Département de neurologie [Lille], Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], 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), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [Aix-en-Provence], Centre Hospitalier du Pays d'Aix, Service de Neurologie [CHU de Saint-Étienne], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Neurologie Vasculaire [Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Différenciation et communication neuronale et neuroendocrine (DC2N), Institut de Biologie François JACOB (JACOB), 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), ANR-17-CE14-0008,CALCIPHOS,ROLE DE L'EXPORTATEUR DE PHOSPHATE DANS LA CALCIFICATION VASCULAIRE(2017), Département de neurologie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), 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), Service de neurologie [CHU de Saint-Étienne], Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Laboratoire de Neurosciences Fonctionnelles et Pathologies, Hôpital Roger Salengro-PRES Université Lille Nord de France-EA 4559/1046-Université de Lille, Droit et Santé, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), and Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)
Subjects: 0301 basic medicine, Proband, Adult, Male, Pathology, medicine.medical_specialty, Heterozygote, Glycoside Hydrolases, [SDV]Life Sciences [q-bio], PDGFRB, medicine.disease_cause, Nervous System Malformations, MESH: phenotype, computed tomography, mutation, genes, pons, brain, autosomal recessive inheritance, cerebellar atrophy, calcification, 03 medical and health sciences, Young Adult, 0302 clinical medicine, medicine, Humans, ComputingMilieux_MISCELLANEOUS, Mutation, Brain Diseases, PDGFB, business.industry, Brain, Calcinosis, Middle Aged, medicine.disease, Penetrance, 3. Good health, Pedigree, 030104 developmental biology, Phenotype, Cerebellar atrophy, Female, Neurology (clinical), Age of onset, business, Xenotropic and Polytropic Retrovirus Receptor, 030217 neurology & neurosurgery, Calcification
Abstract: International audience; Primary familial brain calcification (PFBC) is a rare neurogenetic disorder with diverse neuropsychiatric expression. Mutations in four genes cause autosomal dominant PFBC: SLC20A2, XPR1, PDGFB and PDGFRB. Recently, biallelic mutations in the MYORG gene have been reported to cause PFBC with an autosomal recessive pattern of inheritance. We screened MYORG in 29 unrelated probands negatively screened for the autosomal dominant PFBC genes and identified 11 families with a biallelic rare or novel predicted damaging variant. We studied the clinical and radiological features of 16 patients of these 11 families and compared them to that of 102 autosomal dominant PFBC patients carrying a mutation in one of the four known autosomal dominant PFBC genes. We found that MYORG patients exhibited a high clinical penetrance with a median age of onset of 52 years (range: 21–62) with motor impairment at the forefront. In particular, dysarthria was the presenting sign in 11/16 patients. In contrast to patients with autosomal dominant PFBC, 12/15 (80%) symptomatic patients eventually presented at least four of the following five symptoms: dysarthria, cerebellar syndrome, gait disorder of any origin, akinetic-hypertonic syndrome and pyramidal signs. In addition to the most severe clinical pattern, MYORG patients exhibited the most severe pattern of calcifications as compared to the patients from the four autosomal dominant PFBC gene categories. Strikingly, 12/15 presented with brainstem calcifications in addition to extensive calcifications in other brain areas (lenticular nuclei, thalamus, cerebellar hemispheres, vermis, ±cortex). Among them, eight patients exhibited pontine calcifications, which were observed in none of the autosomal dominant PFBC patients and hence appeared to be highly specific. Finally, all patients exhibited cerebellar atrophy with diverse degrees of severity on CT scans. We confirmed the existence of cerebellar atrophy by performing MRI voxel-based morphometry analyses of MYORG patients with autosomal dominant PFBC mutation carriers as a comparison group. Of note, in three families, the father carried small pallido-dentate calcifications while carrying the mutation at the heterozygous state, suggesting a putative phenotypic expression in some heterozygous carriers. In conclusion, we confirm that MYORG is a novel major PFBC causative gene and that the phenotype associated with such mutations may be recognized based on pedigree, clinical and radiological features.
Published: 2019

13. GLUT1 Deficiency in a Patient Diagnosed as Cerebral Palsy: Is NGS a Valuable Tool to Be Considered in All Cases of CP to Detect Underlying Genetic Disorders?

Author: Emmanuel Roze and Aurélie Méneret
Subjects: Pediatrics, medicine.medical_specialty, Editorial Commentary, Neurology, business.industry, Medicine, Neurology (clinical), business, medicine.disease, Cerebral palsy
Published: 2019

14. ADCY5-related dyskinesia

Author: David Grabli, Wendy H. Raskind, Oriane Trouillard, Steven Parrish Winesett, Domitille Gras, Thomas D. Bird, Bertrand Degos, Marie Y. Davis, Nathalie Damon-Perrière, Emily Bonkowski, Cyril Mignot, Phillip D. Swanson, Laura M. Amendola, Alona Gad, Michael O. Dorschner, Aurélie Méneret, Jennifer Friedman, Christine Tranchant, Marie Vidailhet, Evan E. Eichler, Holly A.F. Stessman, Mathieu Anheim, Ali Torkamani, Saunder Bernes, Dong Hui Chen, Olena Korvatska, Fuki M. Hisama, Katherine M. Mackenzie, Diane Doummar, Michael D. Weiss, and Emmanuel Roze
Subjects: Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Genotype, Bioinformatics, Article, Young Adult, medicine, Humans, Child, Aged, Aged, 80 and over, Genetics, Dystonia, Dyskinesias, ADCY5, Chorea, Middle Aged, Paroxysmal dyskinesia, medicine.disease, Hypotonia, Pedigree, nervous system diseases, Hyperkinetic disorder, Phenotype, Dyskinesia, Child, Preschool, Female, Neurology (clinical), medicine.symptom, Psychology, Myoclonus, Adenylyl Cyclases
Abstract: Objective: To investigate the clinical spectrum and distinguishing features of adenylate cyclase 5 ( ADCY5 )–related dyskinesia and genotype–phenotype relationship. Methods: We analyzed ADCY5 in patients with choreiform or dystonic movements by exome or targeted sequencing. Suspected mosaicism was confirmed by allele-specific amplification. We evaluated clinical features in our 50 new and previously reported cases. Results: We identified 3 new families and 12 new sporadic cases with ADCY5 mutations. These mutations cause a mixed hyperkinetic disorder that includes dystonia, chorea, and myoclonus, often with facial involvement. The movements are sometimes painful and show episodic worsening on a fluctuating background. Many patients have axial hypotonia. In 2 unrelated families, a p.A726T mutation in the first cytoplasmic domain (C1) causes a relatively mild disorder of prominent facial and hand dystonia and chorea. Mutations p.R418W or p.R418Q in C1, de novo in 13 individuals and inherited in 1, produce a moderate to severe disorder with axial hypotonia, limb hypertonia, paroxysmal nocturnal or diurnal dyskinesia, chorea, myoclonus, and intermittent facial dyskinesia. Somatic mosaicism is usually associated with a less severe phenotype. In one family, a p.M1029K mutation in the C2 domain causes severe dystonia, hypotonia, and chorea. The progenitor, whose childhood-onset episodic movement disorder almost disappeared in adulthood, was mosaic for the mutation. Conclusions: ADCY5 -related dyskinesia is a childhood-onset disorder with a wide range of hyperkinetic abnormal movements. Genotype-specific correlations and mosaicism play important roles in the phenotypic variability. Recurrent mutations suggest particular functional importance of residues 418 and 726 in disease pathogenesis.
Published: 2015

15. Comparing ataxias with oculomotor apraxia: a multimodal study of AOA1, AOA2 and AT focusing on video-oculography and alpha-fetoprotein

Author: Michel Koenig, Elodie Hainque, Alexis Brice, Marie-Céline Fleury, D. Grabli, Mathieu Anheim, Marie Vidailhet, P. Charles, Sophie Rivaud-Péchoux, Bertrand Gaymard, Louise-Laure Mariani, I. Le Ber, Bertrand Degos, Aurélie Méneret, Andoni Echaniz-Laguna, Emmanuel Roze, Mathilde Renaud, Dominique Stoppa-Lyonnet, Thierry Maisonobe, Christine Tranchant, Thomas Wirth, Claire Ewenczyk, C. Dubois-d’Enghien, Alexandra Durr, Bondo Ben Monga, 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 [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), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], 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 de référence des maladies rares neuromusculaires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Neuroradiologie [CHU Pitié-Salpêtrière], Université de Strasbourg (UNISTRA), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Centre expert inter-régional de coordination de la maladie de Parkinson [CHU Pitié-Salpêtrière], Institut Curie [Paris], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Service de Neurophysiologie [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)-Centre National de la Recherche Scientifique (CNRS), 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 de référence des maladies rares neuromusculaires [CHU Pitié-Salpétriêre], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Strasbourg, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Movement disorders, Ataxia, Adolescent, genetic structures, Apraxias, [SDV]Life Sciences [q-bio], lcsh:Medicine, Audiology, Multimodal Imaging, Article, Ataxia Telangiectasia, 03 medical and health sciences, 0302 clinical medicine, Hypometric saccades, medicine, Cogan Syndrome, Humans, Oculomotor apraxia, Child, lcsh:Science, Multidisciplinary, business.industry, lcsh:R, Middle Aged, medicine.disease, 3. Good health, 030104 developmental biology, Child, Preschool, Ataxia-telangiectasia, Fixation (visual), Spinocerebellar ataxia, Female, lcsh:Q, Cerebellar atrophy, alpha-Fetoproteins, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: International audience; Whether the recessive ataxias, Ataxia with oculomotor apraxia type 1 (AOA1) and 2 (AOA2) and Ataxia telangiectasia (AT), can be distinguished by video-oculography and alpha-fetoprotein level remains unknown. We compared 40 patients with AOA1, AOA2 and AT, consecutively referred between 2008 and 2015 with 17 healthy subjects. Video-oculography revealed constant impairments in patients such as cerebellar signs, altered fixation, impaired pursuit, hypometric saccades and abnormal antisaccades. Horizontal saccade latencies could be highly increased reflecting oculomotor apraxia in one third of patients. Specific distinctive alpha-fetoprotein thresholds were determined for AOA1 (7-15 \textmug/L), AOA2 (15-65 \textmug/L) and AT (\textgreater65 \textmug/L). Early age onset, severe walking disability, movement disorders, sensori-motor neuropathy and cerebellar atrophy were all shared. In conclusion, alpha-fetoprotein level seems to permit a distinction while video-oculography does not and therefore is not mandatory, even if an appropriate oculomotor examination remains crucial. Our findings are that AOA1, AOA2 and AT form a particular group characterized by ataxia with complex oculomotor disturbances and elevated AFP for which the final diagnosis is relying on genetic analysis. These findings could guide genetic analysis, assist reverse-phenotyping and provide background for the interpretation of the numerous variants of unknown significance provided by next-generation sequencing.
Published: 2017

16. A recessive ataxia diagnosis algorithm for the next generation sequencing era

Author: Renaud, Mathilde, Tranchant, Christine, Group, RADIAL Working, Alonso, Isabel, Azzedine, Hamid, Barbot, Clara, Bereau, Matthieu, Berkovic, Sam, Bernard, Geneviéve, Bindoff, Laurence A, Bompaire, Flavie, Bonneau, Dominique, Martin, Juan Vicente Torres, Bonneau, Patrizia, Boycott, Kym M, Bras, Jose, Brais, Bernard, Brigatti, Karlla W, Cameron, Jillian, Chamova, Teodora, Choquet, Karine, Delague, Valérie, Denizeau, Philippe, Mochel, Fanny, Dotti, Maria Teresa, El-Euch, Ghada, Elmalik, Salah A, Federico, Antonio, Fiskerstrand, Torunn, Gagnon, Cynthia, Guerreiro, Rita, Guissart, Claire, Hassin-Baer, Sharon, Heimdal, Ketil Riddervold, Synofzik, Matthis, Héron, Bénédicte, Isohanni, Pirjo, Kalaydijeva, Luba, Kawarai, Toshitaka, Koht, Jeanette Aimee, Lai, Szu-Chia, Piana, Roberta La, Lecocq, Claire, Linnankivi, Tarja, Lönnqvist, Tuula, van de Warrenburg, Bart, Lu, Chin-Song, Maas, Roderick, Mahlaoui, Nizar, Mallaret, Martial, Marelli, Cecilia, Mariotti, Caterina, Mathieu, Jean, Méneret, Aurélie, Mignarri, Andrea, Monin, Marie Lorraine, Pandolfo, Massimo, Montaut, Solveig, Nanetti, Lorenzo, Nadjar, Yann, Poujois, Aurélia, Salih, Mustafa A, Sousa, Sergio, Stanier, Philip, Stoppa-Lyonnet, Dominique, Strauss, Kevin, Tallaksen, Chantal, Koenig, Michel, Tarnopolsky, Mark, Tinant, Nadége, Tournev, Ivailo, Topaloglu, Haluk, Varhaug, Kristin Nielsen, Woimant, France, Wolf, Nicole I, Yahalom, Gilad, Yoon, Grace, Young, Millie, Kolb, Stefan A, Anheim, Mathieu, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), 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)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Hertie Institute for Clinical Brain Research and Center for Neurology, University of Tübingen, Radboud university [Nijmegen], Department of Neurology, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), School of Mathematics and Statistics, Newcastle University [Newcastle], Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital de Hautepierre [Strasbourg], Université de Strasbourg (UNISTRA), Service de génétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], 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)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, [SDV]Life Sciences [q-bio], trends [High-Throughput Nucleotide Sequencing], Cohort Studies, 0302 clinical medicine, Diagnosis, Medical diagnosis, Child, ComputingMilieux_MISCELLANEOUS, genetics [Cerebellar Ataxia], medicine.diagnostic_test, High-Throughput Nucleotide Sequencing, Autosomal recessive cerebellar ataxia, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, diagnosis [Cerebellar Ataxia], Neurology, Child, Preschool, Female, medicine.symptom, Algorithm, Algorithms, methods [High-Throughput Nucleotide Sequencing], Ataxia, Cerebellar Ataxia, Context (language use), Diagnosis, Differential, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Humans, Medical history, ddc:610, Preschool, Genetic testing, Cerebellar ataxia, business.industry, Infant, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Differential, Neurology (clinical), Differential diagnosis, business, 030217 neurology & neurosurgery
Abstract: International audience; OBJECTIVE: Differential diagnosis of autosomal recessive cerebellar ataxias can be challenging. A ranking algorithm named RADIAL that predicts the molecular diagnosis based on the clinical phenotype of a patient has been developed to guide genetic testing and to align genetic findings with the clinical context. METHODS: An algorithm that follows clinical practice, including patient history, clinical, magnetic resonance imaging, electromyography, and biomarker features, was developed following a review of the literature on 67 autosomal recessive cerebellar ataxias and personal clinical experience. Frequency and specificity of each feature were defined for each autosomal recessive cerebellar ataxia, and corresponding prediction scores were assigned. Clinical and paraclinical features of patients are entered into the algorithm, and a patient's total score for each autosomal recessive cerebellar ataxia is calculated, producing a ranking of possible diagnoses. Sensitivity and specificity of the algorithm were assessed by blinded analysis of a multinational cohort of 834 patients with molecularly confirmed autosomal recessive cerebellar ataxia. The performance of the algorithm was assessed versus a blinded panel of autosomal recessive cerebellar ataxia experts. RESULTS: The correct diagnosis was ranked within the top 3 highest-scoring diagnoses at a sensitivity and specificity of \textgreater90% for 84% and 91% of the evaluated genes, respectively. Mean sensitivity and specificity of the top 3 highest-scoring diagnoses were 92% and 95%, respectively. The algorithm outperformed the panel of ataxia experts (p = 0.001). INTERPRETATION: Our algorithm is highly sensitive and specific, accurately predicting the underlying molecular diagnoses of autosomal recessive cerebellar ataxias, thereby guiding targeted sequencing or facilitating interpretation of next-generation sequencing data. Ann Neurol 2017;82:892-899.
Published: 2017

17. Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance

Author: Amélie Piton, Melanie Bahlo, Paul J. Lockhart, Vesna Lukic, Caroline Nava, David J. Amor, Pierre Bitoun, Vicki Anderson, Fabien Lesne, Greta Gillies, Amanda G. Wood, Justine Guegan, Gail Robinson, Catherine Garel, Alexis Brice, Sarah E.M. Stephenson, Guy A. Rouleau, Aurélie Méneret, Delphine Héron, Kate Pope, Solveig Heide, Cyril Mignot, Emmanuel Roze, Angélique Quartier, Jean-Louis Mandel, Annalisa Paolino, Quentin Welniarz, Sylvie Odent, Florence Riant, George McGillivray, Linda J. Richards, Ilan Gobius, Elliott H. Sherr, Tania Attié-Bitach, Charles A. Galea, Timothy J. Edwards, Myriam Srour, Megan Spencer-Smith, Oriane Trouillard, Laura Morcom, Boris Keren, Christel Depienne, Marie Laure Moutard, Anne Faudet, Richard J. Leventer, Alissandra McIlroy, Agnès Rastetter, Thierry Billette de Villemeur, Simone Mandelstam, Jens Bunt, Martin B. Delatycki, Rick M. Tankard, Ashley P L Marsh, CHU Pitié-Salpêtrière [APHP], Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], 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)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], CHU Trousseau [APHP], Service de Pédiatrie [Jean Verdier], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Service de Radiologie Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique clinique [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Hôpital Sud, Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-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), Montreal Neurological Hospital, McGill University Health Center [Montreal] (MUHC), CHU Necker - Enfants Malades [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), Laboratoire de Diagnostic Génétique, CHU Strasbourg-Hopital Civil, Service des Maladies du Système Nerveux [CHU Pitié-Salpêtrière], Laboratoire de Génétique Moléculaire [CHRU Strasbourg], CHRU Strasbourg, Bioinformatics division, The Walter & Eliza Hall Institute of Medical Research, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], 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), 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 Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Pierre et Marie Curie - Paris 6 (UPMC), 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)-Sorbonne Université (SU), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), 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)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Collège de France (CdF (institution)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), 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), 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), Centre de Référence des Déficiences Intellectuelles de Causes Rares, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme ( GRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut de Génétique et de Biologie Moléculaire et Cellulaire ( IGBMC ), Université de Strasbourg ( UNISTRA ) -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 ), 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], Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris 13 ( UP13 ) -Hôpital Jean Verdier, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes]-Hôpital Sud, Neuroscience Paris Seine ( NPS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), McGill University Health Center [Montreal, Canada] ( MUHC ), 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 ), Neuroprotection du Cerveau en Développement ( PROTECT ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP)-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), 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)-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)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, Developmental Disabilities, Penetrance, Receptors, Cell Surface, Biology, Nervous System Malformations, Corpus callosum, medicine.disease_cause, Mirror movements, Article, Corpus Callosum, 03 medical and health sciences, 0302 clinical medicine, Neural Stem Cells, Netrin, Intellectual disability, Genetics, medicine, Humans, Abnormalities, Multiple, Family, 10. No inequality, Agenesis of the corpus callosum, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Tumor Suppressor Proteins, Brain, DCC Receptor, medicine.disease, Phenotype, 030104 developmental biology, nervous system, Female, Agenesis of Corpus Callosum, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, 030217 neurology & neurosurgery
Abstract: International audience; Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual.
Published: 2017

18. DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome

Author: Gail Robinson, Saumya Shekhar Jamuar, Elizabeth C. Engle, Helen M. Cooper, Guy A. Rouleau, Ashley P L Marsh, Christel Depienne, Thierry Billette de Villemeur, Linda J. Richards, Elliott H. Sherr, Richard J. Leventer, Delphine Héron, Agnès Rastetter, Marie-Laure Moutard, Charles A. Galea, Oriane Trouillard, Paul J. Lockhart, Timothy W. Yu, Megan Spencer-Smith, Emmanuel Roze, Timothy J. Edwards, Aurélie Méneret, Caroline Nava, Christopher A. Walsh, Murdoch Children's Research Institute (MCRI), University of Melbourne, Queensland Brain Institute, University of Queensland [Brisbane], Monash University [Parkville, VIC, Australie], Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Massachusetts Institute of Technology (MIT), KK Women's and Children's Hospital [Singapore], 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Trousseau [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC), McGill University Health Center [Montreal] (MUHC), McGill University = Université McGill [Montréal, Canada], Monash University [Clayton], Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), UCSF Benioff Children's Hospital Oakland, University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Les Hôpitaux Universitaires de Strasbourg (HUS)
Subjects: 0301 basic medicine, Models, Molecular, Deleted in Colorectal Cancer, Protein Conformation, NTN1, Biology, mirror movements, medicine.disease_cause, Germline, Article, 03 medical and health sciences, Protein Domains, Netrin, Databases, Genetic, Genetics, medicine, Missense mutation, Humans, Abnormalities, Multiple, Amino Acid Sequence, Agenesis of the corpus callosum, ACC, Genetics (clinical), Conserved Sequence, Genetic Association Studies, DCC, developmental split brain syndrome, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Binding Sites, axon guidance, fungi, Anatomy, Syndrome, Netrin-1, medicine.disease, Phenotype, Magnetic Resonance Imaging, 030104 developmental biology, Genes, DCC, horizontal gaze palsy with progressive scoliosis, Axon guidance, agenesis of the corpus callosum, Agenesis of Corpus Callosum, mutation, Protein Binding
Abstract: The deleted in colorectal cancer (DCC) gene encodes the netrin-1 receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline DCC mutations disrupt the development of predominantly commissural tracts in the central nervous system (CNS) and cause a spectrum of neurological disorders. Monoallelic, missense and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum, or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome. Although the underlying molecular mechanisms leading to disease remain poorly understood, they are thought to stem from reduced or perturbed Netrin-1 signaling. Here we review the 26 reported DCC mutations associated with abnormal CNS development in humans, including 14 missense and 12 predicted loss-of-function mutations, and discuss their associated clinical characteristics and diagnostic features. We provide an update on the observed genotype-phenotype relationships of congenital mirror movements, isolated agenesis of the corpus callosum and developmental split brain syndrome, and correlate this to our current understanding of the biological function of DCC in the development of the CNS. All mutations and their associated phenotypes were deposited into a locus specific LOVD (https://databases.lovd.nl/shared/genes/DCC).
Published: 2017

19. RAD51 deficiency disrupts the corticospinal lateralization of motor control

Author: Cécile Hubsch, Nicolas Alexandre, Romain Valabregue, Eric Bardinet, Traian Popa, Lucie Hertz-Pannier, Constance Flamand-Roze, Emmanuel Roze, Sabine Meunier, Prantik Kundu, Christine Delmaire, Cecile Gallea, Massimo Cincotta, Aurélie Méneret, Eric Bertasi, Stéphane Lehéricy, Marie Vidailhet, B Schmitt, Cyril Poupon, Vanessa Brochard, and Christel Depienne
Subjects: medicine.medical_specialty, Supplementary motor area, Motor control, medicine.disease, Lateralization of brain function, Motor coordination, Physical medicine and rehabilitation, medicine.anatomical_structure, Corticospinal tract, Motor system, medicine, Mirror movement disorder, Neurology (clinical), Primary motor cortex, Psychology, Neuroscience
Abstract: Mirror movements are involuntary symmetrical movements of one side of the body that mirror voluntary movements of the other side. Congenital mirror movement disorder is a rare condition characterized by mirror movements that persist throughout adulthood in subjects with no other clinical abnormalities. The affected individuals have mirror movements predominating in the muscles that control the fingers and are unable to perform purely unimanual movements. Congenital mirror movement disorder thus provides a unique paradigm for studying the lateralization of motor control. We conducted a multimodal, controlled study of patients with congenital mirror movements associated with RAD51 haploinsufficiency (n = 7, mean age 33.3 ± 16.8 years) by comparison with age- and gender-matched healthy volunteers (n = 14, mean age 33.9 ± 16.1 years). We showed that patients with congenital mirror movements induced by RAD51 deficiency had: (i) an abnormal decussation of the corticospinal tract; (ii) abnormal interhemispheric inhibition and bilateral cortical activation of primary motor areas during intended unimanual movements; and (iii) an abnormal involvement of the supplementary motor area during both unimanual and bimanual movements. The lateralization of motor control thus requires a fine interplay between interhemispheric communication and corticospinal wiring. This fine interplay determines: (i) the delivery of appropriate motor plans from the supplementary motor area to the primary motor cortex; (ii) the lateralized activation of the primary motor cortex; and (iii) the unilateral transmission of the motor command to the limb involved in the intended movement. Our results also unveil an unexpected function of RAD51 in corticospinal development of the motor system.
Published: 2013

20. PRRT2mutations and paroxysmal disorders

Author: C. Gaudebout, Aurélie Méneret, Christel Depienne, Marie Vidailhet, Emmanuel Roze, and Florence Riant
Subjects: Episodic ataxia, Benign familial infantile epilepsy, business.industry, Migraine Disorders, Membrane Proteins, Nerve Tissue Proteins, PRRT2 Gene, Paroxysmal dyskinesia, medicine.disease, Epilepsy, Benign Neonatal, Epilepsy, Phenotype, Neurology, Migraine, Chorea, Seizures, Mutation, medicine, Animals, Humans, Neurology (clinical), business, Neuroscience, PRRT2, Loss function
Abstract: In the past year, mutations in the PRRT2 gene have been identified in patients with paroxysmal kinesigenic dyskinesia and other paroxysmal disorders. We conducted a review of the literature on PRRT2 mutation-associated disorders. Our objectives were to describe the wide clinical spectrum associated with PRRT2 mutations, and to present the current hypotheses on the underlying pathophysiology. PRRT2 mutations are associated with a wide range of clinical syndromes: the various paroxysmal dyskinesias, infantile seizures, paroxysmal torticollis, migraine, hemiplegic migraine, episodic ataxia and even intellectual disability in the homozygous state. The PRRT2 protein, through its interaction with SNAP-25, could play a role in synaptic regulation in the cortex and the basal ganglia. The pathogenesis may be caused by PRRT2 loss of function, which may induce synaptic deregulation and neuronal hyperexcitability. However, this does not explain the phenotypic variability, which is likely modulated by environmental factors, modifier genes or age-dependent expression. The clinical spectrum of PRRT2 mutations has expanded among paroxysmal disorders and beyond. Unraveling the molecular pathways linking the genetic defect to its clinical expression will be crucial for the diagnosis and treatment of these disorders.
Published: 2013

21. A randomized, controlled, double-blind, crossover trial of zonisamide in myoclonus-dystonia

Author: Noël Zahr, Stéphane Thobois, Fanny Charbonnier-Beaupel, Elodie Hainque, Sophie Dupont, Eugénie Mutez, Anne Doé De Maindreville, Nathalie Cozic, Cécile Hubsch, Alain Mallet, Aurélie Méneret, Christine Tranchant, Sophie Drapier, Fabienne Clot, Cecilia Bonnet, Vanessa Brochard, Emmanuel Roze, David Grabli, André-Pierre Legrand, Emmanuelle Apartis, Thibaud Lebouvier, Marie Vidailhet, Jean-Philippe Azulay, Bertrand Degos, Anne Bissery, Jean-Christophe Corvol, Gérald Glibert, 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 [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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Pôle Tête-Cou-CETD, Les Hôpitaux Universitaires de Strasbourg (HUS), Comportement et noyaux gris centraux = Behavior and Basal Ganglia [Rennes], CHU Pontchaillou [Rennes]-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université européenne de Bretagne - European University of Brittany (UEB)-Institut des Neurosciences Cliniques de Rennes (INCR), Service de Neurologie [Rennes] = Neurology [Rennes], CHU Pontchaillou [Rennes], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Hôpital de la Timone [CHU - APHM] (TIMONE), 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 Génétique Cytogénétique et Embryologie [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), Equipe NEMESIS - Centre de Recherches de l'Institut du Cerveau et de la Moelle épinière (NEMESIS-CRICM), 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)-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 Saint-Antoine [AP-HP], Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière] (CIC Neurosciences), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), Université de Rennes (UR)-Université européenne de Bretagne - European University of Brittany (UEB)-CHU Pontchaillou [Rennes]-Institut des Neurosciences Cliniques de Rennes = Institute of Clinical Neurosciences of Rennes (INCR), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], 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 [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), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université européenne de Bretagne - European University of Brittany (UEB)-CHU Pontchaillou [Rennes]-Institut des Neurosciences Cliniques de Rennes (INCR), 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)-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), Service de Neurologie [CHU Pitié-Salpêtrière], and IFR70-CHU Pitié-Salpêtrière [AP-HP]
Subjects: Adult, Male, 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, [SDV]Life Sciences [q-bio], Zonisamide, Placebo, Severity of Illness Index, law.invention, Disability Evaluation, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, law, Sarcoglycans, Severity of illness, mental disorders, medicine, Humans, Dystonia, Cross-Over Studies, Isoxazoles, medicine.disease, Crossover study, Confidence interval, 3. Good health, nervous system diseases, Treatment Outcome, 030104 developmental biology, Dystonic Disorders, Anesthesia, Female, Neurology (clinical), medicine.symptom, Psychology, Myoclonus, 030217 neurology & neurosurgery, Central Nervous System Agents, medicine.drug
Abstract: International audience; Objective: To evaluate the efficacy and safety of zonisamide in patients with myoclonus-dystonia. Methods: We conducted a randomized, double-blind, placebo-controlled crossover trial of zonisamide (300 mg/d) in 24 patients with myoclonus-dystonia. Each treatment period consisted of a 6-week titration phase followed by a 3-week fixed-dose phase. The periods were separated by a 5-week washout period. The co–primary outcomes were action myoclonus severity (section 4 of the Unified Myoclonus Rating Scale [UMRS 4]) and myoclonus-related functional disability (UMRS 5). Secondary outcomes included dystonia severity, assessed with the movement and disability subscales of the Burke-Fahn-Marsden-Dystonia Rating Scale (BFM), the Clinical Global Impression–Improvement scale (CGI), and safety measures. Wilcoxon signed-rank tests for paired data were used to analyze treatment effects. Results: Twenty-three patients (11 men, 12 women) were analyzed in the intention-to-treat analysis. Zonisamide significantly improved both action myoclonus (median improvement [95% confidence limits] −5 [−9.25 to −1.44], p = 0.003) and myoclonus-related functional disability (median improvement [95% confidence limits] −2 [−2.58 to −2.46], p = 0.007) compared to placebo. Zonisamide also significantly improved dystonia (BFM movement) compared to placebo (median improvement [95% confidence limits] −3 [−8.46 to 0.03], p = 0.009). No difference was found between zonisamide and placebo with respect to the CGI (median improvement [95% confidence limits] −1 [−1.31 to 0.09], p = 0.1). Zonisamide was well-tolerated. Conclusions: Zonisamide is well-tolerated and effective on the motor symptoms of myoclonus-dystonia. Classification of evidence: This study provides Class I evidence that zonisamide improves myoclonus and related disability in patients with myoclonus-dystonia
Published: 2016

22. Paroxysmal movement disorders: An update

Author: Emmanuel Roze and Aurélie Méneret
Subjects: 0301 basic medicine, Pediatrics, medicine.medical_specialty, Ataxia, Movement disorders, Choreiform movement, Diagnostic Techniques, Neurological, Nerve Tissue Proteins, Diagnosis, Differential, 03 medical and health sciences, 0302 clinical medicine, Chorea, Terminology as Topic, medicine, Humans, Episodic ataxia, business.industry, Paroxysmal dyskinesia, medicine.disease, 030104 developmental biology, PNKD, Neurology, Dyskinesia, Mutation, Neurology (clinical), medicine.symptom, business, Neuroscience, 030217 neurology & neurosurgery, PRRT2
Abstract: Paroxysmal movement disorders comprise both paroxysmal dyskinesia, characterized by attacks of dystonic and/or choreic movements, and episodic ataxia, defined by attacks of cerebellar ataxia. They may be primary (familial or sporadic) or secondary to an underlying cause. They can be classified according to their phenomenology (kinesigenic, non-kinesigenic or exercise-induced) or their genetic cause. The main genes involved in primary paroxysmal movement disorders include PRRT2, PNKD, SLC2A1, ATP1A3, GCH1, PARK2, ADCY5, CACNA1A and KCNA1. Many cases remain genetically undiagnosed, thereby suggesting that additional culprit genes remain to be discovered. The present report is a general overview that aims to help clinicians diagnose and treat patients with paroxysmal movement disorders.
Published: 2016

23. A randomized, controlled, double-blind, crossover trial of triheptanoin in alternating hemiplegia of childhood

Author: A Roubergue, Mariana Atencio, Marta Ruiz, Aurélie Méneret, Vanessa Brochard, Maryvonne Retail, Samantha Caillet, Sandrine Leroy, Jean-Christophe Corvol, Emmanuel Roze, Elodie Hainque, Florence Habarou, Isaac Adanyeguh, Sophie Rivaud-Péchoux, Benjamin Le Toullec, Chris Ottolenghi, Constance Flamand-Roze, Fanny Mochel, Mohamed Doulazmi, Fanny Charbonnier-Beaupel, Marie Vidailhet, Florence Cormier, BMC, BMC, 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 [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), 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), Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière] (CIC Neurosciences), Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), EpiScience [London, UK], Service de Neurologie et Unité Neurovasculaire [Centre Hospitalier Sud-Francilien], Université Paris-Sud - Paris 11 (UP11)-Centre Hospitalier Sud Francilien, IFPPC - Institut de formation et de recherche pour les professionnels de la santé & Centre de santé et de thérapies Psycho Corporelles [Paris], CAMKeys [Paris], Service de biochimie métabolique [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), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), 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)-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)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Groupe de Recherche Clinique Neurométabolique [Paris], 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)-Centre National de la Recherche Scientifique (CNRS), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CH Evry-Corbeil-CH Evry-Corbeil, 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 de Biologie Paris Seine (IBPS), 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)-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 ), 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], Département de Neurologie [Paris], Assistance publique - Hôpitaux de Paris (AP-HP)-IFR70-Hôpital de la Salpétrière, CIC Pitié Neurosciences, Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP], Service de Diététique [AP-HP Hôpital Pitié-Salpêtrière], AP-HP Hôpital Pitié-Salpétrière, Université Paris-Sud - Paris 11 ( UP11 ) -Centre Hospitalier Sud Francilien, Pharmacie [AP-HP Hôpital Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing ( B2A ), 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 ), Sorbonne Universités, Département de Neurologie [AP-HP Hôpital Saint-Antoine], AP-HP - Hôpital Saint-Antoine, Département de Génétique [AP-HP Hôpital Pitié-Salpêtrière], 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)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], 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 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), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-IFR70-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Adolescent, [SDV]Life Sciences [q-bio], lcsh:Medicine, Hemiplegia, Placebo, Double blind, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Double-Blind Method, ATP1A3, Humans, Medicine, Pharmacology (medical), Ictal, In patient, Triglycerides, Genetics (clinical), Cross-Over Studies, [ SDV ] Life Sciences [q-bio], business.industry, Research, Alternating hemiplegia of childhood, lcsh:R, General Medicine, Triheptanoin, medicine.disease, Crossover trial, Crossover study, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, chemistry, Dietary Supplements, Female, business, 030217 neurology & neurosurgery
Abstract: International audience; AbstractBackgroundBased on the hypothesis of a brain energy deficit, we investigated the safety and efficacy of triheptanoin on paroxysmal episodes in patients with alternating hemiplegia of childhood due to ATP1A3 mutations.MethodsWe conducted a randomized, double-blind, placebo-controlled crossover study of triheptanoin, at a target dose corresponding to 30% of daily calorie intake, in ten patients with alternating hemiplegia of childhood due to ATP1A3 mutations. Each treatment period consisted of a 12-week fixed-dose phase, separated by a 4-week washout period. The primary outcome was the total number of paroxysmal events. Secondary outcomes included the number of paroxysmal motor-epileptic events; a composite score taking into account the number, severity and duration of paroxysmal events; interictal neurological manifestations; the clinical global impression-improvement scale (CGI-I); and safety parameters. The paired non-parametric Wilcoxon test was used to analyze treatment effects.ResultsIn an intention-to-treat analysis, triheptanoin failed to reduce the total number of paroxysmal events (p = 0.646), including motor-epileptic events (p = 0.585), or the composite score (p = 0.059). CGI-I score did not differ between triheptanoin and placebo periods. Triheptanoin was well tolerated.ConclusionsTriheptanoin does not prevent paroxysmal events in Alternating hemiplegia of childhood. We show the feasibility of a randomized placebo-controlled trial in this setting.Trial registrationThe study has been registered with clinicaltrials.gov (NCT002408354) the 03/24/2015.
Published: 2016

24. PRRT2 mutations: A major cause of paroxysmal kinesigenic dyskinesia in the European population

Author: Domitille Gras, Emmanuel Roze, Thierry Billette de Villemeur, Charles Pierre Jedynak, Fabienne Picard, Christine Tranchant, Mathieu Anheim, Cécile Gaudebout, Dominique Steschenko, Pierre Burbaud, Delphine Bouteiller, David Devos, Alexandra Durr, Isabelle Lagroua, Marie Vidailhet, Alexis Brice, David Grabli, Christel Depienne, Diane Doummar, Cyril Mignot, and Aurélie Méneret
Subjects: Adult, Pediatrics, medicine.medical_specialty, Movement disorders, Mutation/genetics, Choreoathetosis, Nerve Tissue Proteins, Genetic analysis, White People, Epilepsy, Epilepsy, Benign Neonatal/diagnosis/genetics, Seizures/diagnosis/genetics, Chorea, Seizures, medicine, Nerve Tissue Proteins/genetics, Humans, European Continental Ancestry Group/genetics, Membrane Proteins/genetics, Age of Onset, Dyskinesias, business.industry, Membrane Proteins, Syndrome, European population, Paroxysmal dyskinesia, musculoskeletal system, medicine.disease, Epilepsy, Benign Neonatal, ddc:616.8, Pedigree, Mutation, Chorea/diagnosis/genetics, Dyskinesias/diagnosis/genetics, cardiovascular system, Neurology (clinical), Age of onset, medicine.symptom, business, PRRT2
Abstract: Objective: Paroxysmal kinesigenic dyskinesia (PKD) is a rare disorder characterized by recurrent attacks of hyperkinetic movements. PKD can be isolated or associated with benign infantile seizures as part of the infantile convulsions with choreoathetosis (ICCA) syndrome. Mutations in the PRRT2 gene were recently identified in patients with PKD and ICCA. We studied the prevalence of PRRT2 mutations and characteristics of the patients in a European population of patients with PKD and ICCA. Methods: Patients were recruited through the 1996−2011 database of our DNA bank, to which physicians refer DNA with a putative diagnosis and clinical information. Two movement disorders experts reviewed the information on patients with a putative diagnosis of PKD. Patients who fulfilled the criteria for PKD and ICCA were included. The PRRT2 coding sequence was analyzed by direct sequencing. Results: Among 42 index cases of unrelated families referred with a putative diagnosis of PKD, a total of 34 patients, including 32 with isolated PKD and 2 with ICCA, were selected for genetic analysis. Mutations introducing premature termination codons were identified in 22 of 34 patients including 13 of 14 families and 9 of 20 patients with sporadic cases. The previously described c.649dupC/pArg217ProfsX8 and c.629dupC/pAla211SerfsX14 were present, respectively, in 17 patients and 1 patient; we also report 3 novel mutations: c.649delC/pArg217GlufsX12 in 2 patients, and c.562C>T/pGln188X and c.649C>T/pArg217X, each in 1 patient. The group with mutations was characterized by a younger age at onset (9 years) compared with the patients without mutations (15 years; p Conclusion: Mutations in PRRT2 are a major cause of PKD in familial and sporadic cases in the European population.
Published: 2012

25. Lichen plan buccal érosif associé à un syndrome de Good

Author: E. Brian, Kiarash Khosrotehrani, C. Bachmeyer, M. Blanchard, M. Baron, B. Bazelly, Philippe Moguelet, and A. Méneret
Subjects: Gynecology, Hypogammaglobulinemia, stomatognathic diseases, medicine.medical_specialty, stomatognathic system, business.industry, Gastroenterology, Internal Medicine, medicine, Oral cavity, medicine.disease, business
Abstract: Resume Introduction Le syndrome de Good est caracterise par l’association d’un thymome a une hypogammaglobulinemie, une lymphopenie B circulante, et de maniere variable, une lymphopenie T CD4 circulante avec un rapport CD4/CD8 inverse, s’accompagnant d’infections et de maladies auto-immunes. Observation Nous rapportons l’observation d’une femme de 85 ans qui presentait un lichen plan buccal erosif associe a un syndrome de Good. L’amelioration des lesions buccales etait observee apres l’exerese du thymome benin, alors que le deficit immunitaire persistait. Seulement 11 observations associant un syndrome de Good et un lichen plan ont ete precedemment rapportees dans la litterature. Conclusion L’association d’un lichen plan buccal erosif a un syndrome de Good est rare, mais ne parait pas fortuite.
Published: 2010

26. Abnormalities of motor function, transcription and cerebellar structure in mouse models of THAP1 dystonia

Author: Patrick R. Hof, Maitane Ortiz-Virumbrales, Marta Ruiz, Tania Fuchs, Laurie J. Ozelius, Andrika Morant, Georgina Perez-Garcia, Pedro Gonzalez-Alegre, Justine Bonet, Aurélie Méneret, Jessica Kottwitz, and Michelle E. Ehrlich
Subjects: Male, Cerebellum, Nonsense mutation, Dystonia Musculorum Deformans, Neuropathology, Biology, Deep cerebellar nuclei, Mice, Genetics, medicine, Missense mutation, Animals, RNA, Messenger, Molecular Biology, Transcription factor, Genetics (clinical), Dystonia, General Medicine, Articles, medicine.disease, Null allele, Mice, Mutant Strains, DNA-Binding Proteins, medicine.anatomical_structure, Mutation
Abstract: DYT6 dystonia is caused by mutations in THAP1 [Thanatos-associated (THAP) domain-containing apoptosis-associated protein] and is autosomal dominant and partially penetrant. Like other genetic primary dystonias, DYT6 patients have no characteristic neuropathology, and mechanisms by which mutations in THAP1 cause dystonia are unknown. Thap1 is a zinc-finger transcription factor, and most pathogenic THAP1 mutations are missense and are located in the DNA-binding domain. There are also nonsense mutations, which act as the equivalent of a null allele because they result in the generation of small mRNA species that are likely rapidly degraded via nonsense-mediated decay. The function of Thap1 in neurons is unknown, but there is a unique, neuronal 50-kDa Thap1 species, and Thap1 levels are auto-regulated on the mRNA level. Herein, we present the first characterization of two mouse models of DYT6, including a pathogenic knockin mutation, C54Y and a null mutation. Alterations in motor behaviors, transcription and brain structure are demonstrated. The projection neurons of the deep cerebellar nuclei are especially altered. Abnormalities vary according to genotype, sex, age and/or brain region, but importantly, overlap with those of other dystonia mouse models. These data highlight the similarities and differences in age- and cell-specific effects of a Thap1 mutation, indicating that the pathophysiology of THAP1 mutations should be assayed at multiple ages and neuronal types and support the notion of final common pathways in the pathophysiology of dystonia arising from disparate mutations.
Published: 2015

27. Paroxysmal Movement Disorders

Author: Aurélie Méneret, Emmanuel Roze, and Marie Vidailhet
Subjects: Episodic ataxia, Movement disorders, Paroxysmal nonkinesigenic dyskinesia, Channelopathy, Basic research, business.industry, medicine, Paroxysmal dyskinesia, medicine.symptom, medicine.disease, business, Neuroscience
Abstract: Paroxysmal movement disorders comprise paroxysmal dyskinesias and episodic ataxias of various types. They are mainly of genetic origin but are occasionally symptomatic of an underlying nongenetic disorder. Their current classification is based mainly on the phenomenology of the attacks, especially their triggering factors and duration. Basic research is providing new insights into these disorders, notably by showing that a given paroxysmal movement disorder can be caused by mutations in various genes, and that mutations of a given gene can result in various types of paroxysmal movement disorders. This chapter describes the broad clinical spectrum of paroxysmal movement disorders and their main known genetic causes. An algorithm is provided to help clinicians avoid diagnostic pitfalls.
Published: 2015

28. Generalized dystonia, athetosis, and parkinsonism associated with FOXG1 mutation

Author: Aurélia Jacquette, Emmanuel Roze, Cyril Mignot, Marie Vidailhet, Isabelle An, Aurélie Méneret, Thierry Bienvenu, and Marie-Odile Habert
Subjects: Involuntary movement, Dystonia, Athetosis, Pediatrics, medicine.medical_specialty, business.industry, Parkinsonism, Neurological disorder, medicine.disease, FOXG1, Neurology, Generalized dystonia, Mutation (genetic algorithm), medicine, Neurology (clinical), business, Neuroscience
Published: 2011

29. The pleiotropic movement disorders phenotype of adult ataxia-telangiectasia

Author: Michel Koenig, Aurélie Méneret, Nizar Mahlaoui, Marc-Henri Stern, Catherine Dubois d'Enghien, Emmanuelle Apartis, Alexandra Durr, Felipe Suarez, Guillaume Rieunier, Sophie Rivaud-Péchoux, Bertrand Gaymard, Thierry Maisonobe, Marie Vidailhet, Dominique Stoppa-Lyonnet, Bertrand Degos, David Grabli, Alain Fischer, Baya Benyahia, Mathieu Anheim, Yara Ahmar-Beaugendre, Christine Tranchant, Assistance Publique-Hôpitaux de Paris, Service d'Immunologie et d'Hématologie Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neurophysiologie [CHU Pitié-Salpêtrière], 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), Les chimiokines et leurs récepteurs : fonctions cérébrales et neuroendocriniennes, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, 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 [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), Service de Neuroradiologie [CHU Pitié-Salpêtrière], Thérapie des maladies du muscle strié, 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), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), INSERM, U975, Université Paris 06, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Curie [Paris], 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), 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), and Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Male, Myoclonus, medicine.medical_specialty, Pathology, Movement disorders, Ataxia, [SDV]Life Sciences [q-bio], Mutation, Missense, Immunoglobulins, Ataxia Telangiectasia Mutated Proteins, Gastroenterology, Severity of Illness Index, Cohort Studies, 03 medical and health sciences, Dysarthria, Ataxia Telangiectasia, Young Adult, 0302 clinical medicine, Ocular Motility Disorders, Internal medicine, Chromosomal Instability, medicine, Missense mutation, Humans, Oculomotor apraxia, Age of Onset, Mobility Limitation, Eye Movement Measurements, 030304 developmental biology, Dystonia, 0303 health sciences, Movement Disorders, Genetic Pleiotropy, medicine.disease, 3. Good health, Phenotype, Ataxia-telangiectasia, Disease Progression, Female, Neurology (clinical), alpha-Fetoproteins, medicine.symptom, Psychology, 030217 neurology & neurosurgery
Abstract: International audience; OBJECTIVE:To assess the clinical spectrum of ataxia-telangiectasia (A-T) in adults, with a focus on movement disorders.METHODS:A total of 14 consecutive adults with A-T were included at 2 tertiary adult movement disorders centers and compared to 53 typical patients with A-T. Clinical evaluation, neurophysiologic and video-oculographic recording, imaging, laboratory investigations, and ATM analysis were performed.RESULTS:In comparison with typical A-T cases, our patients demonstrated later mean age at onset (6.1 vs 2.5 years, p < 0.0001), later loss of walking ability (p = 0.003), and longer survival (p = 0.0039). The presenting feature was ataxia in 71% and dysarthria and dystonia in 14% each. All patients displayed movement disorders, among which dystonia and subcortical myoclonus were the most common (86%), followed by tremor (43%). Video-oculographic recordings revealed mostly dysmetric saccades and 46% of patients had normal latencies (i.e., no oculomotor apraxia) and velocities. The α-fetoprotein (AFP) level was normal in 7%, chromosomal instability was found in 29% (vs 100% of typical patients, p = 0.0006), and immunoglobulin deficiency was found in 29% (vs 69%, p = 0.057). All patients exhibited 2 ATM mutations, including at least 1 missense mutation in 79% of them (vs 36%, p = 0.0067).CONCLUSION:There is great variability of phenotype and severity in A-T, including a wide spectrum of movement disorders. Karyotype and repeated AFP level assessments should be performed in adults with unexplained movement disorders as valuable clues towards the diagnosis. In case of a compatible phenotype, A-T should be considered even if age at onset is late and progression is slow
Published: 2014

30. Une dyspnée d’effort récente

Author: A. Parrot, A. Méneret, C. Ridel, Alexandre Hertig, Claude Bachmeyer, and Antoine Khalil
Subjects: Basement membrane, Autoimmune disease, Pathology, medicine.medical_specialty, business.industry, Respiratory disease, Gastroenterology, medicine.disease, medicine.anatomical_structure, Immunopathology, Internal Medicine, Medicine, Goodpasture syndrome, Respiratory system, Pulmonary alveolus, business, Kidney disease
Published: 2009

31. GLUT1 deficiency syndrome: an update

Author: Fanny Mochel, Marie Vidailhet, T. Billette de Villemeur, Emmanuel Roze, Diane Doummar, D. Gras, Aurélie Méneret, and S. Caillet
Subjects: medicine.medical_specialty, Microcephaly, Monosaccharide Transport Proteins, medicine.medical_treatment, Bioinformatics, Epilepsy, Internal medicine, medicine, Humans, Generalized epilepsy, Triglycerides, Glucose Transporter Type 1, biology, Thioctic Acid, business.industry, Glucose transporter, medicine.disease, Endocrinology, Phenotype, Neurology, Dyskinesia, biology.protein, GLUT1, Neurology (clinical), medicine.symptom, business, Diet, Ketogenic, Ketogenic diet, Carbohydrate Metabolism, Inborn Errors
Abstract: Introduction Glucose transporter type 1 deficiency syndrome is caused by heterozygous, mostly de novo, mutations in the SLC2A1 gene encoding the glucose transporter GLUT1. Mutations in this gene limit brain glucose availability and lead to cerebral energy deficiency. State of the art The phenotype is characterized by the variable association of mental retardation, acquired microcephaly, complex motor disorders, and paroxysmal manifestations including seizures and non-epileptic paroxysmal episodes. Clinical severity varies from mild motor dysfunction to severe neurological disability. In patients with mild phenotypes, paroxysmal manifestations may be the sole manifestations of the disease. In particular, the diagnosis should be considered in patients with paroxysmal exercise-induced dyskinesia or with early-onset generalized epilepsy. Low CSF level of glucose, relative to blood level, is the best biochemical clue to the diagnosis although not constantly found. Molecular analysis of the SLC2A1 gene confirms the diagnosis. Ketogenic diet is the cornerstone of the treatment and implicates a close monitoring by a multidisciplinary team including trained dieticians. Non-specific drugs may be used as add-on symptomatic treatments but their effects are often disappointing. Conclusion Glucose transporter type 1 deficiency syndrome is likely under diagnosed due to its complex and pleiotropic phenotype. Proper identification of the affected patients is important for clinical practice since the disease is treatable.
Published: 2013

32. A Serine Synthesis Defect Presenting With a Charcot-Marie-Tooth–Like Polyneuropathy

Author: Cecilia Marelli, Frédéric Sedel, Emile Van Schaftingen, Aurélie Méneret, Elsa Wiame, and Timothée Lenglet
Subjects: Adult, Male, medicine.medical_specialty, Pathology, DNA Mutational Analysis, Administration, Oral, Plasma amino acid chromatography, Serine, Arts and Humanities (miscellaneous), Charcot-Marie-Tooth Disease, Humans, Medicine, In patient, Amino acid metabolism, Amino Acid Metabolism, Inborn Errors, Phosphoglycerate Dehydrogenase, business.industry, medicine.disease, Dehydrogenase deficiency, Surgery, Congenital cataracts, Neurology (clinical), business, Polyneuropathy, Psychomotor delay, Metabolic Networks and Pathways
Abstract: Serine synthesis defects, characterized by developmental delay and seizures, have been described in children.To describe a case of serine synthesis defect due to 3-phosphoglycerate dehydrogenase deficiency in an adult with prominent chronic polyneuropathy.Case report.Neurologic referral center.A 31-year-old man with congenital cataracts, mild psychomotor retardation, slight cerebellar ataxia, and chronic axonal sensorimotor polyneuropathy.Electrophysiologic, metabolic, and genetic testing and treatment with oral L-serine.Serine values in plasma and cerebrospinal fluid and clinical examination.Amino acid analysis showed low serine levels in plasma and cerebrospinal fluid, and genetic analysis revealed 2 heterozygous mutations in the PGDH gene. Treatment with high-dose serine resulted in normalization of plasma serine values and subjective functional improvement.This case expands the phenotypic spectrum of 3-phosphoglycerate dehydrogenase deficiency. Plasma amino acid chromatography should be added to the list of investigations performed in patients with Charcot-Marie-Tooth–like polyneuropathy, especially if it is associated with psychomotor delay and congenital cataracts.
Published: 2012

33. Congenital mirror movements: a clue to understanding bimanual motor control

Author: Christel Depienne, Cecile Gallea, Emmanuel Roze, Traian Popa, Ségolène Billot, and Aurélie Méneret
Subjects: Movement Disorders, Deleted in Colorectal Cancer, Kallmann syndrome, Motor control, Motor Activity, Corpus callosum, medicine.disease, Pathogenesis, Neurology, Neuroimaging, Corticospinal tract, medicine, Animals, Humans, Neurology (clinical), Psychology, Neuroscience, Pathological
Abstract: Mirror movements (MM) are involuntary movements of one side of the body that accompany and mirror intentional movements on the opposite side. Physiological MM can occur during normal childhood development, probably owing to corpus callosum immaturity. Pathological congenital MM may be clinically isolated or part of a complex congenital syndrome, including Kallmann syndrome, Klippel-Feil syndrome, and congenital hemiplegia. Congenital isolated MM are usually familial. Recently, heterozygous mutations of the DCC gene, with autosomal dominant inheritance, were shown to cause some cases of MM. The pathogenesis of congenital MM may involve (i) abnormal interhemispheric inhibition between the two motor cortices; (ii) functional alteration of motor planning and motor execution; and/or (iii) abnormal persistence of the ipsilateral corticospinal tract. Fundamental and clinical research is providing novel insights into the complex underlying molecular pathways, and recent experimental work has identified several mechanisms that may mediate the motor network dysfunction. In this review, we analyze clinical, genetic, neurophysiologic, and neuroimaging data on congenital MM, and discuss how this knowledge may improve our understanding of bimanual motor control.
Published: 2011

34. PRRT2 mutations cause hemiplegic migraine

Author: Agnès Trébuchon, Cecile Barbance, Pascal Sabouraud, Elisabeth Tournier-Lasserve, Christel Depienne, Aurélie Méneret, Christian Lucas, Florence Riant, Emmanuel Roze, and Lucie Guyant-Maréchal
Subjects: Male, Mutation, Benign familial infantile epilepsy, Adolescent, business.industry, Migraine with Aura, Choreoathetosis, Membrane Proteins, Nerve Tissue Proteins, Paroxysmal dyskinesia, Bioinformatics, medicine.disease_cause, medicine.disease, Phenotype, Culprit, Migraine with aura, medicine, Humans, Female, Neurology (clinical), medicine.symptom, business, Child, PRRT2
Abstract: Objective: Hemiplegic migraine (HM) is a rare subtype of migraine with aura that occurs as a familial or sporadic condition. The 3 culprit genes identified so far do not account for all familial forms of HM. PRRT2 mutations have recently been shown to cause various childhood-onset episodic syndromes including paroxysmal kinesigenic dyskinesia, infantile convulsions with choreoathetosis syndrome, and benign familial infantile epilepsy. Our objective was to test the possible implication of PRRT2 in HM, another episodic disorder with early onset in most cases. Methods: The whole genomic coding region of PRRT2 was sequenced in 101 index cases with HM that started before age 20 years and for whom no mutation was found in the 3 known HM genes. Affected relatives of mutated patients were analyzed when available. Results: PRRT2 mutations were identified in 4 patients: the previously reported c.649dupC mutation was found in 2 cases, and a novel mutation, c.649delC, was found in the other 2. One patient with mutation subsequently developed paroxysmal dyskinesia, as well as generalized epileptic seizures. Conclusions: PRRT2 mutations can occasionally cause HM. This underscores the complexity of the phenotypic consequences of PRRT2 mutations.

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34 results on '"Méneret A"'

1. Somatotopy of cervical dystonia in motor-cerebellar networks: Evidence from resting state fMRI

2. Long-term effect of apomorphine infusion in advanced Parkinson’s disease: a real-life study

3. Renal Pathological Findings in Action Myoclonus-Renal Failure Syndrome

4. Sleep in ADCY5 -Related Dyskinesia: Prolonged Awakenings Caused by Abnormal Movements

5. Biallelic AOPEP Loss‐of‐Function Variants Cause Progressive Dystonia with Prominent Limb Involvement

6. Isolated parkinsonism is an atypical presentation of GRN and C9orf72 gene mutations Authors

7. Current challenges in the pathophysiology, diagnosis, and treatment of paroxysmal movement disorders

8. Systematic review of movement disorders and oculomotor abnormalities in Whipple's disease

9. Increased diagnostic yield in complex dystonia through exome sequencing

10. Dystonia: genetics, phenomenology, and pathophysiology

11. Transition from ketogenic diet to triheptanoin in patients with GLUT1 deficiency syndrome

12. Biallelic MYORG mutation carriers exhibit primary brain calcification with a distinct phenotype

13. GLUT1 Deficiency in a Patient Diagnosed as Cerebral Palsy: Is NGS a Valuable Tool to Be Considered in All Cases of CP to Detect Underlying Genetic Disorders?

14. ADCY5-related dyskinesia

15. Comparing ataxias with oculomotor apraxia: a multimodal study of AOA1, AOA2 and AT focusing on video-oculography and alpha-fetoprotein

16. A recessive ataxia diagnosis algorithm for the next generation sequencing era

17. Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance

18. DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome

19. RAD51 deficiency disrupts the corticospinal lateralization of motor control

20. PRRT2mutations and paroxysmal disorders

21. A randomized, controlled, double-blind, crossover trial of zonisamide in myoclonus-dystonia

22. Paroxysmal movement disorders: An update

23. A randomized, controlled, double-blind, crossover trial of triheptanoin in alternating hemiplegia of childhood

24. PRRT2 mutations: A major cause of paroxysmal kinesigenic dyskinesia in the European population

25. Lichen plan buccal érosif associé à un syndrome de Good

26. Abnormalities of motor function, transcription and cerebellar structure in mouse models of THAP1 dystonia

27. Paroxysmal Movement Disorders

28. Generalized dystonia, athetosis, and parkinsonism associated with FOXG1 mutation

29. The pleiotropic movement disorders phenotype of adult ataxia-telangiectasia

30. Une dyspnée d’effort récente

31. GLUT1 deficiency syndrome: an update

32. A Serine Synthesis Defect Presenting With a Charcot-Marie-Tooth–Like Polyneuropathy

33. Congenital mirror movements: a clue to understanding bimanual motor control

34. PRRT2 mutations cause hemiplegic migraine

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