1. Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study
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Eléonore Tollard, Christel Depienne, Carola G.M. van Berkel, Graziella Uziel, Céline Dupuits, Maarten Kamermans, Truus E.M. Abbink, Suzanna G.M. Frints, Nienke L. Postma, Alexis Brice, Adeline Vanderver, Christine E. M. de Die-Smulders, Emiel Polder, Marjo S. van der Knaap, Nicole I. Wolf, Frédéric Sedel, Marianna Bugiani, Damien Galanaud, J. S. H. Vles, Vera M. Kalscheuer, Valerie Touitou, Jan Klooster, Frédéric Darios, Cengiz Yalcinkaya, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], 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), Pathology Department, VU University Medical Center [Amsterdam], Child Neurology Department, Fondazione IRCCS Istituto Neurologico, Service de Neuroradiologie [CHU Pitié-Salpêtrière], Neurologie, Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Radiologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Department of Clinical Genetics [Maastricht], Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht]-Maastricht University [Maastricht], Department of Child Neurology [Maastricht], Department of Neurology, Children's National Medical Center, Unit of Child Neurology, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Division of Child Neurology, Istanbul University -Cerrahpasa Medical School, Department Human Molecular Genetics [MPIMG Berlin], Max Planck Institute for Molecular Genetics (MPIMG), Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Department of Retinal Signal Processing, Netherlands Institute for Neuroscience-KNAW, Department of Neurogenetics, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), ELA, APHP, INSERM, Pathology, Pediatric surgery, NCA - Brain mechanisms in health and disease, Cerrahpasa Medical School-Istanbul University, Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), Genetica & Celbiologie, RS: MHeNs School for Mental Health and Neuroscience, RS: GROW - School for Oncology and Reproduction, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, UF Neurométabolique Bioclinique et Génétique [CHU Pitié-Salpêtrière], Algorithms, models and methods for images and signals of the human brain (ARAMIS), Inria Paris-Rocquencourt, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Service d'ophtalmologie [CHU Pitié-Salpêtrière], Maastricht University [Maastricht], Cerrahpasa Faculty of Medicine, Istanbul University, Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW), University of Amsterdam [Amsterdam] (UvA), Service de neurologie 1 [CHU Pitié-Salpétrière], Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Depienne, Christel, Other departments, ANS - Amsterdam Neuroscience, and Genome Analysis
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Male ,Pathology ,Candidate gene ,Brain Edema ,[SDV.GEN] Life Sciences [q-bio]/Genetics ,Polymerase Chain Reaction ,Leukoencephalopathy ,0302 clinical medicine ,[INFO.INFO-TS]Computer Science [cs]/Signal and Image Processing ,Leukoencephalopathies ,Image Processing, Computer-Assisted ,Exome ,Age of Onset ,10. No inequality ,Child ,Exome sequencing ,Myelin Sheath ,media_common ,Neurologic Examination ,0303 health sciences ,education.field_of_study ,biology ,Homozygote ,Brain ,Genetic Diseases, X-Linked ,SDG 10 - Reduced Inequalities ,Middle Aged ,Immunohistochemistry ,Magnetic Resonance Imaging ,3. Good health ,medicine.anatomical_structure ,Connexin 32 ,Female ,medicine.symptom ,[SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing ,Signal Transduction ,Adult ,medicine.medical_specialty ,Adolescent ,Cerebellar Ataxia ,White matter ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Chloride Channels ,medicine ,media_common.cataloged_instance ,Humans ,RNA, Messenger ,European union ,education ,030304 developmental biology ,Aged ,CLCN2 ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Cerebellar ataxia ,Fibroblasts ,medicine.disease ,CLC-2 Chloride Channels ,biology.protein ,Neurology (clinical) ,030217 neurology & neurosurgery - Abstract
International audience; BACKGROUND: Mutant mouse models suggest that the chloride channel ClC-2 has functions in ion and water homoeostasis, but this has not been confirmed in human beings. We aimed to define novel disorders characterised by distinct patterns of MRI abnormalities in patients with leukoencephalopathies of unknown origin, and to identify the genes mutated in these disorders. We were specifically interested in leukoencephalopathies characterised by white matter oedema, suggesting a defect in ion and water homoeostasis. METHODS: In this observational analytical study, we recruited patients with leukoencephalopathies characterised by MRI signal abnormalities in the posterior limbs of the internal capsules, midbrain cerebral peduncles, and middle cerebellar peduncles from our databases of patients with leukoencephalopathies of unknown origin. We used exome sequencing to identify the gene involved. We screened the candidate gene in additional patients by Sanger sequencing and mRNA analysis, and investigated the functional effects of the mutations. We assessed the localisation of ClC-2 with immunohistochemistry and electron microscopy in post-mortem human brains of individuals without neurological disorders. FINDINGS: Seven patients met our inclusion criteria, three with adult-onset disease and four with childhood-onset disease. We identified homozygous or compound-heterozygous mutations in CLCN2 in three adult and three paediatric patients. We found evidence that the CLCN2 mutations result in loss of function of ClC-2. The remaining paediatric patient had an X-linked family history and a mutation in GJB1, encoding connexin 32. Clinical features were variable and included cerebellar ataxia, spasticity, chorioretinopathy with visual field defects, optic neuropathy, cognitive defects, and headaches. MRI showed restricted diffusion suggesting myelin vacuolation that was confined to the specified white matter structures in adult patients, and more diffusely involved the brain white matter in paediatric patients. We detected ClC-2 in all components of the panglial syncytium, enriched in astrocytic endfeet at the perivascular basal lamina, in the glia limitans, and in ependymal cells. INTERPRETATION: Our observations substantiate the concept that ClC-2 is involved in brain ion and water homoeostasis. Autosomal-recessive CLCN2 mutations cause a leukoencephalopathy that belongs to an emerging group of disorders affecting brain ion and water homoeostasis and characterised by intramyelinic oedema. FUNDING: European Leukodystrophies Association, INSERM and Assistance Publique-Hôpitaux de Paris, Dutch Organisation for Scientific Research (ZonMw), E-Rare, Hersenstichting, Optimix Foundation for Scientific Research, Myelin Disorders Bioregistry Project, National Institute of Neurological Disorders and Stroke, and Genetic and Epigenetic Networks in Cognitive Dysfunction (GENCODYS) Project (funded by the European Union Framework Programme 7).
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- 2013