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  Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study

Depienne, C., Bugiani, M., Dupuits, C., Galanaud, D., Touitou, V., Postma, N., et al. (2013). Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study. Lancet Neurology, 12(7), 659-668. doi:10.1016/S1474-4422(13)70053-X.

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 Urheber:
Depienne, C., Autor
Bugiani, M., Autor
Dupuits, C., Autor
Galanaud, D., Autor
Touitou, V., Autor
Postma, N., Autor
van Berkel, C., Autor
Polder, E., Autor
Tollard, E., Autor
Darios, F., Autor
Brice, A., Autor
de Die-Smulders, C. E., Autor
Vles, J. S., Autor
Vanderver, A., Autor
Uziel, G., Autor
Yalcinkaya, C., Autor
Frints, S. G., Autor
Kalscheuer, V. M.1, Autor           
Klooster, J., Autor
Kamermans, M., Autor
Abbink, T. E., AutorWolf, N. I., AutorSedel, F., Autorvan der Knaap, M. S., Autor mehr..
Affiliations:
1Chromosome Rearrangements and Disease (Vera Kalscheuer), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479642              

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Schlagwörter: Adolescent Adult Age of Onset Aged Brain/pathology Brain Edema/*etiology/*genetics/pathology Cerebellar Ataxia/genetics/pathology Child Chloride Channels/*deficiency/ultrastructure Exome/genetics Female Fibroblasts/metabolism Genetic Diseases, X-Linked Homozygote Humans Image Processing, Computer-Assisted Immunohistochemistry Leukoencephalopathies/pathology Magnetic Resonance Imaging Male Middle Aged Myelin Sheath/pathology Neurologic Examination Polymerase Chain Reaction RNA, Messenger/biosynthesis/genetics Signal Transduction/genetics/physiology
 Zusammenfassung: 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-Hopitaux 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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Sprache(n): eng - English
 Datum: 2013-05-222013-07
 Publikationsstatus: Erschienen
 Seiten: -
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: DOI: 10.1016/S1474-4422(13)70053-X
ISSN: 1474-4465 (Electronic)1474-4422 (Print)
URI: http://www.ncbi.nlm.nih.gov/pubmed/23707145
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Titel: Lancet Neurology
  Andere : Lancet Neurol.
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: London, UK : Elsevier
Seiten: - Band / Heft: 12 (7) Artikelnummer: - Start- / Endseite: 659 - 668 Identifikator: ISSN: 1474-4422
CoNE: https://pure.mpg.de/cone/journals/resource/111025286560038