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

Christel Depienne, Marianna Bugiani, Céline Dupuits, Damien Galanaud, Valérie Touitou, Nienke Postma, Carola van Berkel, Emiel Polder, Eleonore Tollard, Frédéric Darios, Alexis Brice, Christine E. de Die-Smulders, Johannes S. Vles, Adeline Vanderver, Graziella Uziel, Cengiz Yalcinkaya, Suzanna G. Frints, Vera M. Kalscheuer, Jan Klooster, Maarten KamermansTruus E M Abbink, Nicole I. Wolf, Frédéric Sedel, Marjo S. van der Knaap

Research output: Contribution to journalArticle

Abstract

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).

Original languageEnglish
Pages (from-to)659-668
Number of pages10
JournalThe Lancet Neurology
Volume12
Issue number7
DOIs
Publication statusPublished - Jul 2013

Fingerprint

Observational Studies
Edema
Leukoencephalopathies
Brain
Homeostasis
Mutation
Ions
Water
Pediatrics
Myelin Sheath
National Institute of Neurological Disorders and Stroke
Genes
Exome
White Matter
ClC-2 chloride channels
Internal Capsule
Cerebellar Ataxia
Optic Nerve Diseases
Brain Diseases
Paris

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

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

Brain white matter oedema due to ClC-2 chloride channel deficiency : An observational analytical study. / Depienne, Christel; Bugiani, Marianna; Dupuits, Céline; Galanaud, Damien; Touitou, Valérie; Postma, Nienke; van Berkel, Carola; Polder, Emiel; Tollard, Eleonore; Darios, Frédéric; Brice, Alexis; de Die-Smulders, Christine E.; Vles, Johannes S.; Vanderver, Adeline; Uziel, Graziella; Yalcinkaya, Cengiz; Frints, Suzanna G.; Kalscheuer, Vera M.; Klooster, Jan; Kamermans, Maarten; Abbink, Truus E M; Wolf, Nicole I.; Sedel, Frédéric; van der Knaap, Marjo S.

In: The Lancet Neurology, Vol. 12, No. 7, 07.2013, p. 659-668.

Research output: Contribution to journalArticle

Depienne, C, Bugiani, M, Dupuits, C, Galanaud, D, Touitou, V, Postma, N, van Berkel, C, Polder, E, Tollard, E, Darios, F, Brice, A, de Die-Smulders, CE, Vles, JS, Vanderver, A, Uziel, G, Yalcinkaya, C, Frints, SG, Kalscheuer, VM, Klooster, J, Kamermans, M, Abbink, TEM, Wolf, NI, Sedel, F & van der Knaap, MS 2013, 'Brain white matter oedema due to ClC-2 chloride channel deficiency: An observational analytical study', The Lancet Neurology, vol. 12, no. 7, pp. 659-668. https://doi.org/10.1016/S1474-4422(13)70053-X
Depienne, Christel ; Bugiani, Marianna ; Dupuits, Céline ; Galanaud, Damien ; Touitou, Valérie ; Postma, Nienke ; van Berkel, Carola ; Polder, Emiel ; Tollard, Eleonore ; Darios, Frédéric ; Brice, Alexis ; de Die-Smulders, Christine E. ; Vles, Johannes S. ; Vanderver, Adeline ; Uziel, Graziella ; Yalcinkaya, Cengiz ; Frints, Suzanna G. ; Kalscheuer, Vera M. ; Klooster, Jan ; Kamermans, Maarten ; Abbink, Truus E M ; Wolf, Nicole I. ; Sedel, Frédéric ; van der Knaap, Marjo S. / Brain white matter oedema due to ClC-2 chloride channel deficiency : An observational analytical study. In: The Lancet Neurology. 2013 ; Vol. 12, No. 7. pp. 659-668.
@article{840bddd0171e4192bb326949338ad30f,
title = "Brain white matter oedema due to ClC-2 chloride channel deficiency: An observational analytical study",
abstract = "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-H{\^O}pitaux 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).",
author = "Christel Depienne and Marianna Bugiani and C{\'e}line Dupuits and Damien Galanaud and Val{\'e}rie Touitou and Nienke Postma and {van Berkel}, Carola and Emiel Polder and Eleonore Tollard and Fr{\'e}d{\'e}ric Darios and Alexis Brice and {de Die-Smulders}, {Christine E.} and Vles, {Johannes S.} and Adeline Vanderver and Graziella Uziel and Cengiz Yalcinkaya and Frints, {Suzanna G.} and Kalscheuer, {Vera M.} and Jan Klooster and Maarten Kamermans and Abbink, {Truus E M} and Wolf, {Nicole I.} and Fr{\'e}d{\'e}ric Sedel and {van der Knaap}, {Marjo S.}",
year = "2013",
month = "7",
doi = "10.1016/S1474-4422(13)70053-X",
language = "English",
volume = "12",
pages = "659--668",
journal = "The Lancet Neurology",
issn = "1474-4422",
publisher = "Lancet Publishing Group",
number = "7",

}

TY - JOUR

T1 - Brain white matter oedema due to ClC-2 chloride channel deficiency

T2 - An observational analytical study

AU - Depienne, Christel

AU - Bugiani, Marianna

AU - Dupuits, Céline

AU - Galanaud, Damien

AU - Touitou, Valérie

AU - Postma, Nienke

AU - van Berkel, Carola

AU - Polder, Emiel

AU - Tollard, Eleonore

AU - Darios, Frédéric

AU - Brice, Alexis

AU - de Die-Smulders, Christine E.

AU - Vles, Johannes S.

AU - Vanderver, Adeline

AU - Uziel, Graziella

AU - Yalcinkaya, Cengiz

AU - Frints, Suzanna G.

AU - Kalscheuer, Vera M.

AU - Klooster, Jan

AU - Kamermans, Maarten

AU - Abbink, Truus E M

AU - Wolf, Nicole I.

AU - Sedel, Frédéric

AU - van der Knaap, Marjo S.

PY - 2013/7

Y1 - 2013/7

N2 - 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).

AB - 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).

UR - http://www.scopus.com/inward/record.url?scp=84879026505&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84879026505&partnerID=8YFLogxK

U2 - 10.1016/S1474-4422(13)70053-X

DO - 10.1016/S1474-4422(13)70053-X

M3 - Article

C2 - 23707145

AN - SCOPUS:84879026505

VL - 12

SP - 659

EP - 668

JO - The Lancet Neurology

JF - The Lancet Neurology

SN - 1474-4422

IS - 7

ER -