| Title: |
Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study |
| Authors: |
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, C.; Vles, J.; Vanderver, A.; Uziel, G.; Yalcinkaya, C.; Frints, S.; Kalscheuer, V.; Klooster, J.; Kamermans, M.; Abbink, T.; Wolf, N.; Sedel, F.; van der Knaap, M. |
| Source: |
Lancet Neurology |
| Publication Year: |
2013 |
| Collection: |
Max Planck Society: MPG.PuRe |
| Description: |
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 ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| ISSN: |
1474-4465 |
| Relation: |
info:eu-repo/semantics/altIdentifier/pissn/1474-4465 (Electronic)1474-4422 (Print); info:eu-repo/semantics/altIdentifier/urn/http://www.ncbi.nlm.nih.gov/pubmed/23707145 |
| Availability: |
http://hdl.handle.net/11858/00-001M-0000-0018-F3BD-9; http://hdl.handle.net/11858/00-001M-0000-0018-F3C2-C |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.5EFA3684 |
| Database: |
BASE |