大脑白质水肿ClC-2氯通道不足:一项观察性的分析研究。
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Depienne C, Bugiani M,裘布依C, Galanaud D, Touitou V, Postma N,效力过C,低地E, Tollard E, F达里奥,布莱斯•A•德•Die-Smulders CE、呋喃JS, Vanderver, Uziel G、C的契机,Frints SG, Kalscheuer VM, Klooster J, Kamermans M, Abbink TE,狼倪,Sedel F, van der Knaap女士
大脑白质水肿ClC-2氯通道不足:一项观察性的分析研究。
柳叶刀神经。2013年7月,12 (7):659 - 68。doi: 10.1016 / s1474 - 4422 (13) 70053 - x。2013年5月22日Epub。
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23707145 (在PubMed]
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背景:突变体小鼠模型表明,氯通道ClC-2功能离子和水的恒定性,但这在人类尚未得到证实。我们旨在定义新型疾病的特点是不同的患者的MRI异常模式来历不明的脑白质病,并确定基因突变在这些障碍。我们特别感兴趣的是脑白质病的特点是白质水肿,建议一个缺陷在离子和水恒定性。方法:观察分析研究中,我们招募患者脑白质病的特点是异常MRI信号的后四肢内部胶囊,中脑脑总花梗,小脑中间总花梗从我们的数据库来历不明的脑白质病的患者。我们使用外显子组测序来识别基因。我们筛选候选基因的额外病人Sanger测序和mRNA分析和研究功能基因突变的影响。我们评估了本地化ClC-2免疫组织化学和电镜在事后人类大脑的个体没有神经障碍。发现:七个病人满足我们的入选标准,三个与成人病和四个儿童疾病。我们确定了纯合子或compound-heterozygous突变在CLCN2三成人和儿科患者。我们发现的证据CLCN2 ClC-2的突变导致的损失函数。 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).