成人型亚历山大病：GFAP基因新的致病序列变异
Adult-Onset Alexander Disease: New Causal Sequence Variant in the GFAP Gene.
作者信息
Goerttler Tsepo, Zanetti Letizia, Regoni Maria, Egger Karl, Kellner Elias, Deuschl Cornelius, Kleinschnitz Christoph, Sassone Jenny, Klebe Stephan
机构信息
Department of Neurology (T.G., C.K., S.K.), Essen University Hospital, Germany; Division of Neuroscience (L.Z., M.R., J.S.), San Raffaele Scientific Institute; Vita-Salute San Raffaele University (L.Z., M.R., J.S.), Milan, Italy; Department of Radiology (K.E.), Tauernklinikum Zell am See, Academic Teaching Hospital of the Paracelsus University Salzburg, and Medical University of Vienna, Austria; Department of MR Physics (E.K.), Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Germany; and Institute of Diagnostic and Interventional Radiology and Neuroradiology (C.D.), University Hospital Essen, Germany.
出版信息
Neurol Genet. 2022 May 20;8(3):e681. doi: 10.1212/NXG.0000000000000681. eCollection 2022 Jun.
OBJECTIVES
Alexander disease (AD) is a rare disorder of the CNS. Diagnosis is based on clinical symptoms, typical MRI findings, and mutations in the glial fibrillary acid protein (GFAP) gene. In this case study, we describe a new mutation (p.L58P) in that caused a phenotype of adult-onset AD (AOAD).
METHODS
In our outpatient clinic, a patient presented with cerebellar and bulbar symptoms after brain concussion. We used MRI and performed next-generation exome sequencing (NGS) to find mutations in to diagnose AD. The mutation was then transfected into HeLa cell lines to prove its pathogenicity.
RESULTS
The brain MRI finding showed typical AD alterations. The NGS found a heterozygous variant of unknown significance in (c.173T>C; p.L58P). After transfecting HeLa cell lines with this mutation, we showed that GFAP-L58P formed pathogenic clusters of cytoplasmic aggregates.
DISCUSSION
We have found a new mutation that causes AOAD. We recommend that AOAD is included in the diagnostic workup in adult patients with gait ataxia and cerebellar and bulbar symptoms in association with a traumatic head injury.
目的
亚历山大病（AD）是一种罕见的中枢神经系统疾病。诊断基于临床症状、典型的MRI表现以及胶质纤维酸性蛋白（GFAP）基因突变。在本病例研究中，我们描述了GFAP基因中的一种新突变（p.L58P），该突变导致了成人型亚历山大病（AOAD）的表型。
方法
在我们的门诊诊所，一名患者在脑震荡后出现小脑和延髓症状。我们使用MRI并进行了下一代外显子组测序（NGS）以寻找GFAP基因中的突变来诊断AD。然后将该突变转染到HeLa细胞系中以证明其致病性。
结果
脑部MRI检查结果显示典型的AD改变。NGS在GFAP基因中发现了一个意义不明的杂合变异（c.173T>C；p.L58P）。用该突变转染HeLa细胞系后，我们发现GFAP-L58P形成了致病性的细胞质聚集体簇。
讨论
我们发现了一种导致AOAD的新突变。我们建议，对于有步态共济失调以及与头部外伤相关的小脑和延髓症状的成年患者，在诊断检查中应考虑AOAD。
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