Scharf Madeleine, Miske Ramona, Heidenreich Fedor, Giess Ralf, Landwehr Peter, Blöcker Inga-Madeleine, Begemann Nora, Denno Yvonne, Tiede Stephan, Dähnrich Cornelia, Schlumberger Wolfgang, Unger Mandy, Teegen Bianca, Stöcker Winfried, Probst Christian, Komorowski Lars
From the Institute of Experimental Immunology (M.S., R.M., I.-M.B., N.B., Y.D., S.T., C.D., W. Schlumberger, M.U., B.T., W. Stöcker, C.P., L.K.), EUROIMMUN AG, Lübeck; and Departments of Neurology and Clinical Neurophysiology (F.H., R.G.) and Diagnostic and Interventional Radiology (P.L.), Hospital of the Henriettenstiftung, Hannover, Germany.
Neurology. 2015 Apr 21;84(16):1673-9. doi: 10.1212/WNL.0000000000001493. Epub 2015 Mar 25.
To identify an autoreactivity in a 66-year-old woman who presented with combined brainstem and cerebellar syndrome including vertical gaze palsy, severe progressive ataxia, and spastic tetraparesis, an acute deterioration of vision, dysarthria, and dysphagia with concurrent diagnosis of a colon adenocarcinoma.
Patient's serum and CSF underwent comprehensive autoantibody screening by indirect immunofluorescence assay and immunoblot. For autoantigen purification, a histo-immunoprecipitation technique was developed followed by mass spectrometrical analysis. Recombinant candidate antigens were expressed in HEK293 and used to verify the identification.
Indirect immunofluorescence assay screening revealed strong immunoglobulin G reactivity with neural tissues in serum and CSF, but not with a panel of 28 recombinantly expressed established neural autoantigens. The hitherto unknown target antigen was identified as the neuronal Na(+)/K(+) ATPase. Epitope mapping and competitive inhibition experiments showed that the autoantibodies were directed against the membrane-spanning alpha 3 subunit (ATP1A3) of the enzyme but did not bind to extracellular epitopes. Immunohistochemical analysis revealed overexpression of this subunit in the patient's tumor.
We describe a case of an anti-ATP1A3-associated neurologic disorder. Mutations in the gene encoding this neuronal surface protein have already been recognized as the cause of infantile alternating hemiplegia, rapid-onset dystonia parkinsonism, and CAPOS syndrome. Although the autoantibodies are unlikely to be pathogenic, they are likely to be rare biomarkers for the apparently paraneoplastic neurologic syndrome or for the tumor itself.
在一名66岁女性患者中鉴定自身反应性，该患者表现为脑干和小脑综合征合并症，包括垂直凝视麻痹、严重进行性共济失调和痉挛性四肢瘫，视力急性恶化、构音障碍和吞咽困难，同时诊断为结肠腺癌。
通过间接免疫荧光测定和免疫印迹对患者的血清和脑脊液进行全面的自身抗体筛查。为了纯化自身抗原，开发了一种组织免疫沉淀技术，随后进行质谱分析。重组候选抗原在HEK293中表达并用于验证鉴定结果。
间接免疫荧光测定筛查显示血清和脑脊液中的免疫球蛋白G与神经组织有强烈反应，但与一组28种重组表达的既定神经自身抗原无反应。迄今未知的靶抗原被鉴定为神经元钠/钾ATP酶。表位作图和竞争抑制实验表明，自身抗体针对该酶的跨膜α3亚基（ATP1A3），但不与细胞外表位结合。免疫组织化学分析显示该亚基在患者肿瘤中过表达。
我们描述了一例抗ATP1A3相关神经系统疾病的病例。编码这种神经元表面蛋白的基因突变已被确认为婴儿交替性偏瘫、快速发作性肌张力障碍帕金森综合征和CAPOS综合征的病因。虽然自身抗体不太可能具有致病性，但它们可能是明显的副肿瘤性神经系统综合征或肿瘤本身的罕见生物标志物。
