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摘要: 多系统萎缩(MSA)是一种快速进展的罕见神经退行性疾病，以自主神经功能障碍、帕金森症、小脑性共济失调和锥体束征的不同组合为主要临床表现。该病起病隐匿、进展快、临床异质性大、早期确诊困难，阻碍了神经保护剂的开发。本文就MSA目前诊断标准、早期诊断标志物和治疗进展进行重点讨论，以期对临床医师临床诊疗提供帮助。Abstract: Multiple system atrophy (MSA) is a rare and rapidly-progressive neurodegenerative disorder, characterized by the combination of dysautonomia, poor levodopa responsive parkinsonism, cerebellar ataxia, and pyramidal tract signs. Insidious onset, clinical heterogeneity and progression of the disease complicate the difficulty of early diagnosis and challenge, the development of neuroprotective drugs. In order to improve the knowledge of diagnosis and treatment of the disease, this paper reviews advances in its diagnostic criteria, biomarkers of early diagnosis and management of the disease.
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表 1 MSA遗传学标志物汇总
Table 1. Summary of MSA genetic markers
作者 基因 位点 病例数 结果 参考文献 Scholz SW, et al. SNCA rs11931074；rs3857059 413例MSA；3974例HC 增加MSA发病风险 [19] Al-Chalabi A, et al. SNCA rs3822086 239例MSA；617例HC 增加MSA发病风险 [20] Chen Y, et al. SNCA rs3775444、rs3822086和
rs119310741276例PD；885例ALS；
364例MSA；846例HC与MSA发病无关 [21] Perez-Rodriguez D, et al. SNCA 基因拷贝数变异 26例PD；15例MSA；
18例HC体细胞SNCA基因的拷贝数变异与MSA的发病机制有关 [22] The Multiple-System
Atrophy Research
CollaborationCOQ2 V393A 6个MSA家系；
日本：363例MSA；2903例HC
欧洲：223例MSA；315例HC
北美：172例MSA；294例HC增加MSA发病风险 [25] Zhao Q, et al. COQ2 V393A 82例MSA；484例HC；以及meta分析 增加MSA发病风险 [26] Porto KJ, et al. COQ2 V393A 400例MSA；821例HC；以及meta分析 增加MSA发病风险 [27] Wernick AI, et al. GBA p.T408M 167例MSA；834例HC 增加MSA发病风险 [29] Lee K, et al. LRRK2 p.Ile1371Val 1例病理证实的MSA 一例病理证实的MSA患者中有LRRK2基因p.Ile1371Val变异 [30] Sklerov M, et al. GBA N370S；T369M；R496H 17例MSA；82例AD MSA患者携带GBA基因突变位点的频率高于AD患者 [31] Heckman MG, et al. LRRK2 p.M2397T；p.G1624G；
p.N2081D；p.G1624G-
M2397T177例MSA；768例HC LRRK2外显子变异可能与MSA易感性有关 [32] Ogaki K, et al. TREM2 p.R47H 257例MSA；1695例HC 增加MSA发病风险 [33] Cao B, et al. NOD2 rs3135500 431例MSA；441例HC 增加MSA发病风险 [34] Goldman JS, et al. C9orf72 六核苷酸重复序列扩增 1例MSA和ALS共存家系 C9orf72六核苷酸重复序列扩增的患者可表现为MSA、ALS或额颞痴呆 [35] Bonapace G, et al. C9orf72 六核苷酸重复序列扩增 100例MSA C9orf72六核苷酸重复序列扩增可能增加MSA发病风险 [36] Chen X, et al. C9orf72 六核苷酸重复序列扩增 619例PD；381例MSA；
632例HCC9orf72六核苷酸重复序列扩增与MSA和PD无关 [37] Sun Z, et al. C9orf72 六核苷酸重复序列扩增 141例MSA；
184例HCC9orf72六核苷酸重复序列扩增与MSA无关 [38] Schottlaender LV, et al. C9orf72 六核苷酸重复序列扩增 96例MSA；177例PSP；
18例CBDC9orf72六核苷酸重复序列扩增与MSA、PSP和CBD无关 [39] Labbé C, et al. MAPT H2；H1E；H1x；H1J 213例MSA；1312例HC MAPT基因变异与MSA发病风险相关 [40] Sailer A, et al. EDN1
MAPT
FBXO47
ELOVL7rs16872704
rs9303521
rs78523330
rs7715147918例MSA；3864例HC 发现4个可能与MSA发病相关有意义的新变异位点 [41] Gu X, et al. EDN1
MAPT
FBXO47
ELOVL7rs16872704
rs9303521
rs78523330
rs7715147906例MSA；941例HC 4个新变异位点与MSA无关 [42] MSA：多系统萎缩；HC：健康对照；PD：帕金森病；ALS：肌萎缩侧索硬化；AD：阿尔兹海默症；PSP：进行性核上性麻痹；CBD：皮质基底节变性 
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表 2 MSA对症治疗策略
Table 2. Symptomatic treatment strategies for MSA
症状 治疗方案 共济失调 丁螺环酮；物理治疗 帕金森样症状 左旋多巴；多巴胺受体激动剂；金刚烷胺等 肌张力障碍(眼睑痉挛、颈部前屈等) 肉毒毒素治疗 体位性低血压 增加液体和盐的摄入；穿弹力袜或使用腹部压力带；米多君；氟氢可的松；屈昔多巴等 尿频、尿急、急迫性尿失禁 抗胆碱药在内的解痉药；肉毒毒素治疗 尿潴留 坦索罗辛；哌唑嗪；间歇性自我清洁导尿 快动眼睡眠行为障碍 营造安全的睡眠环境，如安装床边护栏、在地上铺软垫等；氯硝西泮；褪黑素 喘鸣 持续气道正压通气或气管造口术
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表 3 MSA药物临床试验总结
Table 3. Summary of clinical trials of MSA drugs
药物名称 机制 试验阶段 试验结果 参考文献或注册号 利福平 抑制α-突触核蛋白聚集 Ⅱ期 对延缓疾病进展无效 [94] 锂剂 抑制α-突触核蛋白聚集 Ⅱ期 因严重副作用试验终止 [95] EGCG(绿茶提取物) 抑制α-突触核蛋白聚集 Ⅲ期 对延缓疾病进展无效 NCT02008721 雷帕霉素 mTOR抑制剂 Ⅱ期 对延缓疾病进展无效 NCT03589976 PBT434 抑制α-突触核蛋白聚集 Ⅱ期 正在进行中 NCT05109091 NPT200-11 抑制α-突触核蛋白错误折叠 Ⅰ期 等待Ⅰb期研究 NCT02606682 Anle138b 调节α-突触核蛋白寡聚化 Ⅰ期 正在进行中 NCT04208152 PD03A 针对α-突触核蛋白的疫苗 Ⅰ期 显示了安全性、耐受性及免疫原性证据 [96] 米诺环素 调节神经炎症 Ⅲ期 对延缓疾病进展无效 NCT00146809 IVIg 调节神经炎症 - 患者的临床评分改善 [97] 利鲁唑 神经保护剂 Ⅲ期 对延缓疾病进展无效 NCT00211224 雷沙吉兰 神经保护剂 Ⅱ期 对延缓疾病进展无效 NCT00977665 氟西汀 神经保护剂 Ⅱ期 对延缓疾病进展无效 NCT01146548 BHV3241(AZD3241) 神经保护剂 Ⅲ期 未达到满意的终点指标 NCT03952806 辅酶Q10 保护线粒体功能 Ⅱ期 正在进行中 NCT01793168 艾塞那肽[227]NMBI 螯合剂和抗氧化剂 Ⅱ期 正在进行中 NCT04184063 KM-819 神经保护剂 Ⅰ期 良好的耐受性 NCT03022799 间充质干细胞 神经保护/营养支持 Ⅰ期 延缓疾病进展 [101]
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