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中国循证儿科杂志

中国循证儿科杂志 ›› 2023, Vol. 18 ›› Issue (4): 286-290.DOI: 10.3969/j.issn.1673-5501.2023.04.008

• 论著 • 上一篇    下一篇

诺西那生钠治疗5q型脊髓性肌萎缩患儿68例病例系列报告

马凯1a，郭晓华1b，于春梅1a，金瑞锋1a，刘芳芳2，高敏1c   

  1. 1 山东大学附属儿童医院 济南，250022；a 神经内科，b 康复科，c 儿科研究所；2 山东第一医科大学附属中心医院 济南，250013
  • 收稿日期:2023-05-16 修回日期:2023-07-22 出版日期:2023-08-25 发布日期:2023-08-25
  • 通讯作者: 刘芳芳，高敏

Nusinersen treatment in 68 children with 5q spinal muscular atrophy: A case series report

MA Kai1a, GUO Xiaohua1b, YU Chunmei1a, JIN Ruifeng1a, LIU Fangfang2, GAO Min1c   

  1. 1 Children's Hospital Affiliated to Shandong University, Jinan 250022,China; a.Department of Neurology, b.Department of Rehabilitation, c.Pediatric Research Institute; 2 Central Hospital Affiliated to Shandong First Medical University, Jinan 250013,China
  • Received:2023-05-16 Revised:2023-07-22 Online:2023-08-25 Published:2023-08-25
  • Contact: LIU Fangfang,GAO Min

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摘要： 背景 诺西那生钠正式进入中国临床用于治疗5q型脊髓性肌萎缩（SMA）不久，目前国内关于诺西那生钠治疗SMA的病例报告不多。 目的 了解诺西那生钠治疗5q型SMA患儿的疗效、安全性和脑脊液神经纤维丝轻链蛋白（NFL）水平。 设计 病例系列报告。 方法 纳入2020年1月至2023年6月30日山东大学附属儿童医院神经内科以诺西那生钠为单药初始治疗≥14个月的5q型SMA患儿。采用多重连接依赖探针扩增（MLPA）技术或荧光定量PCR（qPCR）技术检测SMN1基因7号外显子。临床分型依据患儿发病年龄和所获得的最大运动功能里程碑。行常规或超声引导下腰椎穿刺留取脑脊液标本检测NFL水平，并通过鞘内注射完成诺西那生钠给药。由接受过专业培训、具有评分资质的康复医师完成治疗前后费城儿童医院神经肌肉评估量表（CHOP INTEND）、修订的上肢模块测试(RULM）、汉默史密斯运动功能扩展量表（HFMSE）和6 min步行试验（6MWT）评分。采集患儿性别、发病日期等一般信息和治疗期间不良事件。 主要结局指标 诺西那生钠治疗14个月后的运动功能量表评分。 结果 68例诺西那生钠治疗≥14个月的SMA患儿进入本文分析，女32例（47.0%）。Ⅰ型9例（13.2%），Ⅱ型40例（58.8%），Ⅲ型19例（27.9%）。中位发病年龄为10（7,13.8）月龄，中位确诊年龄为17.5（12,37）月龄。SMN1基因7号外显子纯合缺失64例（94.1%），SMN1基因突变4例。60例患儿（88.2%）运动功能改善具有临床意义，其中Ⅰ型7例、Ⅱ型37例、Ⅲ型16例。CHOP INTEND量表评分提升≥4分占90.0%（18/20），HFMSE量表评分提升≥3分占97.8%（44/45）; 6MWT行走距离延长≥30 m占92.3%（12/13）;RULM评分提升≥2分占66.7%（12/18）;2例治疗后获得新的运动功能里程碑。15例Ⅱ型SMA患儿治疗前脑脊液NFL水平为176.6（104.5，199.6） pg·mL-1，负荷剂量治疗结束后（首次用药后第184天）NFL水平为69.2（40.5，89.3） pg·mL-1，差异有统计学意义。治疗期间不良事件：发热3例，Ⅲ型1例，Ⅱ型2例，均自行缓解；呼吸道感染2例，Ⅰ型和Ⅱ型各1例，治疗后缓解；便秘、肌痛、眩晕和咳嗽各1例，均为Ⅱ型，均自行缓解；眩晕1例（Ⅰ型），自行缓解；肝功能异常1例（Ⅱ型），治疗7 d恢复正常。未发生严重不良事件。 结论 诺西那生钠治疗14个月可以改善5q型SMA患儿的运动功能，且安全性好；诺西那生钠负荷剂量治疗后可明显降低Ⅱ型SMA患儿脑脊液NFL水平。

关键词: 脊髓性肌萎缩, 诺西那生钠, 神经纤维丝轻链蛋白, 儿童, 治疗

Abstract: Background Nusinersen has been officially used for the treatment of 5q spinal muscular atrophy (SMA) in China recently. By now there are few domestic case reports on the treatment of SMA with nusinersen. Objective To investigate the efficacy, safety and levels of neurofilament light chain protein (NFL) in cerebrospinal fluid with treatment of nusinersen in children with 5q spinal muscular atrophy. Design Case series report. Methods Patients with 5q SMA who were initially treated with nusinersen as monotherapy for not less than 14 months in the Department of Neurology, Children's Hospital of Shandong University from January 2020 to June 30, 2023 were enrolled. Multiple ligation dependent probe amplification (MLPA) or fluorescence quantitative PCR (qPCR) methods were used to detect exon 7 of SMN1 gene. Clinical classification is based on the age of symptom onset and the maximum motor function achieved. Cerebrospinal fluid samples for the detection of neurofilament light chain protein (NFL) level were collected by routine lumbar punctures or ultrasound-guided lumbar punctures, and nusinersen was administrated via intrathecal injection. The Children′s Hospital of Philadelphia infant test of neuromuscular disorders (CHOP INTEND), the Revised Upper Limb Module Test (RULM), the Hammersmith functional motor scale expanded (HFMSE), and the 6-minute walk test (6MWT) were performed by a professionally trained and qualified rehabilitation physician before and after treatment. General information such as gender, date of birth, date of symptom onset, and adverse events during treatment were collected. Main outcome measures The scores of motor function scale after 14 months treatment with nusinersen. Results In total, 68 SMA pediatric patients with treatment duration not less than 14 months were included in this study, including 32 girls (47.0%). There were 9 cases of type I (13.2%), 40 cases of typeⅡ (58.8%), and 19 cases of type Ⅲ (27.9%). The median age of disease onset is 10 (7,13.8) months, and the median age of diagnosis is 17.5 (12,37) months. Homozygous deletion of exon 7 in SMN1 gene occurred in 64 cases (94.1%), and intragenic mutation of SMN1 gene occurred in 4 cases. The improvement of motor function in 60 children (88.2%) had clinical significance, including 7 cases of type I, 37 cases of typeⅡ, and 16 cases of type Ⅲ. In total, 90.0% (18/20) cases showed a score improvement by ≥4 points on the CHOP INTEND scale, while 97.8% (44/45) cases showed a score improvement by ≥3 points on the HFMSE scale. In total, 92.3% (12/13) cases showed a distance extension by ≥30 meters on the 6MWT; 66.7% (12/18) cases showed a score improvement by ≥2 points on the RULM scale. Two cases achieved new motor function milestones after treatment. The NFL level in the cerebrospinal fluid of 15 children with SMA typeⅡ declined to 69.2 (40.5, 89.3) pg·mL-1 after the loading dose therapy (184th day after first drug administration) comparing with 176.6 (104.5,199.6) pg·mL-1 before treatment, the difference is statistically significant. Adverse events during treatment included fever in 3 cases with 1 case of type Ⅲ, 2 cases of type Ⅱ, all of which were relieved spontaneously; respiratory tract infection in 2 cases with 1 case of type I and 1 case of type Ⅱ, which were relieved after treatment; constipation, myalgia, vertigo and cough occurred in 1 type Ⅱ case each, all of which were relieved spontaneously and 1 case of typeⅡ with abnormal liver function, which normalized after 7 days treatment. No serious adverse event occurred. Conclusions Nusinersen can improve the motor function of children with 5q SMA after 14 months of treatment with good safety. The NFL level in cerebrospinal fluid of children with SMA typeⅡ can be significantly decreased after the nusinersen loading dose therapy.

Key words: Spinal muscular atrophy, Nusinersen, Neurofilament light chain, Children, Treatment