北京大学学报(医学版) ›› 2021, Vol. 53 ›› Issue (5): 957-963. doi: 10.19723/j.issn.1671-167X.2021.05.025

• 论著 • 上一篇    下一篇

远端型遗传性运动神经病8例的临床、病理及遗传学特点

刘梅歌1,方朴2,王严1,丛璐1,范洋溢1,袁远1,徐燕1,张俊1,洪道俊1,2,()   

  1. 1.北京大学人民医院神经内科,北京 100044
    2.南昌大学第一附属医院神经内科,南昌 330006
  • 收稿日期:2019-10-14 出版日期:2021-10-18 发布日期:2021-10-11
  • 通讯作者: 洪道俊 E-mail:hongdaojun@hotmail.com
  • 基金资助:
    国家自然科学基金(81870996)

Clinical, pathological and genetic characteristics of 8 patients with distal hereditary motor neuropathy

LIU Mei-ge1,FANG Pu2,WANG Yan1,CONG Lu1,FAN Yang-yi1,YUAN Yuan1,XU Yan1,ZHANG Jun1,HONG Dao-jun1,2,()   

  1. 1. Department of Neurology, Peking University People’s Hospital, Beijing 100044, China
    2. Department of Neurology, the First Affiliated Hospital of Nanchang University, Nanchang 330006, China
  • Received:2019-10-14 Online:2021-10-18 Published:2021-10-11
  • Contact: Dao-jun HONG E-mail:hongdaojun@hotmail.com
  • Supported by:
    National Natural Science Foundation of China(81870996)

摘要:

目的: 远端型遗传性运动神经病(distal hereditary motor neuropathy, dHMN)是一组选择性累及运动神经及其神经元的退行性病变,可引起肢体远端肌肉进行性萎缩无力。总结8例dHMN先证者的临床、电生理、病理及遗传学特点,丰富我国dHMN先证者的临床表型和基因型资料,提高临床工作者对dHMN的认识和诊治水平。方法: 选择2018年6月至2019年4月于北京大学人民医院神经内科就诊的8例dHMN先证者并进而追踪其家系,回顾性分析先证者的临床症状、神经电生理改变、病理特点及基因突变情况。运用基因靶向二代测序技术对所有先证者进行周围神经病相关基因检测,通过 Sanger测序验证突变位点,并对可获得的家系成员进行遗传共分离分析。结果: 先证者发病年龄11~64岁,中位数39.5岁,均为慢性起病,进行性发展,主要表现为远端肢体无力,并逐渐出现肌肉萎缩。神经电生理结果示选择性运动神经损害,运动神经复合肌肉动作电位波幅下降伴神经传导速度减慢,感觉神经不受累,针刺肌电图符合神经源性损害表现。2例先证者肌肉活检显示神经源性骨骼肌损害,1例先证者腓肠神经活检提示感觉神经受累轻微。基因测序显示8例先证者携带了8种不同的已知dHMN致病基因,3例有已报道的致病突变位点,基因诊断率为37.5%,其余5例为临床意义未明的新发点突变,其中2例突变在家系内共分离。结论: dHMN是一组临床和基因均具有显著异质性的遗传性周围神经病,二代测序技术广泛运用于dHMN先证者的致病基因搜寻,但仍有超过一半的先证者不能得到明确的基因诊断。

关键词: 远端型遗传性运动神经病, 临床表现, 肌电图, 病理, 基因

Abstract:

Objective: Distal hereditary motor neuropathy (dHMN) comprises a heterogeneous group of inherited disorders associated with neurodegeneration of motor nerves and neurons, mainly charac-terized by progressive atrophy and weakness of distal muscle without clinical or electrophysiological sensory abnormalities. To improve the recognition and diagnosis of the disease, we summarized the clinical manifestations, electrophysiological, pathological, and genetic characteristics in eight patients with dHMN. Methods: Eight probands from different families diagnosed with dHMN were recruited in this study between June 2018 and April 2019 at Peking University People’s Hospital. Eight patients underwent complete neurological examination and standard electrophysiological examinations. The clinical criteria were consistent with the patients presenting with a pure motor neuropathy with no sensory changes on electrophysiology. The detailed clinical symptoms, neurophysiological examinations, pathological features and gene mutations were analyzed retrospectively. Genetic testing was performed on the eight patients using targeted next-generation sequencing panel for inherited neuromuscular disorder and was combined with segregation analysis. Results: The age of onset ranged between 11 and 64 years (median 39.5 years) in our dHMN patients. All the cases showed a slowly progressive disease course, mainly characterized by distal limb muscle weakness and atrophy. The motor nerve conduction revealed decreased compound muscle action potential amplitude and velocity, while the sensory nerve conduction velocities and action potentials were not affected. Needle electromyography indicated neurogenic chronic denervation in all patients. Muscle biopsy performed in two patients demonstrated neurogenic skeletal muscle damage. Sural nerve biopsy was performed in one patient, Semithin sections shows relatively normal density and structure of large myelinated fibers, except very few fibers with thin myelin sheaths, which suggested very mild sensory nerve involvement. Eight different genes known to be associated with dHMN were identified in the patients by next-generation sequencing, pathogenic dHMN mutations were identified in three genes, and the detection rate of confirmed genetic diagnosis of dHMN was 37.5% (3/8). Whereas five variants of uncertain significance (VUS) were identified, among which two novel variants co-segregated the phenotype. Conclusion: dHMN is a group of inherited peripheral neuropathies with great clinical and genetic heterogeneity. Next-generation sequencing is widely used to discover pathogenic genes in patients with dHMN, but more than half of the patients still remain genetically unknown.

Key words: Distal hereditary motor neuropathy, Clinical manifestations, Electromyography, Pathology, Gene

中图分类号: 

  • R596

表1

8例dHMN先证者的临床表现、体征及实验室检查结果"

Pt Gender AAD/
years
AAO/
years
Distal limb atrophy Foot deformities Deep tendon
reflexes UL/LL
Sensory loss CK/(U/L) Needle EMG Muscle biopsy
1 M 63 60 Yes No +/- No 400-700 Neurogenic No
2 F 36 33 Yes Yes +++/+ No 189 Neurogenic Neurogenic
3 M 45 27 Yes No +/- No 700-987 Neurogenic No
4 M 65 64 Yes No +++/+++ Yes Normal Neurogenic No
5 M 29 24 Yes Yes +/+ No 428 Neurogenic Neurogenic
6 F 47 46 Yes No -/- No Normal Neurogenic No
7 F 16 11 Yes Yes +/+++ No 189-217 Neurogenic No
8 F 51 49 Yes No -/+ No Unknown Neurogenic No

表2

8例dHMN先证者的神经传导速度检查结果"

Pt MCV SCV
Median nerve
(wrist)
Ulnar nerve
(wrist)
Peroneal nerve
(ankle)
Tibial nerve
(ankle)
Median nerve
(wrist)
Ulnar nerve
(wrist)
radial nerve
(forearm)
Sural nerve
(lower leg)
Amp/
mV
CV/
(m/s)
Amp/
mV
CV/
(m/s)
Amp/
mV
CV/
(m/s)
Amp/
mV
CV/
(m/s)
Amp/
μV
CV/
(m/s)
Amp/
μV
CV/
(m/s)
Amp/
μV
CV/
(m/s)
Amp/
μV
CV/
(m/s)
1 L - - - - NR NR - - - - - - 7.0 43.0
R 13.2 56.0 8.4 47↓ 1.6↓ 36.0↓ 0.4↓ 41↓ 24.0 55.0 34.0 56.0 24.0 55.0 12.0 44.0
2 L 17.9 58.3 14.8 63.6 * 6.6↓ 49.2 74.6 63.6 62.8 59.7 41.0 54.5 *
R 11.9 66.0 9.4 62.0 0.2↓ 39.4↓ 5.8↓ 50.4 31.9 58 53.2 63.7 36.1 63.6 19.7 48.3
3 L 6.5 52.4 7.0 39.6 2.7 43.1 3.1↓ 37.5↓ 7.6 48.3 5.8 40.0 - - 3.9 50.0
R 7.3 40.2 8.5 52.4 3.9 30↓ 3.7↓ 37.6↓ 10.0 46.7 6.7 44.6 - - 1.9 46.7
4 L 13.1 56.0 19.9 56.0 5.2 41↓ 23.6 46.0 30.0 58.0 16.0 52.0 31.0 57.0 1.0 50.0
R 11.6 55.0 14.9 54.0 3.0 41↓ 24.1 44.0 39.0 60.0 27.0 57.0 26.0 59.0 3.0 43.0
5 L 19.9 56.0 21.6 55.0 3.9 43.0 2.0↓ 44.0 60.0 59.0 34.0 57.0 16.0 59.0 9.0 53.0
R 26.3 58.0 20.3 57.0 3.6 43.0 3.4↓ 44.0 37.0 58.0 42,0 54.0 23.0 53.0 11.0 50.0
6 L 18.2 56.0 14.7 56.4 7.4 43.5 15.0 46.7 85.5 60.8 38.4 54.7 15.9 57.8 19.1 50.0
R 14.6 60.6 14.7 65.0 10.6 49.2 16.7 46.7 32.2 60.4 22.2 50.0 15.9 57.8 24.4 50.0
7 L 9.2 60.0 6.5↓ 55.5 NR 0.7↓ 44.1 68.4 61.3 40.0 51.4 24.8 54.7 7.8 47.6
R 0.4↓ 52.3 0.8↓ 55.5 NR 0.9↓ 48.1 51.2 59.0 20.4 55.0 18.7 61.7 17.7 48.4
8 L 17.9 60.7 13.2 71.0 6.1 50.0 19.3 49.3 50.4 56 19 52.1 35.8 56.8 4.6 59.4
R 21.5 57.6 13.1 73.6 5.0 54.4 19.7 48.7 28.8 59 29.1 58.2 38.3 58.8 5.8 57.0

图1

先证者2肌肉活检结果"

图2

先证者2腓肠神经活检结果"

表3

8例dHMN先证者的基因突变特点"

Pt Gene cDNA change AA change Inheritance Haplotype Function ACMG class
1 HSPB1 c.379C>T p.Arg127Trp AD het Chaperone protein P
2 AARS c.2177+1G>A - AD het tRNA Synthetase VUS
3 SETX c.3631C>T p.Arg1211Cys AD het RNA/DNA metabolism VUS
4 DYNC1H1 c.12823A>C p.Thr4275Pro AD het Cytoskeleton VUS
5 DNAJB2 c.184C>T p.Arg62Trp AR hoz Chaperone protein VUS
6 HSPB8 c.137C>A p.Ala46Asp AD het Chaperone protein VUS
7 BSCL2 c.269C>T p.Ser90Leu AD het ER protein P
8 BICD2 c.1823C>T p.Ser608Leu AD het Cytoskeleton P

图3

先证者3、先证者5的家系图及Sanger测序结果"

[1] Garg N, Park SB, Vucic S, et al. Differentiating lower motor neuron syndrome [J]. J Neurol Neurosurg Psychiatry, 2017, 88(6):474-483.
doi: 10.1136/jnnp-2016-313526
[2] Frasquet M, Rojas-García R, Argente-Escrig H, et al. Distal hereditary motor neuropathies: mutation spectrum and genotype-phenotype correlation [J]. Eur J Neurol, 2021, 28(4):1334-1343.
doi: 10.1111/ene.14700 pmid: 33369814
[3] Bansagi B, Griffin H, Whittaker RG, et al. Genetic heterogeneity of motor neuropathies [J]. Neurology, 2017, 88(13):1226-1234.
doi: 10.1212/WNL.0000000000003772
[4] Bacquet J, Stojkovic T, Boyer A, et al. Molecular diagnosis of inherited peripheral neuropathies by targeted next-generation sequencing: molecular spectrum delineation [J]. BMJ Open, 2018, 8(10):e21632.
[5] Echaniz-Laguna A, Geuens T, Petiot P, et al. Axonal neuropathies due to mutations in small heat shock proteins: clinical, genetic, and functional insights into novel mutations [J]. Hum Mutat, 2017, 38(5):556-568.
doi: 10.1002/humu.23189 pmid: 28144995
[6] Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology [J]. Genet Med, 2015, 17(5):405-424.
doi: 10.1038/gim.2015.30 pmid: 25741868
[7] Tanabe H, Higuchi Y, Yuan JH, et al. Clinical and genetic features of charcot-marie-tooth disease 2F and hereditary motor neuropathy 2B in Japan [J]. J Peripher Nerv Syst, 2018, 23(1):40-48.
doi: 10.1111/jns.2018.23.issue-1
[8] Windpassinger C, Auer-Grumbach M, Irobi J, et al. Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome [J]. Nat Genet, 2004, 36(3):271-276.
doi: 10.1038/ng1313
[9] Novarino G, Fenstermaker AG, Zaki MS, et al. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders [J]. Science, 2014, 343(6170):506-511.
doi: 10.1126/science.1247363 pmid: 24482476
[10] Xie Y, Lin Z, Pakhrin PS, et al. Genetic and clinical features in 24 Chinese distal hereditary motor neuropathy families [J/OL]. Front Neurol, 2020, 11:603003(2020-12-14)[2020-12-15]. https://pubmed-ncbi-nlm-nih-gov-443.webvpn.bjmu.edu.cn/33 3810781/ .
[11] 张付峰, 卢晓琴, 严新翔, 等. 远端型遗传性运动神经病的临床特征分析 [J]. 第二军医大学学报, 2009, 30(1):57-60.
[12] De Jonghe P, Auer-Grumbach M, Irobi J, et al. Autosomal dominant juvenile amyotrophic lateral sclerosis and distal hereditary motor neuronopathy with pyramidal tract signs: synonyms for the same disorder [J]. Brain, 2002, 125(Pt 6):1320-1325.
pmid: 12023320
[13] Motley WW, Griffin LB, Mademan I, et al. A novel AARS mutation in a family with dominant myeloneuropathy [J]. Neurology, 2015, 84(20):2040-2047.
doi: 10.1212/WNL.0000000000001583
[14] Luigetti M, Fabrizi GM, Madia F, et al. Seipin S90L mutation in an Italian family with CMT2/dHMN and pyramidal signs [J]. Muscle Nerve, 2010, 42(3):448-451.
doi: 10.1002/mus.21734 pmid: 20806400
[15] Beecroft SJ, McLean CA, Delatycki MB, et al. Expanding the phenotypic spectrum associated with mutations of DYNC1H1 [J]. Neuromuscul Disord, 2017, 27(7):607-615.
doi: 10.1016/j.nmd.2017.04.011
[16] Dierick I, Baets J, Irobi J, et al. Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study [J]. Brain, 2008, 131(Pt 5):1217-1227.
doi: 10.1093/brain/awn029 pmid: 18325928
[17] Rossor AM, Evans MR, Reilly MM. A practical approach to the genetic neuropathies [J]. Pract Neurol, 2015, 15(3):187-198.
doi: 10.1136/practneurol-2015-001095
[18] Liu X, Duan X, Zhang Y, Sun A, et al. Molecular analysis and clinical diversity of distal hereditary motor neuropathy [J]. Eur J Neurol, 2020, 27:1319-1326.
doi: 10.1111/ene.14260 pmid: 32298515
[19] Beijer D, Baets J. The expanding genetic landscape of hereditary motor neuropathies [J]. Brain, 2020, 143(Pt 12):3540-3563.
doi: 10.1093/brain/awaa311
[1] 朱小玲,李文静,王宪娥,宋文莉,徐莉,张立,冯向辉,路瑞芳,释栋,孟焕新. 细胞色素B-245α链及胆固醇酯转运蛋白基因多态性与广泛型侵袭性牙周炎易感性的关系[J]. 北京大学学报(医学版), 2022, 54(1): 18-22.
[2] 薛江,张建运,时瑞瑞,谢晓艳,白嘉英,李铁军. 105例口腔颅颌面部纤维性结构不良的临床病理分析[J]. 北京大学学报(医学版), 2022, 54(1): 54-61.
[3] 张梅香,史文芝,刘建新,王春键,李燕,王蔚,江滨. MLL-AF6融合基因阳性急性髓系白血病的临床特征及预后[J]. 北京大学学报(医学版), 2021, 53(5): 915-920.
[4] 冯科,倪菁菁,夏彦清,曲晓伟,张慧娟,万锋,洪锴,张翠莲,郭海彬. 3例SUN5基因变异导致无头精子症的遗传学分析和助孕治疗结局[J]. 北京大学学报(医学版), 2021, 53(4): 803-807.
[5] 郭子宁, 梁志生, 周仪, 张娜, 黄捷. 基于国际疾病分类的心血管疾病亚型的基因组学研究[J]. 北京大学学报(医学版), 2021, 53(3): 453-459.
[6] 周川, 马雪, 邢云昆, 李璐迪, 陈洁, 姚碧云, 傅娟玲, 赵鹏. 基于肿瘤基因组图谱数据库探索性筛选潜在泛癌生物标志物[J]. 北京大学学报(医学版), 2021, 53(3): 602-607.
[7] 赵凯,常志芳,王志华,庞春艳,王永福. 基因沉默肽基精氨酸脱亚胺酶4的表达对胶原诱导关节炎小鼠肺间质病变的影响[J]. 北京大学学报(医学版), 2021, 53(2): 235-239.
[8] 刘建,王宪娥,吕达,乔敏,张立,孟焕新,徐莉,毛铭馨. 广泛型侵袭性牙周炎患者牙根形态异常与相关致病基因的关联[J]. 北京大学学报(医学版), 2021, 53(1): 16-23.
[9] 吴君怡,余淼,孙仕晨,樊壮壮,郑静蕾,张刘陶,冯海兰,刘洋,韩冬. 少汗性外胚层发育不良患者EDA基因突变检测及表型分析[J]. 北京大学学报(医学版), 2021, 53(1): 24-33.
[10] 王迎春,黄永辉,常虹,姚炜,闫秀娥,李柯,张耀鹏,郑炜. 十二指肠乳头息肉良、恶性病变比较及活检准确性[J]. 北京大学学报(医学版), 2021, 53(1): 204-209.
[11] 高鹏,雒艳萍,李俊峰. B/C基因型的乙型肝炎病毒对不同免疫阶段慢性乙型肝炎患者T淋巴细胞及其亚群的影响[J]. 北京大学学报(医学版), 2020, 52(6): 1153-1156.
[12] 刘滕飞,林涛,任利辉,李广平,彭建军. CMTM5基因与冠状动脉粥样硬化性心脏病的关联研究及机制探讨[J]. 北京大学学报(医学版), 2020, 52(6): 1082-1087.
[13] 程功,张霞,杨菲,程嘉渝,刘燕鹰. 以发热、关节炎、皮肤色素沉着为主要表现的血管免疫母细胞性T细胞淋巴瘤1例[J]. 北京大学学报(医学版), 2020, 52(6): 1150-1152.
[14] 李文咏,王梦莹,周仁,王斯悦,郑鸿尘,朱洪平,周治波,吴涛,王红,石冰. 中国人群Hedgehog通路基因与非综合征型唇腭裂的亲源效应[J]. 北京大学学报(医学版), 2020, 52(5): 809-814.
[15] 王梦莹,李文咏,周仁,王斯悦,刘冬静,郑鸿尘,李静,李楠,周治波,朱洪平,吴涛,胡永华. WNT代谢通路相关基因与中国人群非综合征型唇腭裂发病风险的交互作用[J]. 北京大学学报(医学版), 2020, 52(5): 815-820.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed   
[1] 赵磊, 王天龙 . 右心室舒张末期容量监测用于肝移植术中容量管理的临床研究[J]. 北京大学学报(医学版), 2009, 41(2): 188 -191 .
[2] 万有, , 韩济生, John E. Pintar. 孤啡肽基因敲除小鼠电针镇痛作用增强[J]. 北京大学学报(医学版), 2009, 41(3): 376 -379 .
[3] 张燕, 韩志慧, 钟延丰, 王盛兰, 李玲玲, 郑丹枫. 骨骼肌活组织检查病理诊断技术的改进及应用[J]. 北京大学学报(医学版), 2009, 41(4): 459 -462 .
[4] 赵奇, 薛世华, 刘志勇, 吴凌云. 同向施压测定自酸蚀与全酸蚀粘接系统粘接强度[J]. 北京大学学报(医学版), 2010, 42(1): 82 -84 .
[5] 林红, 王玉凤, 吴野平. 学校生活技能教育对小学三年级学生行为问题影响的对照研究[J]. 北京大学学报(医学版), 2007, 39(3): 319 -322 .
[6] 丰雷, 程嘉, 王玉凤. 注意缺陷多动障碍儿童的运动协调功能[J]. 北京大学学报(医学版), 2007, 39(3): 333 -336 .
[7] 李岳玲, 钱秋瑾, 王玉凤. 儿童注意缺陷多动障碍成人期预后及其预测因素[J]. 北京大学学报(医学版), 2007, 39(3): 337 -340 .
[8] . 书讯[J]. 北京大学学报(医学版), 2007, 39(3): 225 -328 .
[9] 牟向东, 王广发, 刁小莉, 阙呈立. 肺黏膜相关淋巴组织型边缘区B细胞淋巴瘤一例[J]. 北京大学学报(医学版), 2007, 39(4): 346 -350 .
[10] 韩金涛, 赵军, 栾景源, 张龙. 多发结核性腹主动脉瘤一例[J]. 北京大学学报(医学版), 2007, 39(4): 361 -364 .