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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)

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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"

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