PMP22基因相关性周围神经病的遗传学和临床特点分析

doi:10.3969/j.issn.1674-8115.2022.05.008

上海交通大学学报（医学版） ›› 2022, Vol. 42 ›› Issue (5): 609-616.doi: 10.3969/j.issn.1674-8115.2022.05.008

PMP22基因相关性周围神经病的遗传学和临床特点分析

朱啸巍¹^,²(), 詹飞霞¹, 张超², 刘时华², 钟平², 曹立¹^,², 栾兴华¹^,²()

^1.上海交通大学医学院附属第六人民医院神经内科，上海 200030
^2.安徽医科大学附属宿州医院神经内科，宿州 234000

收稿日期:2021-12-06 接受日期:2022-05-06 出版日期:2022-05-28 发布日期:2022-05-28
通讯作者: 栾兴华 E-mail:zhuxw@rjlab.cn;green_lxh@sina.com
作者简介:朱啸巍（1997—），女，硕士生；电子信箱：zhuxw@rjlab.cn。
基金资助:
国家自然科学基金(81870889)

Analysis of genetic and clinical characteristics of PMP22-associated peripheral neuropathy

ZHU Xiaowei¹^,²(), ZHAN Feixia¹, ZHANG Chao², LIU Shihua², ZHONG Ping², CAO Li¹^,², LUAN Xinghua¹^,²()

^1.Department of Neurology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
^2.Department of Neurology, Suzhou Hospital of Anhui Medical University, Suzhou 234000, China

Received:2021-12-06 Accepted:2022-05-06 Online:2022-05-28 Published:2022-05-28
Contact: LUAN Xinghua E-mail:zhuxw@rjlab.cn;green_lxh@sina.com
Supported by:
National Natural Science Foundation of China(81870889)

摘要/Abstract

摘要：

目的·研究周围髓鞘蛋白22（peripheral myelin protein-22，PMP22）基因相关性周围神经病患者的遗传学特点和临床特征，并探讨基因型和临床表型的相关性。方法·收集2006年—2022年就诊于上海交通大学医学院附属第六人民医院神经内科的162例周围神经病患者，应用多重连接依赖的探针扩增（multiplex ligation-dependent probe amplification，MLPA）、全外显子测序（whole exon sequencing，WES）和Sanger测序技术等分子诊断技术综合分析筛选出26例PMP22基因相关性周围神经病先证者及其33例家系成员患者的基因变异情况，包括重复突变、缺失突变及点突变。进一步分析26例PMP22基因相关性周围神经病患者的遗传学和临床特点，临床特点包括人口学数据、临床表现、神经电生理特点、病理学特点等。结果·PMP22基因相关性周围神经病患者共59例（男性37例，女性22例），其中46例为家系病例（来自13个家系），余13例为散发病例。所有患者发病年龄34.0（14.0，49.5）岁，首发症状为肢体无力或肢体麻木。51例为PMP22重复突变，临床表型为腓骨肌萎缩症1A型（Charcot-Marie-Tooth type-1A，CMT1A）；6例PMP22缺失突变，临床表型为遗传性压迫易感性神经病（hereditary neuropathy with liability to pressure palsies，HNPP）；2例PMP22点突变（p.S72L和p.G100V），表型为Dejerine-Sottas综合征（Dejerine-Sottas syndrome，DSS）。16例PMP22基因相关性周围神经病患者进行神经电生理检测，12例PMP22重复突变患者的运动神经传导速度（motor nerve conduction velocity，MCV）、复合肌肉动作电位波幅（compound muscle action potential，CMAP）和感觉传导速度（sensory nerve conduction velocities，SCV）较4例PMP22缺失突变患者明显降低（均P<0.05），2种突变类型均可出现传导阻滞现象。12例PMP22基因相关性周围神经病患者进行腓肠神经活检，包括8例PMP22重复突变、3例PMP22缺失突变和1例PMP22点突变，可见不同程度有髓神经纤维变薄、“洋葱球样”变及神经纤维密度减低等病理改变。结论·PMP22基因相关性周围神经病可表现为CMT1A、HNPP及DSS等表型，具有临床异质性。对于电生理检测和腓肠神经活检呈脱髓鞘表现的患者，排除获得性病因后，应予以PMP22基因重复、缺失和点突变的基因检测，有助于该病的优化诊断以及遗传咨询。

关键词: 腓骨肌萎缩症1A型, 遗传性压迫易感性神经病, Dejerine-Sottas综合征, PMP22基因, 突变

Abstract:

Objective·To investigate the genetic and clinical features of peripheral neuropathy patients with PMP22 gene variations and the association between genotype and clinical phenotype.

Methods·A total of 162 patients with peripheral neuropathy who were treated in Department of Neurology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine from 2006 to 2022 were collected. Molecular detecting techniques including combining multiplex ligation-dependent probe amplification (MLPA), whole exon sequencing (WES) and Sanger sequencing were used to comprehensively analyze the genetic variation of 162 patients, and 26 probands with PMP22 gene variations and their 33 family members were screened out. The genetic variations included duplication, deletion and point mutations. The clinical and genetic characteristics of 26 patients with PMP22-associated peripheral neuropathy were further analyzed. The clinical characteristics included clinical demographic data, clinical manifestations, electrophysiological and pathological characteristics.

Results·There were a total of 59 (37 male and 22 female) individuals with PMP22-associated peripheral neuropathy, among whom 46 patients in 13 families had positive family histories and 13 did not. The median age at onset of neuropathy was 34.0 (14.0, 49.5) years old. The initial symptom was limb weakness or limb numbness. There were 51 Charcot-Marie-Tooth type-1A (CMT1A) patients with PMP22 duplication, 6 hereditary neuropathy with liability to pressure palsies (HNPP) patients with PMP22 deletion and 2 Dejerine-Sottas syndrome (DSS) patients with PMP22 point mutations (p.S72L and p.G100V). Sixteen patients underwent electrophysiological detections. Compared with the 4 PMP22 deletion patients, the motor nerve conduction velocity (MCV), compound muscle action potential (CMAP) and sensory nerve conduction velocities (SCV) of 12 PMP22 duplication patients were obviously decreased (all P<0.05). Conduction block was found in both kinds of mutation types. Sural nerve biopsies were performed in 12 patients, including 8 PMP22 duplication, 3 PMP22 deletion and 1 PMP22 point mutation, and pathological changes such as thinning of myelinated nerve fibers, “onion bulbs” and decreased nerve fiber density were observed in varying degrees.

Conclusion·PMP22 gene-associated neuropathies can be characterized by CMT1A, HNPP and DSS with high clinical heterogeneity. Patients with demyelinating manifestations on electrophysiological detections and sural nerve biopsy need genetic testing for PMP22 gene duplication, deletion and point mutation after ruling out acquired etiology. It is available to help optimize diagnosis and genetic counseling of the disease.

Key words: Charcot-Marie-Tooth type-1A (CMT1A), hereditary neuropathy with liability to pressure palsies (HNPP), Dejerine-Sottas syndrome (DSS), PMP22 gene, mutation

中图分类号:

R745.4⁺9

朱啸巍, 詹飞霞, 张超, 刘时华, 钟平, 曹立, 栾兴华. PMP22基因相关性周围神经病的遗传学和临床特点分析[J]. 上海交通大学学报（医学版）, 2022, 42(5): 609-616.

ZHU Xiaowei, ZHAN Feixia, ZHANG Chao, LIU Shihua, ZHONG Ping, CAO Li, LUAN Xinghua. Analysis of genetic and clinical characteristics of PMP22-associated peripheral neuropathy[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(5): 609-616.

图/表 4

参考文献 35

1	PANTERA H, MORAN J J, HUNG H A, et al. Regulation of the neuropathy-associated Pmp22 gene by a distal super-enhancer[J]. Hum Mol Genet, 2018, 27(16): 2830-2839.
2	LIU X X, DUAN X H, ZHANG Y S, et al. Clinical and genetic diversity of PMP22 mutations in a large cohort of Chinese patients with Charcot-Marie-tooth disease[J]. Front Neurol, 2020, 11: 630.
3	朱啸巍, 钟平, 栾兴华. PMP22相关性周围神经病的临床及遗传学特点[J]. 中国实用神经疾病杂志, 2021, 24(14): 1265-1270.
	ZHU X W, ZHONG P, LUAN X H. The clinical and genetic characteristics of PMP22-associated peripheral neuropathy[J]. Chin J Pract Nerv Dis, 2021, 24(14): 1265-1270.
4	GENTILE L, RUSSO M, FABRIZI G M, et al. Charcot-Marie-Tooth disease: experience from a large Italian tertiary neuromuscular center[J]. Neurol Sci, 2020, 41(5): 1239-1243.
5	WATILA M M, BALARABE S A. Molecular and clinical features of inherited neuropathies due to PMP22 duplication[J]. J Neurol Sci, 2015, 355(1/2): 18-24.
6	IVANOVIC V, BRANKOVIC M, BJELICA B, et al. Yield of the PMP22 deletion analysis in patients with compression neuropathies[J]. J Neurol, 2020, 267(12): 3617-3623.
7	D'ARRIGO S, TESSAROLLO V, TARONI F, et al. A case of severe early-onset neuropathy caused by a compound heterozygous deletion of the PMP22 gene: clinical and neurographic aspects[J]. Neuropediatrics, 2020, 51(3): 173-177.
8	MORINI A, MALAGUTI M C, MARANGONI S, et al. Neuropathic tremor in chronic inflammatory demyelinating polyneuropathy: the acquired equivalent of the roussy-levy syndrome[J]. Mov Disord Clin Pract, 2015, 3(2): 173-175.
9	徐佳露, 章毅, 赵聪颖, 等. 13例早发型腓骨肌萎缩症的基因分型研究[J]. 中国当代儿科杂志, 2019, 21(7): 670-675.
	XU J L, ZHANG Y, ZHAO C Y, et al. A genotyping study of 13 cases of early-onset Charcot-Marie-Tooth disease[J]. Chin J Contemp Pediat, 2019, 21(7): 670-675.
10	ROA B B, DYCK P J, MARKS H G, et al. Dejerine-Sottas syndrome associated with point mutation in the peripheral myelin protein 22 (PMP22) gene[J]. Nat Genet, 1993, 5(3): 269-273.
11	MARQUES W Jr, THOMAS P K, SWEENEY M G, et al. Dejerine-Sottas neuropathy and PMP22 point mutations: a new base pair substitution and a possible “hot spot” on Ser72[J]. Ann Neurol, 1998, 43(5): 680-683.
12	RUSSO M, LAURÁ M, POLKE J M, et al. Variable phenotypes are associated with PMP22 missense mutations[J]. Neuromuscul Disord, 2011, 21(2): 106-114.
13	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.
14	WU R, LV H, ZHANG W, et al. Clinical and pathological variation of Charcot-Marie-tooth 1A in a large Chinese cohort[J]. Biomed Res Int, 2017, 2017: 6481367.
15	LOUSA M, VÁZQUEZ-HUARTE-MENDICOA C, GUTIÉRREZ A J, et al. Genetic epidemiology, demographic, and clinical characteristics of Charcot-Marie-tooth disease in the island of Gran Canaria (Spain)[J]. J Peripher Nerv Syst, 2019, 24(1): 131-138.
16	BROŽKOVÁ D, MAZANEC R, RYCHLÝ Z, et al. Four novel point mutations in the PMP22 gene with phenotypes of HNPP and Dejerine-Sottas neuropathy[J]. Muscle Nerve, 2011, 44(5): 819-822.
17	AZEVEDO H, PUPE C, PEREIRA R, et al. Pain in Charcot-Marie-Tooth disease: an update[J]. Arq Neuropsiquiatr, 2018, 76(4): 273-276.
18	KAWARAI T, YAMAZAKI H, MIYAMOTO R, et al. PMP22-related disease: a novel splice site acceptor variant and intrafamilial phenotype variability[J]. Neuromuscul Disord, 2019, 29(6): 422-426.
19	MITTENDORF K F, MARINKO J T, HAMPTON C M, et al. Peripheral myelin protein 22 alters membrane architecture[J]. Sci Adv, 2017, 3(7): e1700220.
20	ZHOU Y, MILES J R, TAVORI H, et al. PMP22 regulates cholesterol trafficking and ABCA1-mediated cholesterol efflux[J]. J Neurosci, 2019, 39(27): 5404-5418.
21	SVAREN J, MORAN J J, WU X Y, et al. Schwann cell transcript biomarkers for hereditary neuropathy skin biopsies[J]. Ann Neurol, 2019, 85(6): 887-898.
22	PANTERA H, SHY M E, SVAREN J. Regulating PMP22 expression as a dosage sensitive neuropathy gene[J]. Brain Res, 2020, 1726: 146491.
23	LI J. Genetic factors for nerve susceptibility to injuries: lessons from PMP22 deficiency[J]. Neural Regen Res, 2014, 9(18): 1661-1664.
24	TYSON J, ELLIS D, FAIRBROTHER U, et al. Hereditary demyelinating neuropathy of infancy. A genetically complex syndrome[J]. Brain, 1997, 120 ( Pt 1): 47-63.
25	NELIS E, HAITES N, VAN BROECKHOVEN C. Mutations in the peripheral myelin genes and associated genes in inherited peripheral neuropathies[J]. Hum Mutat, 1999, 13(1): 11-28.
26	WU R, FU J, MENG L C, et al. Homozygous splice-site mutation c.78+5G>A in PMP22 causes congenital hypomyelinating neuropathy[J]. Neuropathology, 2019, 39(6): 441-446.
27	LIAO Y C, TSAI P C, LIN T S, et al. Clinical and molecular characterization of PMP22 point mutations in Taiwanese patients with inherited neuropathy[J]. Sci Rep, 2017, 7(1): 15363.
28	RAMCHANDREN S. Charcot-Marie-tooth disease and other genetic polyneuropathies[J]. Continuum (Minneap Minn), 2017, 23(5, Peripheral Nerve and Motor Neuron Disorders): 1360-1377.
29	NAGAPPA M, SHARMA S, GOVINDARAJ P, et al. PMP22 gene-associated neuropathies: phenotypic spectrum in a cohort from India[J]. J Mol Neurosci, 2020, 70(5): 778-789.
30	ABE A, NAKAMURA K, KATO M, et al. Compound heterozygous PMP22 deletion mutations causing severe Charcot-Marie-Tooth disease type 1[J]. J Hum Genet, 2010, 55(11): 771-773.
31	AGOSTONI E, GOBESSI S, BRANCOLINI C, et al. Identification and characterization of a new member of the gas3/PMP22 gene family in C. elegans[J]. Gene, 1999, 234(2): 267-274.
32	ABE K T, LINO A M M, HIRATA M T A, et al. A novel stop codon mutation in the PMP22 gene associated with a variable phenotype[J]. Neuromuscul Disord, 2004, 14(5): 313-320.
33	TRACY J A, DYCK P J, KLEIN C J, et al. Onion-bulb patterns predict acquired or inherited demyelinating polyneuropathy[J]. Muscle Nerve, 2019, 59(6): 665-670.
34	MOSS K R, BOPP T S, JOHNSON A E, et al. New evidence for secondary axonal degeneration in demyelinating neuropathies[J]. Neurosci Lett, 2021, 744: 135595.
35	ZHAO H T, DAMLE S, IKEDA-LEE K, et al. PMP22 antisense oligonucleotides reverse Charcot-Marie-Tooth disease type 1A features in rodent models[J]. J Clin Invest, 2018, 128(1): 359-368.

Index	PMP22 duplication （n=12）		P value^①	PMP22 deletion （n=4）		P value^①	P value^②
Index	Left	Right	P value^①	Left	Right	P value^①	P value^②
CMAP/mV
Median nerve （wrist-APB）	3.401±1.559	3.434±1.886	0.972	6.100±2.823	7.275±1.227	0.553	0.008
Median nerve （elbow-wrist）	2.803±1.509	2.849±1.715	0.959	6.100±3.122	6.850±2.585	0.724	0.006
Ulnar nerve （wrist-ADM）	2.002±1.065	1.828±1.117	0.789	6.400±2.203	7.000±2.483	0.730	0.000
Ulnar nerve （below elbow-wrist）	1.487±1.087	1.243±0.951	0.688	6.075±2.095	6.475±2.294	0.805	0.000
Tibial nerve （ankle-AH）	16.375±1.576	16.775±3.163	0.661	39.033±0.850	37.533±2.774	0.421	0.000
Common peroneal nerve （ankle-EDB）	0.200±0.257	0.223±0.473	0.918	3.023±1.583	3.290±2.532	0.864	0.004
MCV/（m·s^-1）
Median nerve	18.943±3.114	18.529±4.095	0.835	49.65±3.074	50.525±2.344	0.765	0.000
Ulnar nerve	17.833±2.420	18.767±3.266	0.586	50.900±4.809	50.675±8.207	0.964	0.000
Tibial nerve	0.315±0.574	0.343±0.346	0.920	7.533±2.937	8.633±2.754	0.661	0.001
Common peroneal nerve	14.143±3.629	17.100±4.964	0.227	36.775±2.136	35.425±4.751	0.623	0.000
SCV/（m·s^-1）
Median nerve	12.843 （0.000， 310.200）	8.210 （0.000， 33.600）	0.548	41.575±2.990	41.475±2.666	0.962	0.000
Ulnar nerve	12.580 （0.000， 32.700）	9.060 （0.000， 39.300）	0.575	42.450±4.211	43.350±4.807	0.788	0.000
Sural nerve	9.691 （0.000， 34.600）	7.792 （0.000， 27.600）	0.717	40.850±8.009	41.575±7.374	0.898	0.000

Index	PMP22 duplication （n=12）		P value^①	PMP22 deletion （n=4）		P value^①	P value^②
Index	Left	Right	P value^①	Left	Right	P value^①	P value^②
CMAP/mV
Median nerve （wrist-APB）	3.401±1.559	3.434±1.886	0.972	6.100±2.823	7.275±1.227	0.553	0.008
Median nerve （elbow-wrist）	2.803±1.509	2.849±1.715	0.959	6.100±3.122	6.850±2.585	0.724	0.006
Ulnar nerve （wrist-ADM）	2.002±1.065	1.828±1.117	0.789	6.400±2.203	7.000±2.483	0.730	0.000
Ulnar nerve （below elbow-wrist）	1.487±1.087	1.243±0.951	0.688	6.075±2.095	6.475±2.294	0.805	0.000
Tibial nerve （ankle-AH）	16.375±1.576	16.775±3.163	0.661	39.033±0.850	37.533±2.774	0.421	0.000
Common peroneal nerve （ankle-EDB）	0.200±0.257	0.223±0.473	0.918	3.023±1.583	3.290±2.532	0.864	0.004
MCV/（m·s^-1）
Median nerve	18.943±3.114	18.529±4.095	0.835	49.65±3.074	50.525±2.344	0.765	0.000
Ulnar nerve	17.833±2.420	18.767±3.266	0.586	50.900±4.809	50.675±8.207	0.964	0.000
Tibial nerve	0.315±0.574	0.343±0.346	0.920	7.533±2.937	8.633±2.754	0.661	0.001
Common peroneal nerve	14.143±3.629	17.100±4.964	0.227	36.775±2.136	35.425±4.751	0.623	0.000
SCV/（m·s^-1）
Median nerve	12.843 （0.000， 310.200）	8.210 （0.000， 33.600）	0.548	41.575±2.990	41.475±2.666	0.962	0.000
Ulnar nerve	12.580 （0.000， 32.700）	9.060 （0.000， 39.300）	0.575	42.450±4.211	43.350±4.807	0.788	0.000
Sural nerve	9.691 （0.000， 34.600）	7.792 （0.000， 27.600）	0.717	40.850±8.009	41.575±7.374	0.898	0.000

[1]	张咪, 柳淑君, 李福彬, 张燕. 哺乳动物细胞表面展示IgG抗体Fc组合突变库的构建及评估[J]. 上海交通大学学报（医学版）, 2022, 42(4): 510-517.
[2]	罗思敏, 叶菱秀, 郝茜. 抗体基因点突变、插入和缺失体外检测方法的建立及应用[J]. 上海交通大学学报（医学版）, 2022, 42(4): 518-527.
[3]	马韵芳, 潘丽娜, 李圳, 高蓓莉, 胡家安, 徐志红. 司美替尼下调KRAS G12V突变型非小细胞肺癌细胞PD-L1水平的探索性研究[J]. 上海交通大学学报(医学版), 2021, 41(6): 741-748.
[4]	程盛, 赵益, 王永琛, 黄平. BRAF基因突变对肝切除后的结直肠癌肝转移患者预后影响的meta分析[J]. 上海交通大学学报(医学版), 2021, 41(6): 786-792.
[5]	刘伟, 朱敏闻, 吴岚. 口腔白斑癌变DNA损伤修复相关基因的芯片检测及表达验证[J]. 上海交通大学学报(医学版), 2021, 41(3): 302-307.
[6]	谢雨婕, 谢利娟, 朱天闻, 王依闻. 白介素-10受体A基因突变致新生儿极早发炎性肠病2例[J]. 上海交通大学学报(医学版), 2021, 41(3): 409-412.
[7]	朱之星1, 2，纪伟3，顾坚磊1, 4，吕晖1, 2, 4，田国力3. 葡萄糖 -6- 磷酸脱氢酶基因4种突变及蛋白结构分析[J]. 上海交通大学学报(医学版), 2020, 40(12): 1571-1578.
[8]	王静，金理辉，张琪，孙锟，于昱. 完全性肺静脉异位引流患儿的ARHGEF16基因突变筛查及突变功能分析[J]. 上海交通大学学报（医学版）, 2020, 40(1): 70-.
[9]	刘思捷 1，李婷婷 1，陈笋 1，李奋 2，孙锟 1，徐让 3. CITED2基因在内脏反位患者中的突变分析[J]. 上海交通大学学报（医学版）, 2019, 39(5): 500-.
[10]	严天奇 1，陈立伟 2，朱勇梅 2，李剑峰 2，代雨婷 2, 3，崔舒雅 2，姜璐 2，陈冰 2，黄金艳 2. 急性淋巴细胞白血病基因融合与突变知识库的构建[J]. 上海交通大学学报（医学版）, 2018, 38(9): 1027-.
[11]	杨莹，石晓东，戴钰俊，王月英. 雷帕霉素抑制DNMT3A突变相关急性髓系白血病的发展[J]. 上海交通大学学报（医学版）, 2018, 38(9): 1039-.
[12]	李青丽，文君，闵雪洁，赵丽，赵小平. 异柠檬酸脱氢酶基因突变在急性髓细胞白血病发生中的作用[J]. 上海交通大学学报（医学版）, 2018, 38(8): 960-.
[13]	蒋玲玉 1，李雨浓 1，胡鹏 2*，佘莎 1，张振芳 1. 基因1型HCV/HIV共同感染患者直接抗病毒药物预存耐药突变流行情况分析[J]. 上海交通大学学报（医学版）, 2018, 38(4): 411-.
[14]	王炳华 1，许无恨 2，汤晓君 2，兰小平 2. 中国汉族人群KRT9基因突变分析[J]. 上海交通大学学报（医学版）, 2018, 38(12): 1425-.
[15]	刘改玲 1, 2，陶琨 3，都爱莲 2，刘晓黎 4，梁辉 1. 伴发癫痫的痣样基底细胞癌综合征的临床特点及基因突变分析[J]. 上海交通大学学报（医学版）, 2018, 38(11): 1322-.

PMP22基因相关性周围神经病的遗传学和临床特点分析

Analysis of genetic and clinical characteristics of PMP22-associated peripheral neuropathy

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

图/表 4

参考文献 35

相关文章 15

编辑推荐

Metrics