Abstract
目的
遗传性压力易感性周围神经病(hereditary neuropathy with liability to pressure palsy，HNPP)是一种少见的常染色体显性遗传周围神经病，通常由周围髓鞘蛋白22(peripheral myelin protein 22，PMP22)基因杂合缺失突变引起。本研究旨在探讨HNPP患者的临床和分子遗传学特征。
方法
纳入2009至2023年就诊于中南大学湘雅三医院神经内科的HNPP患者，收集并分析患者的一般临床资料、神经电生理和分子遗传学检查结果。分子遗传学检查为提取外周血基因组DNA后采用多重连接探针扩增技术(multiplex ligation-dependent probe amplification，MLPA)进行PMP22大片段缺失的筛查；若未检测到PMP22缺失突变，则用二代测序法筛查PMP22点突变。进一步对HNPP相关文献进行回顾，分析HNPP患者的临床和分子遗传学特征。
结果
共纳入来自24个无血缘关系的中国汉族家系的34例HNPP患者，包括25名男性和9名女性，平均22.0岁起病，有阳性家族史的家系占62.5%。30例患者出现周围神经麻痹的症状，常表现为发作性单肢无力伴/或麻木(25/30)，亦可表现为发作性单侧喉返神经(迷走神经)麻痹(2/30)。体格检查可发现受累神经相应支配区域的肌肉无力(23/29)和浅感觉减退(9/29)，踝反射减弱或消失(20/29)，肢体远端肌肉萎缩(8/29)及高弓足(5/29)。多数患者(26/30)在急性发作后可完全恢复正常。有31例患者完成神经电生理检查，均表现为多发性周围神经损害，以运动及感觉神经髓鞘损害为主，多数患者可有远端运动潜伏期(distal motor latency，DML)明显延长，轻至中度的神经传导速度减慢，复合肌肉动作电位(compound muscle action potential，CMAP)及感觉神经动作电位(sensory nerve action potential，SNAP)波幅降低，有时可出现传导阻滞。正中神经运动传导速度为(48.5±5.5) m/s，CMAP波幅为(8.4±5.1) mV；正中神经感觉传导速度为(37.4±10.5) m/s，SNAP波幅为(14.4±13.0) μV。在24个HNPP家系中，经MLPA检测证实有23个家系为PMP22杂合缺失突变导致，经二代测序证实剩余1个家系为PMP22 c.434delT突变所致。文献检索到1 734个进行了基因检测的HNPP确诊家系，其基因检测结果再次证实了PMP22杂合缺失突变是最常见的突变类型，占93.4%，其余突变类型包括PMP22微小突变(4.0%)、PMP22杂合不完全缺失突变(0.6%)、PMP22复杂易位突变(0.1%)。目前HNPP相关的PMP22微小突变共报道38种，包括错义突变(10/38)、无义突变(4/38)、碱基缺失突变(13/38)、碱基插入突变(3/38)、剪切位点突变(8/38)。HNPP患者最常表现为发作性无痛性单神经麻痹，腓总神经、尺神经和臂丛神经受累最为常见，约占75%。颅神经受累的患者仅有18例报道。
结论
PMP22杂合缺失突变是HNPP最常见的突变类型。HNPP以发作性无痛性单神经麻痹为主要特点，主要累及腓总神经、尺神经等周围神经。神经电生理检查对于诊断本病具有较高的灵敏度和特异度，表现为广泛的脱髓鞘改变。对于怀疑HNPP的患者，首选完善神经电生理检查及PMP22大片段杂合缺失的检测。必要时可以完善Sanger测序或二代测序，对PMP22其他突变类型进行检测以防漏诊。
Keywords: 遗传性压力易感性周围神经病, 周围髓鞘蛋白22, 单神经麻痹, 脱髓鞘改变, 杂合缺失突变
Abstract
Objective
Hereditary neuropathy with liability to pressure palsy (HNPP) is a rare autosomal dominant peripheral neuropathy, usually caused by heterozygous deletion mutations in the peripheral myelin protein 22 (PMP22) gene. This study aims to investigate the clinical and molecular genetic characteristics of HNPP.
Methods
HNPP patients in the Department of Neurology at Third Xiangya Hospital of Central South University from 2009 to 2023 were included in this study. The general clinical data, nervous electrophysiological and molecular genetic examination results were collected and analyzed. Molecular genetic examination was to screen for deletion of PMP22 gene using multiplex ligation-dependent probe amplification (MLPA) after extracting genomic DNA from peripheral blood; and if no PMP22 deletion mutation was detected, next-generation sequencing was used to screen for PMP22 point mutations. The related literatures of HNPP were reviewed, and the clinical and molecular genetic characteristics of HNPP patients were analyzed.
Results
A total of 34 HNPP patients from 24 unrelated Chinese Han families were included in this study, including 25 males and 9 females. The average age at illness onset was 22.0 years. Sixty-two point five percent of the families had a positive family history. Among them, 30 patients had symptoms of peripheral nerve paralysis. Patients often presented with paroxysmal single limb weakness with (or) numbness (25/30), and some patients had paroxysmal unilateral recurrent laryngeal nerve (vagus nerve) paralysis (2/30). Physical examination revealed muscle weakness (23/29), hypoesthesia (9/29), weakened or absent ankle reflexes (20/29), distal limb muscle atrophy (8/29) and high arched feet (5/29). Most patients (26/30) could fully recover to normal after an acute attack. Thirty-one patients in our group underwent nervous electrophysiological examination, and showed multiple demyelinating peripheral neuropathies with both motor and sensory nerves involved. Most patients showed significantly prolonged distal motor latency (DML), mild to moderate nerve conduction velocity slowing, decreased amplitude of compound muscle action potential (CMAP) and sensory nerve action potential (SNAP), and sometimes with conduction block. Nerve motor conduction velocity was (48.5±5.5) m/s, and the CMAP amplitude was (8.4±5.1) mV. Nerve sensory conduction velocity was (37.4±10.5) m/s, and the SNAP amplitude was (14.4±15.2) μV. There were 24 families, 23 of whom had the classical PMP22 deletion, the last one had a heterozygous pathogenic variant in the PMP22 gene sequence (c.434delT). By reviewing clinical data and genetic testing results of reported 1 734 HNPP families, we found that heterozygous deletion mutation of PMP22 was the most common pathogenic mutation of HNPP (93.4%). Other patients were caused by PMP22 small mutations (4.0%), PMP22 heterozygous gross deletions (0.6%), and PMP22 complex rearrangements (0.1%). Thirty-eight sorts of HNPP-related PMP22 small mutations was reported, including missense mutations (10/38), nonsense mutations (4/38), base deletion mutations (13/38), base insertion mutations (3/38), and shear site mutations (8/38). HNPP patients most often presented with episodic painless single nerve palsy. Common peroneal nerve, ulnar nerve, and brachial plexus nerve were the most common involved nerves, accounting for about 75%. Only eighteen patients with cranial nerve involved was reported.
Conclusion
Heterozygous deletion mutation of PMP22 is the most common pathogenic mutation of HNPP. Patients is characterized by episodic and painless peripheral nerve paralysis, mainly involving common peroneal nerve, ulnar nerve, and other peripheral nerves. Nervous electrophysiological examination has high sensitivity and specificity for the diagnosis of HNPP, which is manifested by extensive demyelinating changes. For patients with suspected HNPP, nervous electrophysiological examination and PMP22-MLPA detection are preferred. Sanger sequencing or next generation sequencing can be considered to detect other mutations of PMP22.
Keywords: hereditary neuropathy with liability to pressure palsy, peripheral myelin protein 22, single nerve paralysis, demyelinating changes, heterozygous deletion mutation
遗传性压力易感性周围神经病(hereditary neuropathy with liability to pressure palsy，HNPP)是一种少见的常染色体显性遗传病，患者常表现为周围神经受牵拉、压迫或外伤后，出现反复发作的无痛性单神经或多神经麻痹[1-4]。多数HNPP由17号染色体短臂11.2区包含周围髓鞘蛋白22(peripheral myelin protein 22，PMP22)基因的1.5 Mb大小片段杂合缺失引起[5]。PMP22杂合重复突变可导致腓骨肌萎缩症(Charcot-Marie-Tooth，CMT)最常见的基因亚型，即CMT1A型。HNPP的PMP22杂合缺失突变和CMT1A型PMP22杂合重复突变可能是生殖细胞进行减数分裂时发生非等位基因重组造成的[4]。然而，HNPP患者的病例报道却明显较CMT1A少，提示可能有部分HNPP患者被漏诊或误诊。本研究收集24个HNPP家系，采集患者详细的临床资料和分子遗传学检查结果，并结合国内外已报道的HNPP病例进行分析，以期通过探讨HNPP患者的临床和分子遗传学特征，进一步提高临床医师对本病的认识和诊断水平。
1. 对象与方法
1.1. 对象
本研究为回顾性研究，纳入2009至2023年就诊于中南大学湘雅三医院神经内科的HNPP患者。本研究已通过中南大学湘雅三医院伦理委员会批准(审批号：快I 21021)，所有患者均已签署知情同意书。
1.2. 方法
1.2.1. 一般临床资料
所有患者均由2名神经内科专科医师进行详细问诊及神经内科专科体格检查，收集患者的年龄、性别、起病年龄、主要症状、伴随症状、家族史、阳性体征等信息。
1.2.2. 神经电生理检查
采用丹麦Keypoint肌电图/诱发电位仪检测神经传导速度(nerve conduction velocity，NCV)。纳入检测的周围神经包括正中神经、尺神经、桡神经、胫神经、腓总神经、腓肠神经、腓浅神经。
1.2.3. 分子遗传学检查
采集患者外周血10 mL，采用常规苯酚-氯仿法提取基因组DNA，使用多重连接探针扩增技术(multiplex ligation-dependent probe amplification，MLPA)进行PMP22大片段缺失的筛查；若未检测到PMP22缺失突变，则用二代测序法筛查PMP22点突变。
1.2.4. 文献检索
使用“遗传性压力易感性周围神经病”“hereditary neuropathy with liability to pressure palsy”作为关键词，在Pubmed、中国知网检索1947年1月1日至2022年12月31日使用中文或英文(包含具有英文摘要的其他语种文献)发表的文献，收集并分析进行了基因诊断的HNPP家系及其患者的性别、发病年龄、主要症状、诱因、家族史等临床资料和分子遗传学检测结果。
2. 结 果
2.1. 临床特征
共纳入来自24个无血缘关系的中国汉族家系(编号为F1~F24)的34例HNPP患者，其中男性25名，女性9名。有阳性家族史的家系占62.5%(15/24)。有30例患者具有临床症状，余4例未曾出现肢体无力或麻木，因家中有患者被确诊为HNPP而就诊(表1)。本组患者起病年龄为1~64(平均22.0)岁，最常表现为发作性单肢乏力伴/或麻木(25/30，83.3%)，5例患者同时有多个肢体受累，其中3例为双侧小腿、双足麻木无力，2例为双侧小指麻木无力。14例患者在发作前有诱因(14/30，46.7%)，如久坐、久睡、剧烈运动、搬运重物、外伤等。本组患者首次发作时最常出现腓总神经麻痹(11/30，36.7%)，表现为小腿外侧麻木和/或足下垂。值得注意的是，家系F7(图1A)中的双胞胎兄妹(II-3、II-4)除肢体无力或麻木外，从10岁左右起出现发作性声音嘶哑、吞咽困难、饮水呛咳等症状，严重时无法发声，伏案睡觉可能诱发，症状持续十余天后可自行缓解，这2名患者可能为发作性单侧喉返神经(迷走神经)麻痹。本组患者均无肢体疼痛。除2例患者进行性加重、2例患者失访外，其余患者均完全恢复。对29例患者进行了体格检查，患者的体征可表现为受累神经相应支配区域的肌肉无力(23/29)和浅感觉减退(9/29)、踝反射减弱或消失(20/29)，部分患者可有肢体远端肌肉萎缩(8/29)及高弓足(5/29)。
表1.
HNPP患者的临床特征(n=34)
Table 1 Clinical characteristics of HNPP patients (n=34)
| 临床表现 | 例数 |
|---|---|
| 性别(男/女) | 25/9 |
| 有症状/无症状 | 30/4 |
| 发病年龄/岁 | |
| ≤10 | 9 |
| 11~20 | 10 |
| >20 | 11 |
| 诱发因素 | |
| 久坐/久睡 | 9 |
| 剧烈运动 | 3 |
| 搬运重物 | 1 |
| 外伤 | 1 |
| 单侧起病/双侧起病 | 25/5 |
| 首次发作时受累的神经 | |
| 尺神经 | 7 |
| 桡神经 | 6 |
| 臂丛 | 2 |
| 腓总神经 | 11 |
| 坐骨神经 | 1 |
| 不详 | 3 |
| 体格检查 | |
| 肌肉无力 | 23 |
| 肌肉萎缩 | 8 |
| 浅感觉减退 | 9 |
| 踝反射减弱/消失 | 20 |
HNPP：遗传性压力易感性周围神经病。
图1.
HNPP-F7家系、HNPP-F24家系的系谱图及F7家系II-4的 PMP22-MLPA检测结果
Figure 1 Lineage of HNPP-F7 and HNPP-F24 families and PMP22-MLPA result of the proband II-4 in the HNPP-F24 family
A: Lineage of HNPP-F7 family. There are 2 patients (II-3, II-4) in the HNPP-F7 family showing symptoms of paroxysmal limb numbness and weakness, hoarseness, and dysphagia. B: PMP22-MLPA result. PMP22-MLPA result of the proband (II-4) in family HNPP-F7 indicates she has a heterozygous deletion mutation of PMP22. C: Lineage of HNPP-F24 family. Two patients from the family HNPP-F24 carry a PMP22 point mutation (c.434delT p.Leu145ArgfsTer10). HNPP: Hereditary neuropathy with liability to pressure palsy; PMP22: Peripheral myelin protein 22; MLPA: Multiplex ligation-dependent probe amplification.
2.2. 神经电生理特征
共有31例患者完成神经电生理检查，受检神经共386条。无论有无临床症状，患者的神经电生理检查结果均表现为多发性周围神经损害，以运动及感觉神经髓鞘损害为主(表2)。患者普遍存在远端运动潜伏期(distal motor latency，DML)延长，最常见于腓总神经(98.2%)。多数患者的运动神经传导速度(motor nerve conduction velocity，MNCV)正常或轻度减慢，而在神经易卡压部位，如尺神经经过肘关节处、腓总神经绕腓骨小头处，MNCV则普遍减慢(减慢的百分比分别为97.2%、96.0%)，尺神经跨肘段的MNCV为(30.7±9.0) m/s，最低为11.9 m/s，腓总神经跨腓骨小头段MNCV为(29.7±6.9) m/s，最低为17.8 m/s。多数患者被检运动神经的复合肌肉动作电位(compound muscle action potential，CMAP)波幅正常或轻度降低，仅有1例患者的腓总神经运动神经传导未引出肯定波形。传导阻滞见于15条受检神经，位于腓总神经腓骨小头段(9/15，60%)和尺神经肘段(6/15，40%)。多数患者的正中神经、胫神经最小F波潜伏期延长。在感觉神经传导中，大多数患者的感觉神经传导速度(sensory nerve conduction velocity，SNCV)可有轻至中度减慢，感觉神经动作电位(sensory nerve action potential，SNAP)波幅常有轻至中度降低。在146条受检的感觉神经中，有21条感觉神经传导未引出肯定波形。
表2.
HNPP患者的神经电生理检查结果(n=31)
Table 2 Nervous electrophysiological examination results of HNPP patients (n=31)
| 指标 | 受检神经数量/条 | 检测结果‡ | 异常/[条(%)] | 参考值范围# |
|---|---|---|---|---|
| 运动神经传导 | ||||
| 远端运动潜伏期 | ||||
| 正中神经 | 44 | 6.1±2.4(3.8~14.4) | 39(88.6) | ≤4.0 |
| 尺神经 | 45 | 3.5±0.7(2.6~5.6) | 31(68.9) | ≤3.1 |
| 桡神经 | 6 | 3.2±1.1(1.8~4.7) | 4(66.7) | ≤2.3 |
| 胫神经 | 55 | 5.1±1.5(3.5~10.3) | 46(83.6) | ≤4.0 |
| 腓总神经 | 55 | 6.4±1.6(3.7~10.7) | 54(98.2) | ≤4.0 |
| 运动神经传导速度 | ||||
| 正中神经(腕-肘) | 44 | 48.5±5.5(37.5~56.9) | 23(52.3) | ≥50.0 |
| 尺神经(腕-肘上)* | 9 | 41.0±6.6(30.8~47.9) | 9(100.0) | ≥50.0 |
| 尺神经(腕-肘下)† | 36 | 51.4±5.6(42.7~60.5) | 12(33.3) | ≥50.0 |
| 尺神经(肘下-肘上)† | 36 | 30.7±9.0(11.7~50.0) | 35(97.2) | ≥50.0 |
| 桡神经 | 6 | 53.6±11.3(39.5~71.4) | 3(50.0) | ≥50.0 |
| 胫神经 | 57 | 39.8±4.5(31.3~50.7) | 40(70.2) | ≥43.0 |
| 腓总神经(踝-腓骨小头上)* | 32 | 37.4±5.6(20.4~45.0) | 27(84.4) | ≥43.0 |
| 腓总神经(踝-腓骨小头下)† | 25 | 37.7±6.2(28.1~55.4) | 9(36.0) | ≥43.0 |
| 腓总神经(腓骨小头上-下)† | 25 | 29.7±6.9(17.8~43.5) | 24(96.0) | ≥43.0 |
| 复合肌肉动作电位波幅 | ||||
| 正中神经(腕) | 44 | 8.4±5.1(1.9~28.5) | 9(20.5) | ≥5.0 |
| 尺神经(腕) | 45 | 8.9±3.3(3.0~17.2) | 1(2.2) | ≥5.0 |
| 尺神经(肘上)† | 36 | 6.5±2.9(0.6~15.5) | 9(25.0) | ≥5.0 |
| 桡神经(肘) | 6 | 4.3±3.7(0.8~9.0) | 3(50.0) | ≥2.5 |
| 胫神经(踝) | 55 | 9.0±6.1(1.2~34.8) | 10(18.2) | ≥5.0 |
| 腓总神经(踝) | 55 | 3.3±2.0(0.1~7.3) | 22(40.0) | ≥2.0 |
| 腓总神经(腓骨小头上)† | 25 | 2.2±1.5(0.1~4.8) | 14(56.0) | ≥2.0 |
| 最小F波潜伏期 | ||||
| 正中神经 | 13 | 31.0±6.9(21.5~38.3) | 11(84.6) | ≤26.0 |
| 胫神经 | 18 | 52.3±9.7(42.8~64.8) | 14(77.8) | ≤48.0 |
| 感觉神经传导 | ||||
| 感觉神经传导速度 | ||||
| 正中神经(腕-掌) | 38 | 37.4±10.5(11.3~52.9) | 35(92.1) | ≥50.0 |
| 尺神经(腕-掌) | 36 | 39.3±9.3(27.2~46.6) | 33(91.7) | ≥50.0 |
| 桡神经 | 10 | 38.9±9.7(19.8~51.9) | 8(80.0) | ≥50.0 |
| 腓肠神经 | 18 | 35.3±7.7(18.6~43.6) | 14(77.8) | ≥41.0 |
| 腓浅神经 | 44 | 39.5±8.0(26.7~52.2) | 24(54.5) | ≥41.0 |
| 感觉神经动作电位波幅 | ||||
| 正中神经(腕-掌) | 38 | 14.4±13.0(1.0~49.0) | 29(76.3) | ≥20.0 |
| 尺神经(腕-掌) | 36 | 11.4±15.2(0.9~39.0) | 31(86.1) | ≥17.0 |
| 桡神经 | 10 | 4.7±3.0(0.7~8.9) | 10(100.0) | ≥10.0 |
| 腓肠神经 | 18 | 4.1±3.3(0.6~9.4) | 13(72.7) | ≥4.0 |
| 腓浅神经 | 44 | 5.2±4.3(0.38~18.0) | 25(56.8) | ≥4.0 |
*未分段进行神经传导速度检查；†分段进行神经传导速度检查；‡远端运动潜伏期单位为ms，运动神经传导速度、感觉神经传导速度的单位均为m/s，复合肌肉动作电位波幅、最小F波潜伏期、感觉神经动作电位波幅的单位分别为mV、ms、μV；#参考值范围来自中南大学湘雅三医院神经电生理室。HNPP：遗传性压力易感性周围神经病。
2.3. 分子遗传学特征
在24个初诊HNPP家系中，经MLPA检测证实，有23个家系(F1~F23)为PMP22杂合缺失突变导致(包括F7家系，图1B)，经二代测序证实，F24家系中的2位患者均携带PMP22 c.434delT(p.Leu145ArgfsTer10)杂合突变(图1C)。
2.4. 文献分析
检索后纳入336篇相关文献，共1 734个具有基因检测结果的HNPP确诊家系。在这1 734个家系中，有1 620个(93.4%)家系存在PMP22杂合缺失突变。81个家系由较少见的PMP22突变类型引起，包括PMP22微小突变(69/1 734，4.0%)[5-39]、PMP22杂合不完全缺失突变(10/1 734，0.6%)[4, 40-45]、PMP22复杂易位突变(2/1 734，0.1%)[46](图2)。目前报道可致HNPP的PMP22微小突变有38种，包括错义突变(10/38)[6-14]、无义突变(4/38)[5, 15-18]、碱基缺失突变(13/38)[15, 19-31]、碱基插入突变(3/38)[11, 32-35]、剪切位点突变(8/38)[14, 16, 36-39]，大多数位于开放编码区。其余33个(1.9%)HNPP家系未检测到PMP22基因杂合缺失突变，亦未进一步进行其他突变检测，故实际基因突变情况未知。
图2.
HNPP患者的 PMP22(NM_000304)突变类型
Figure 2 HNPP related PMP22 (NM_000304) mutations
HNPP: Hereditary neuropathy with liability to pressure palsy; PMP22: Peripheral myelin protein 22; UTR: Untranslated regions.
笔者检索并收集了1 734个HNPP家系中1 594例患者的临床资料，包括男性924人，女性670人，男女比例约为1.4꞉1。有阳性家族史的家系为659个(38.0%)。患者平均起病年龄为26.8岁，年龄跨度大，最小的患者为1名出生时伴有臂丛麻痹的新生儿[47]，最晚起病的是1名83岁时出现腓总神经麻痹的日本女性[48]。12.8%(204/1 594)的患者追溯到在发作前有诱因，包括剧烈运动、保持固定姿势、外伤、手术、减重、分娩等。患者以发作性无痛性单神经麻痹为典型表现，对639例注明受累神经的患者进行统计后发现，腓总神经最常受累(246/639，38.5%)，其次为尺神经(125/639，19.6%)、臂丛(108/639，16.9%)、桡神经(74/639，11.6%)、正中神经(46/639，7.2%)；少数患者为坐骨神经、股神经、股外侧皮神经、胫神经等神经损害[49-50](图3A)。HNPP患者很少出现颅神经受累，目前仅报道了18例患者(图3B、表3)。少数患者(70/1 594，4.4%)有神经性疼痛。部分患者可出现非典型表现，如病情进行性加重或吉兰-巴雷综合征类似症状[2, 24]、CMT类似症状[2]等。
图3.
HNPP患者的周围神经受累情况
Figure 3 Peripheral nerve involvement in HNPP patients
A: Peripheral nerve involvement in HNPP patients; B: Cranial nerve involvement in HNPP patients. HNPP: Hereditary neuropathy with liability to pressure palsy.
表3.
文献报道的HNPP患者伴颅神经受累总结
Table 3 Summary of reported HNPP patients with cranial nerve involvement
| 作者 | 临床表现 | 受累颅神经(例数) |
|---|---|---|
| Görke等[53] | 偏侧头皮的颞顶区麻木 | 三叉神经(1) |
| Yakushiji等[54] | 右侧面部感觉障碍 | 三叉神经(1) |
| Mouton等[2] | 未提及 | 面神经(2) |
| Debruyne等[55] | 未提及 | 面神经(1) |
| Herlicoviez等[56] | 未提及 | 双侧面神经(1) |
| Poloni等[57] | 未提及 | 面神经(1) |
| Drouet等[58] | 未提及 | 面神经(1) |
| Horowitz等[59] | 双侧鼻唇沟变浅 | 双侧面神经(1) |
| Staal等[60] | 双侧听力下降 | 双侧听神经(1) |
| Castaigne等[61] | 双侧听力下降 | 双侧听神经(1) |
| Ohkoshi等[62] | 声音嘶哑 | 迷走神经(1) |
| Cortese等[63] | 发声困难、声音嘶哑 | 迷走神经(1) |
| 刘华等[64] | 声音嘶哑 | 迷走神经(1) |
| Winter等[65] | 伸舌右偏 | 舌下神经(1) |
HNPP：遗传性压力易感性周围神经病。
3. 讨 论
HNPP是一种少见的常染色体显性遗传周围神经病，1947年荷兰医师De Jong报道首例HNPP患者。本组患者绝大多数为PMP22大片段杂合缺失突变所导致，仅发现1个家系(F24)由PMP22单个碱基缺失突变导致，且该突变为已报道的c.434delT位点突变[29-31]。因此，对于可疑的HNPP患者，笔者建议首选MLPA筛查PMP22缺失突变，若MLPA检查结果为阴性，可考虑采用Sanger测序或二代测序进行PMP22其他突变类型的检测以防漏诊。
本组中国汉族HNPP患者的临床表现特点与已报道的HNPP患者大致相同，相较于文献报道的患者平均起病年龄26.8岁，本组患者平均发病年龄为22.0岁，表现出更早的发病趋势。本组患者中有1对双胞胎兄妹首发症状为肢体麻木无力，曾多次在长时间保持伏案姿势或睡醒后出现声音嘶哑、饮水呛咳、吞咽困难等不适，提示发作性单侧喉返神经(迷走神经)麻痹，2位患者行头部MRI平扫未发现异常，颅神经受累的机制尚不明确。已报道的HNPP患者颅神经受累以单侧为主，面神经、三叉神经及后组颅神经(如迷走神经、舌下神经)似乎更易受累，可能与PMP22蛋白质在中枢神经系统的分布有关[66]。三叉神经和面神经位置较表浅，后组颅神经行经路线较长，在反复屈伸颈部、咳嗽、血管搏动等因素的综合影响下也更易发生神经损伤。HNPP患者的神经电生理检查大多表现为弥漫性脱髓鞘改变，包括普遍延长的DML、轻中度减慢的神经传导速度，可伴传导阻滞，且感觉神经指标异常较运动神经更常见。
尽管HNPP患者的临床表现具有相对较高的一致性，但在起病年龄、受累神经、病情严重程度及预后等方面仍具有一定差异，部分患者的临床表现可以与CMT、获得性周围神经病等疾病有重叠，临床医师在接诊时需注意鉴别，尤其是对于儿童、老年及轻症患者，勿漏诊、误诊。
本研究存在一定的局限性：为回顾性分析；研究对象来自单中心，病例数有限；部分患者失访，随访数据不全，且缺乏纵向的神经电生理数据对比。
综上，本研究纳入24个中国汉族HNPP家系的34名患者，除了1个家系为PMP22c.434delT突变所致，其余23个家系均为PMP22杂合缺失突变引起，本组患者以发作性无痛性单神经麻痹为主要特点，主要累及腓总神经、尺神经等周围神经，部分患者有罕见的颅神经受累。神经电生理检查对于诊断本病具有较高的灵敏度和特异度，表现为广泛的脱髓鞘改变。已报道的绝大多数HNPP患者由17p11.2区大片段杂合缺失突变所致(包含PMP22基因在内)，少数由PMP22其他类型突变导致。对于怀疑HNPP的患者，首选完善神经电生理检查及PMP22大片段杂合缺失的检测。必要时可以完善Sanger测序或二代测序对PMP22其他突变类型进行检测以防漏诊。
基金资助
国家自然科学基金(81771366，82171172，82001338)；湖南省自然科学基金(2022JJ30910)。
This work was supported by the National Natural Science Foundation (81771366, 82171172, 82001338) and the Natural Science Foundation of Hunan Province (2022JJ30910), China.
利益冲突声明
作者声称无任何利益冲突。
作者贡献
曹婉芊 研究设计与实施，数据统计与分析，论文起草；黄顺祥 数据统计与分析；赵华栋 数据采集、统计及分析；黎中政、朱习影 数据采集；刘蕾 论文指导；张如旭 研究设计，论文审阅与修订。所有作者阅读并同意最终的文本。
原文网址
http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/2023101572.pdf
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