遗传性压力易感性周围神经病24个家系的临床和分子遗传学特征及文献回顾

Clinical and molecular genetic characteristics of 24 families of hereditary neuropathy with liability to pressure palsy and literature review

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1734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。

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 1734 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.