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Morphofunctional characterisation of axonal damage in different rat models of chemotherapy-induced peripheral neurotoxicity: The role of nerve excitability testing 不同大鼠化疗诱导的周围神经毒性模型轴突损伤的形态功能特征:神经兴奋性测试的作用。
IF 3.8 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-11-27 DOI: 10.1111/jns.12607
Alessia Chiorazzi, Annalisa Canta, Valentina Alda Carozzi, Cristina Meregalli, Eleonora Pozzi, Elisa Ballarini, Virginia Rodriguez-Menendez, Paola Marmiroli, Guido Cavaletti, Paola Alberti

Background and Aims

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common and long-lasting adverse event of several anticancer compounds, for which treatment has not yet been developed. To fill this gap, preclinical studies are warranted, exploiting highly translational outcome measure(s) to transfer data from bench to bedside. Nerve excitability testing (NET) enables to test in vivo axonal properties and can be used to monitor early changes leading to axonal damage.

Methods

We tested NET use in two different CIPN rat models: oxaliplatin (OHP) and paclitaxel (PTX). Animals (female) were chronically treated with either PTX or OHP and compared to respective control animals. NET was performed as soon as the first injection was administered. At the end of the treatment, CIPN onset was verified via a multimodal and robust approach: nerve conduction studies, nerve morphometry, behavioural tests and intraepidermal nerve fibre density.

Results

NET showed the typical pattern of axonal hyperexcitability in the 72 h following the first OHP administration, whereas it showed precocious signs of axonal damage in PTX animals. At the end of the month of treatment, OHP animals showed a pattern compatible with a mild axonal sensory polyneuropathy. Instead, PTX cohort was characterised by a rather severe sensory axonal polyneuropathy with minor signs of motor involvement.

Interpretation

NET after the first administration demonstrated the ongoing OHP-related channelopathy, whereas in PTX cohort it showed precocious signs of axonal damage. Therefore, NET could be suggested as an early surrogate marker in clinical trials, to detect precocious changes leading to axonal damage.

背景和目的:化疗诱导的周围神经毒性(CIPN)是几种抗癌化合物常见且持久的不良事件,其治疗方法仍然缺乏。为了填补这一空白,临床前研究是必要的,利用高度转化的结果测量将数据从实验台转移到床侧。神经兴奋性测试(NET)能够测试体内轴突特性,并可用于监测导致轴突损伤的早期变化。方法:我们在2种不同的CIPN大鼠模型中测试NET的使用:奥沙利铂(OHP)和紫杉醇(PTX)。动物(雌性)长期接受PTX或OHP治疗,并与相应的对照动物进行比较。第一次注射后立即进行NET。在治疗结束时,通过多模式和强大的方法验证CIPN的发生:神经传导研究(NCS)、神经形态测定、行为测试和表皮内神经纤维密度(IENFD)。结果:在第一次OHP给药后72小时内,NET表现出典型的轴突高兴奋性,而PTX动物则表现出轴突损伤的早熟迹象。在治疗一个月结束时,OHP动物表现出与轻度轴突感觉多发性神经病相一致的模式。相反,PTX队列的特征是相当严重的感觉轴索多发性神经病,伴有轻微的运动受累迹象。解释:在第一次给药后,NET显示持续的ohp相关的通道病变,而在PTX队列中,它显示轴突损伤的早熟迹象。因此,NET可以作为临床试验的早期替代标志物,用于检测导致轴突损伤的早熟变化。这篇文章受版权保护。版权所有。
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引用次数: 0
Plasma proteomic analysis on neuropathic pain in idiopathic peripheral neuropathy patients 特发性周围神经病变患者神经性疼痛的血浆蛋白质组学分析。
IF 3.8 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-11-21 DOI: 10.1111/jns.12606
Perry T. C. van Doormaal, Simone Thomas, Senda Ajroud-Driss, Robert N. Cole, Lauren R. DeVine, Mazen M. Dimachkie, Stefanie Geisler, Roy Freeman, David M. Simpson, J. Robinson Singleton, A. Gordon Smith, Amro Stino, PNRR Study Group, Ahmet Höke

Background and Aims

Why only half of the idiopathic peripheral neuropathy (IPN) patients develop neuropathic pain remains unknown. By conducting a proteomics analysis on IPN patients, we aimed to discover proteins and new pathways that are associated with neuropathic pain.

Methods

We conducted unbiased mass-spectrometry proteomics analysis on blood plasma from 31 IPN patients with severe neuropathic pain and 29 IPN patients with no pain, to investigate protein biomarkers and protein–protein interactions associated with neuropathic pain. Univariate modeling was done with linear mixed modeling (LMM) and corrected for multiple testing. Multivariate modeling was performed using elastic net analysis and validated with internal cross-validation and bootstrapping.

Results

In the univariate analysis, 73 proteins showed a p-value <.05 and 12 proteins showed a p-value <.01. None were significant after Benjamini–Hochberg adjustment for multiple testing. Elastic net analysis created a model containing 12 proteins with reasonable discriminatory power to differentiate between painful and painless IPN (false-negative rate 0.10, false-positive rate 0.18, and an area under the curve 0.75). Eight of these 12 proteins were clustered into one interaction network, significantly enriched for the complement and coagulation pathway (Benjamini–Hochberg adjusted p-value = .0057), with complement component 3 (C3) as the central node. Bootstrap validation identified insulin-like growth factor-binding protein 2 (IGFBP2), complement factor H-related protein 4 (CFHR4), and ferritin light chain (FTL), as the most discriminatory proteins of the original 12 identified.

Interpretation

This proteomics analysis suggests a role for the complement system in neuropathic pain in IPN.

背景和目的:为什么只有一半的特发性周围多发性神经病变(IPN)患者发生神经性疼痛尚不清楚。通过对IPN患者进行蛋白质组学分析,我们旨在发现与神经性疼痛相关的蛋白质和新途径。方法:我们对31例伴有严重神经性疼痛的IPN患者和29例无疼痛的IPN患者的血浆进行了无偏倚质谱蛋白质组学分析,以研究与神经性疼痛相关的蛋白质生物标志物和蛋白质-蛋白质相互作用。采用线性混合模型(LMM)进行单变量建模,并对多重检验进行校正。使用弹性网分析进行多变量建模,并通过内部交叉验证和自举进行验证。结果:在单变量分析中,73种蛋白质显示p值解释:该蛋白质组学分析表明补体系统在IPN神经性疼痛中的作用。这篇文章受版权保护。版权所有。
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引用次数: 0
Synergistic effects of immune checkpoints and checkpoint inhibitors in inflammatory neuropathies: Implications and mechanisms 免疫检查点和检查点抑制剂在炎性神经病变中的协同作用:意义和机制。
IF 3.8 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-11-21 DOI: 10.1111/jns.12605
Aritrani Sarkar, Madhu Nagappa, Saikat Dey, Sandipan Mondal, Gopika Suresh Babu, Saptamita Pal Choudhury, Pokala Akhil, Monojit Debnath

Immune checkpoint molecules play pivotal roles in the regulation of immune homeostasis. Disruption of the immune checkpoints causes autoimmune/inflammatory as well as malignant disorders. Over the past few years, the immune checkpoint molecules with inhibitory function emerged as potential therapeutic targets in oncological conditions. The inhibition of the function of these molecules by using immune checkpoint inhibitors (ICIs) has brought paradigmatic changes in cancer therapy due to their remarkable clinical benefits, not only in improving the quality of life but also in prolonging the survival time of cancer patients. Unfortunately, the ICIs soon turned out to be a “double-edged sword” as the use of ICIs caused multiple immune-related adverse effects (irAEs). The development of inflammatory neuropathies such as Guillain–Barré syndrome (GBS) and Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) as the secondary effects of immunotherapy appeared very challenging as these conditions result in significant and often permanent disability. The underlying mechanism(s) through which ICIs trigger inflammatory neuropathies are currently not known. Compelling evidence suggests autoimmune reaction and/or inflammation as the independent risk mechanism of inflammatory neuropathies. There is a lack of understanding as to whether prior exposure to the risk factors of inflammatory neuropathies, the presence of germline genetic variants in immune function-related genes, genetic variations within immune checkpoint molecules, the existence of autoantibodies, and activated/memory T cells act as determining factors for ICI-induced inflammatory neuropathies. Herein, we highlight the available pieces of evidence, discuss the mechanistic basis, and propose a few testable hypotheses on inflammatory neuropathies as irAEs of immunotherapy.

免疫检查点分子在调节免疫稳态中起着关键作用。免疫检查点的破坏导致自身免疫/炎症以及恶性疾病。在过去的几年里,具有抑制功能的免疫检查点分子成为肿瘤疾病的潜在治疗靶点。通过使用免疫检查点抑制剂(ici)抑制这些分子的功能,由于其显着的临床益处,不仅可以改善癌症患者的生活质量,还可以延长癌症患者的生存时间,从而带来了癌症治疗的典范变化。不幸的是,ICIs很快被证明是一把“双刃剑”,因为使用ICIs会引起多种免疫相关的不良反应(irAEs)。炎症性神经病变的发展,如格林-巴勒综合征(GBS)和慢性炎症性脱髓鞘性多根神经病变(CIDP),作为免疫治疗的继发效应,似乎非常具有挑战性,因为这些疾病会导致严重的,通常是永久性的残疾。ICIs触发炎性神经病变的潜在机制目前尚不清楚。令人信服的证据表明,自身免疫反应和/或炎症是炎性神经病变的独立风险机制。对于先前暴露于炎症性神经病变的危险因素、免疫功能相关基因中种系遗传变异的存在、免疫检查点分子中的遗传变异、自身抗体和活化/记忆T细胞的存在是否作为ici诱导的炎症性神经病变的决定因素,尚缺乏了解。在此,我们强调了现有的证据,讨论了机制基础,并提出了一些可测试的假设炎性神经病变作为免疫治疗的irae。这篇文章受版权保护。版权所有。
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引用次数: 0
A novel de novo variant in POLR3B gene associated with a primary axonal involvement of the largest nerve fibers POLR3B基因的一种新的从头变异与最大神经纤维的原发性轴突受累有关。
IF 3.8 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-10-28 DOI: 10.1111/jns.12602
Alessandro Geroldi, Stefano Tozza, Chiara Fiorillo, Maria Nolano, Paola Fossa, Floriana Vitale, Regi Domi, Andrea Gaudio, Alessia Mammi, Serena Patrone, Andrea La Barbera, Paola Origone, Clarissa Ponti, Francesca Sanguineri, Federico Zara, Matteo Cataldi, Vincenzo Salpietro, Consuelo Barbara Venturi, Sara Massucco, Angelo Schenone, Fiore Manganelli, Paola Mandich, Emilia Bellone, Fabio Gotta

Background and Aims

POLR3B gene encodes a subunit of RNA polymerase III (Pol III). Biallelic mutations in POLR3B are associated with leukodystrophies, but recently de novo heterozygous mutations have been described in early onset peripheral demyelinating neuropathies with or without central involvement. Here, we report the first Italian case carrying a de novo variant in POLR3B with a pure neuropathy phenotype and primary axonal involvement of the largest nerve fibers.

Methods

Nerve conduction studies, sympathetic skin response, dynamic sweat test, tactile and thermal quantitative sensory testing and brain magnetic resonance imaging were performed according to standard procedures. Histopathological examination was performed on skin and sural nerve biopsies. Molecular analysis of the proband and his relatives was performed with Next Generation Sequencing. The impact of the identified variant on the overall protein structure was evaluated through rotamers method.

Results

Since his early adolescence, the patient presented with signs of polyneuropathy with severe distal weakness, atrophy, and reduced sensation. Neurophysiological studies showed a sensory-motor axonal polyneuropathy, with confirmed small fiber involvement. In addition, skin biopsy and sural nerve biopsy showed predominant large fibers involvement. A trio's whole exome sequencing revealed a novel de novo variant p.(Arg1046Cys) in POLR3B, which was classified as Probably Pathogenic. Molecular modeling data confirmed a deleterious effect of the variant on protein structure.

Interpretation

Neurophysiological and morphological findings suggest a primary axonal involvement of the largest nerve fibers in POLR3B-related neuropathies. A partial loss of function mechanism is proposed for both neuropathy and leukodystrophy phenotypes.

背景和目的:POLR3B基因编码RNA聚合酶III(Pol III)的一个亚基。POLR3B中的双等位基因突变与白细胞营养不良有关,但最近在伴有或不伴有中枢受累的早发性外周脱髓鞘神经病中描述了新发杂合突变。在这里,我们报道了意大利首例携带POLR3B从头变异的病例,该病例具有纯神经病变表型和最大神经纤维的原发性轴突受累。方法:按照标准程序进行神经传导研究、交感神经皮肤反应、动态汗液测试、触觉和热定量感觉测试以及脑MRI。对皮肤和腓肠神经活检进行组织病理学检查。先证者及其亲属的分子分析采用下一代测序法进行。通过轮调异构体方法评估鉴定的变体对整体蛋白质结构的影响。结果:自青少年早期以来,患者就表现出多发性神经病的症状,伴有严重的远端无力、萎缩和感觉减退。神经生理学研究显示一种感觉运动轴突多发性神经病,证实有小纤维受累。此外,皮肤活检和腓肠神经活检显示主要的大纤维受累。三人组的全外显子组测序(WES)揭示了POLR3B中一种新的从头变异p。(Arg1046Cys),被归类为可能致病。分子建模数据证实了该变体对蛋白质结构的有害影响。解释:神经生理学和形态学结果表明,POLR3B相关神经病中最大神经纤维的原发性轴突受累。神经病变和白细胞营养不良表型的部分功能丧失机制被提出。这篇文章受版权保护。保留所有权利。
{"title":"A novel de novo variant in POLR3B gene associated with a primary axonal involvement of the largest nerve fibers","authors":"Alessandro Geroldi,&nbsp;Stefano Tozza,&nbsp;Chiara Fiorillo,&nbsp;Maria Nolano,&nbsp;Paola Fossa,&nbsp;Floriana Vitale,&nbsp;Regi Domi,&nbsp;Andrea Gaudio,&nbsp;Alessia Mammi,&nbsp;Serena Patrone,&nbsp;Andrea La Barbera,&nbsp;Paola Origone,&nbsp;Clarissa Ponti,&nbsp;Francesca Sanguineri,&nbsp;Federico Zara,&nbsp;Matteo Cataldi,&nbsp;Vincenzo Salpietro,&nbsp;Consuelo Barbara Venturi,&nbsp;Sara Massucco,&nbsp;Angelo Schenone,&nbsp;Fiore Manganelli,&nbsp;Paola Mandich,&nbsp;Emilia Bellone,&nbsp;Fabio Gotta","doi":"10.1111/jns.12602","DOIUrl":"10.1111/jns.12602","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p><i>POLR3B</i> gene encodes a subunit of RNA polymerase III (Pol III). Biallelic mutations in <i>POLR3B</i> are associated with leukodystrophies, but recently de novo heterozygous mutations have been described in early onset peripheral demyelinating neuropathies with or without central involvement. Here, we report the first Italian case carrying a de novo variant in <i>POLR3B</i> with a pure neuropathy phenotype and primary axonal involvement of the largest nerve fibers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Nerve conduction studies, sympathetic skin response, dynamic sweat test, tactile and thermal quantitative sensory testing and brain magnetic resonance imaging were performed according to standard procedures. Histopathological examination was performed on skin and sural nerve biopsies. Molecular analysis of the proband and his relatives was performed with Next Generation Sequencing. The impact of the identified variant on the overall protein structure was evaluated through rotamers method.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Since his early adolescence, the patient presented with signs of polyneuropathy with severe distal weakness, atrophy, and reduced sensation. Neurophysiological studies showed a sensory-motor axonal polyneuropathy, with confirmed small fiber involvement. In addition, skin biopsy and sural nerve biopsy showed predominant large fibers involvement. A trio's whole exome sequencing revealed a novel de novo variant p.(Arg1046Cys) in <i>POLR3B</i>, which was classified as Probably Pathogenic. Molecular modeling data confirmed a deleterious effect of the variant on protein structure.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Neurophysiological and morphological findings suggest a primary axonal involvement of the largest nerve fibers in <i>POLR3B</i>-related neuropathies. A partial loss of function mechanism is proposed for both neuropathy and leukodystrophy phenotypes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"28 4","pages":"620-628"},"PeriodicalIF":3.8,"publicationDate":"2023-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jns.12602","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66783962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Unveiling the clinical and electrophysiological profile of CMTX6: Insights from two Brazilian families 揭示CMTX6的临床和电生理特征:来自两个巴西家族的见解。
IF 3.8 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-10-17 DOI: 10.1111/jns.12601
Victor Augusto Zanesi Maciel, Gustavo Maximiano-Alves, Rodrigo Siqueira Soares Frezatti, Anna Letícia De Moraes Alves, Bianca Mara Alves Andrade, Rita De Cassia Carvalho Leal, Pedro José Tomaselli, Mary M. Reilly, Wilson Marques
BACKGROUND AND AIMSX-linked Charcot-Marie-Tooth disease type 6 (CMTX6) is an extremely rare condition associated with mutations in the PDK3 gene. To date, only three families from different countries have been reported (Australia, South Korea and Germany). In this study, we sought to provide a comprehensive clinical and electrophysiological characterization of two Brazilian families.METHODSWe conducted comprehensive clinical assessments, extensive electrophysiological evaluations, and performed whole-exome sequencing in the probands to investigate the genetic basis of the disease.RESULTSMales in the family carrying the Arg162His mutation displayed early-onset motor and/or sensory axonal neuropathy, absence of tendon jerks, pes cavus, and frequently reported pain. Females in the same family exhibited a milder phenotype of the disease with later onset and some remained asymptomatic into their 50s. In the unrelated family with a single affected male, the clinical presentation was characterized by severe progressive sensorimotor polyneuropathy accompanied by neuropathic pain.INTERPRETATIONWe report two Brazilian families with CMTX6 including one harboring a previously unpublished variant in the PDK3 gene, which co-segregates with the disease as expected in a X-linked disease. Notably, the clinical presentations across the five families with available descriptions, including our study, share striking similarities. Furthermore, the proximity of the three reported mutations suggests potential functional similarities and common underlying mechanisms. This study contributes to the growing knowledge of CMTX6 and underscores the importance of international collaborations in studying rare genetic disorders. This article is protected by copyright. All rights reserved.
背景和目的:6型X连锁Charcot-Marie Tooth病(CMTX6)是一种极为罕见的与PDK3基因突变有关的疾病。迄今为止,只报告了来自不同国家的三个家庭(澳大利亚、韩国和德国)。在这项研究中,我们试图提供两个巴西家庭的全面临床和电生理特征。方法:我们对先证者进行了全面的临床评估、广泛的电生理评估,并进行了全外显子组测序,以研究该疾病的遗传基础。结果:携带Arg162His突变的家族中的男性表现出早发性运动和/或感觉轴索神经病变,没有肌腱痉挛、空腔炎和经常报告的疼痛。同一家族的女性表现出较温和的疾病表型,发病较晚,一些女性在50多岁时仍无症状。在有一名患病男性的无关家族中,临床表现为严重的进行性感觉运动性多发性神经病伴神经性疼痛。解释:我们报道了两个患有CMTX6的巴西家族,其中一个家族在PDK3基因中携带一个先前未发表的变体,该变体与X连锁疾病中预期的疾病共分离。值得注意的是,包括我们的研究在内的五个有可用描述的家族的临床表现有着惊人的相似之处。此外,报告的三种突变的接近性表明了潜在的功能相似性和共同的潜在机制。这项研究有助于增加对CMTX6的了解,并强调了国际合作在研究罕见遗传疾病方面的重要性。这篇文章受版权保护。保留所有权利。
{"title":"Unveiling the clinical and electrophysiological profile of CMTX6: Insights from two Brazilian families","authors":"Victor Augusto Zanesi Maciel,&nbsp;Gustavo Maximiano-Alves,&nbsp;Rodrigo Siqueira Soares Frezatti,&nbsp;Anna Letícia De Moraes Alves,&nbsp;Bianca Mara Alves Andrade,&nbsp;Rita De Cassia Carvalho Leal,&nbsp;Pedro José Tomaselli,&nbsp;Mary M. Reilly,&nbsp;Wilson Marques","doi":"10.1111/jns.12601","DOIUrl":"10.1111/jns.12601","url":null,"abstract":"BACKGROUND AND AIMS\u0000X-linked Charcot-Marie-Tooth disease type 6 (CMTX6) is an extremely rare condition associated with mutations in the PDK3 gene. To date, only three families from different countries have been reported (Australia, South Korea and Germany). In this study, we sought to provide a comprehensive clinical and electrophysiological characterization of two Brazilian families.\u0000\u0000\u0000METHODS\u0000We conducted comprehensive clinical assessments, extensive electrophysiological evaluations, and performed whole-exome sequencing in the probands to investigate the genetic basis of the disease.\u0000\u0000\u0000RESULTS\u0000Males in the family carrying the Arg162His mutation displayed early-onset motor and/or sensory axonal neuropathy, absence of tendon jerks, pes cavus, and frequently reported pain. Females in the same family exhibited a milder phenotype of the disease with later onset and some remained asymptomatic into their 50s. In the unrelated family with a single affected male, the clinical presentation was characterized by severe progressive sensorimotor polyneuropathy accompanied by neuropathic pain.\u0000\u0000\u0000INTERPRETATION\u0000We report two Brazilian families with CMTX6 including one harboring a previously unpublished variant in the PDK3 gene, which co-segregates with the disease as expected in a X-linked disease. Notably, the clinical presentations across the five families with available descriptions, including our study, share striking similarities. Furthermore, the proximity of the three reported mutations suggests potential functional similarities and common underlying mechanisms. This study contributes to the growing knowledge of CMTX6 and underscores the importance of international collaborations in studying rare genetic disorders. This article is protected by copyright. All rights reserved.","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"28 4","pages":"614-619"},"PeriodicalIF":3.8,"publicationDate":"2023-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41236386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Identification of blood metabolic biomarkers associated with diabetic distal symmetric sensorimotor polyneuropathy in patients with type 2 diabetes mellitus 2型糖尿病患者中与糖尿病远端对称性感觉运动多发性神经病相关的血液代谢生物标志物的鉴定。
IF 3.8 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-10-13 DOI: 10.1111/jns.12600
Kuo-Hsuan Chang, Chiung-Mei Chen, Chia-Ni Lin, Sung-Sheng Tsai, Rong-Kuo Lyu, Chun-Che Chu, Long-Sun Ro, Ming-Feng Liao, Hong-Shiu Chang, Yi-Ching Weng, Jawl-Shan Hwang, Hung-Chou Kuo

Background

Distal symmetric sensorimotor polyneuropathy (DSPN) is a common neurologic complication of type 2 diabetes mellitus (T2DM), but the underlying mechanisms and changes in serum metabolites remain largely undefined. This study aimed to characterize the plasma metabolite profiles of participants with T2DM using targeted metabolomics analysis and identify potential biomarkers for DSPN.

Methods

A combined liquid chromatography MS/MS and direct flow injection were used to quantify plasma metabolite obtained from 63 participants with T2DM, 81 with DSPN, and 33 nondiabetic control participants. A total of 130 metabolites, including amino acids, biogenic amines, sphingomyelins (SM), phosphatidylcholines, carnitines, and hexose, were analyzed.

Results

A total of 16 plasma metabolites and 3 cholesterol-related laboratory parameters were found to have variable importance in the projection score >1.0 and false discovery rate <5.0% between control, T2DM, and DSPN. Among these variables, five serum metabolites, including phenylalanine (AUC = 0.653), alanine (AUC = 0.630), lysine (AUC = 0.622) tryptophan (AUC = 0.620), and SM C16:0 (AUC = 0.630), are potential biomarkers (all p < .05) in distinguishing T2DM with DSPN from those without (AUC = 0.720).

Conclusions

In this cross-sectional study, derangement of several metabolites in the plasma was observed in T2DM with and without DSPN, and these metabolites may be potential biomarkers for predicting DSPN. Longitudinal studies are warranted.

背景:远端对称性感觉运动性多发性神经病(DSPN)是2型糖尿病(T2DM)常见的神经并发症,但其潜在机制和血清代谢产物的变化在很大程度上尚不清楚。本研究旨在通过靶向代谢组学分析来表征T2DM参与者的血浆代谢产物谱,并确定DSPN的潜在生物标志物。方法:采用液相色谱MS/MS和直接流式注射相结合的方法对63名T2DM患者、81名DSPN患者和33名非糖尿病对照组患者的血浆代谢产物进行定量。共分析了130种代谢产物,包括氨基酸、生物胺、鞘磷脂(SM)、磷脂酰胆碱、肉碱和己糖。结果:共发现16种血浆代谢物和3种胆固醇相关实验室参数在预测得分中具有可变重要性> 1.0和错误发现率结论:在这项横断面研究中,在有和没有DSPN的T2DM患者中观察到血浆中几种代谢产物的紊乱,这些代谢产物可能是预测DSPN的潜在生物标志物。有必要进行纵向研究。这篇文章受版权保护。保留所有权利。
{"title":"Identification of blood metabolic biomarkers associated with diabetic distal symmetric sensorimotor polyneuropathy in patients with type 2 diabetes mellitus","authors":"Kuo-Hsuan Chang,&nbsp;Chiung-Mei Chen,&nbsp;Chia-Ni Lin,&nbsp;Sung-Sheng Tsai,&nbsp;Rong-Kuo Lyu,&nbsp;Chun-Che Chu,&nbsp;Long-Sun Ro,&nbsp;Ming-Feng Liao,&nbsp;Hong-Shiu Chang,&nbsp;Yi-Ching Weng,&nbsp;Jawl-Shan Hwang,&nbsp;Hung-Chou Kuo","doi":"10.1111/jns.12600","DOIUrl":"10.1111/jns.12600","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Distal symmetric sensorimotor polyneuropathy (DSPN) is a common neurologic complication of type 2 diabetes mellitus (T2DM), but the underlying mechanisms and changes in serum metabolites remain largely undefined. This study aimed to characterize the plasma metabolite profiles of participants with T2DM using targeted metabolomics analysis and identify potential biomarkers for DSPN.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A combined liquid chromatography MS/MS and direct flow injection were used to quantify plasma metabolite obtained from 63 participants with T2DM, 81 with DSPN, and 33 nondiabetic control participants. A total of 130 metabolites, including amino acids, biogenic amines, sphingomyelins (SM), phosphatidylcholines, carnitines, and hexose, were analyzed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 16 plasma metabolites and 3 cholesterol-related laboratory parameters were found to have variable importance in the projection score &gt;1.0 and false discovery rate &lt;5.0% between control, T2DM, and DSPN. Among these variables, five serum metabolites, including phenylalanine (AUC = 0.653), alanine (AUC = 0.630), lysine (AUC = 0.622) tryptophan (AUC = 0.620), and SM C16:0 (AUC = 0.630), are potential biomarkers (all <i>p</i> &lt; .05) in distinguishing T2DM with DSPN from those without (AUC = 0.720).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In this cross-sectional study, derangement of several metabolites in the plasma was observed in T2DM with and without DSPN, and these metabolites may be potential biomarkers for predicting DSPN. Longitudinal studies are warranted.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"28 4","pages":"651-663"},"PeriodicalIF":3.8,"publicationDate":"2023-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41204138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
European Academy of Neurology/Peripheral Nerve Society Guideline on diagnosis and treatment of Guillain–Barré syndrome 欧洲神经病学学会/外周神经学会格林-巴利综合征诊断和治疗指南。
IF 3.8 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-10-10 DOI: 10.1111/jns.12594
Pieter A. van Doorn, Peter Y. K. Van den Bergh, Robert D. M. Hadden, Bert Avau, Patrik Vankrunkelsven, Shahram Attarian, Patricia H. Blomkwist-Markens, David R. Cornblath, H. Stephan Goedee, Thomas Harbo, Bart C. Jacobs, Susumu Kusunoki, Helmar C. Lehmann, Richard A. Lewis, Michael P. Lunn, Eduardo Nobile-Orazio, Luis Querol, Yusuf A. Rajabally, Thirugnanam Umapathi, Haluk A. Topaloglu, Hugh J. Willison
<p>Guillain–Barré syndrome (GBS) is an acute polyradiculoneuropathy. Symptoms may vary greatly in presentation and severity. Besides weakness and sensory disturbances, patients may have cranial nerve involvement, respiratory insufficiency, autonomic dysfunction and pain. To develop an evidence-based guideline for the diagnosis and treatment of GBS, using Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology, a Task Force (TF) of the European Academy of Neurology (EAN) and the Peripheral Nerve Society (PNS) constructed 14 Population/Intervention/Comparison/Outcome questions (PICOs) covering diagnosis, treatment and prognosis of GBS, which guided the literature search. Data were extracted and summarised in GRADE Summaries of Findings (for treatment PICOs) or Evidence Tables (for diagnostic and prognostic PICOs). Statements were prepared according to GRADE Evidence-to-Decision (EtD) frameworks. For the six intervention PICOs, evidence-based recommendations are made. For other PICOs, good practice points (GPPs) are formulated. For diagnosis, the principal GPPs are: GBS is more likely if there is a history of recent diarrhoea or respiratory infection; CSF examination is valuable, particularly when the diagnosis is less certain; electrodiagnostic testing is advised to support the diagnosis; testing for anti-ganglioside antibodies is of limited clinical value in most patients with typical motor-sensory GBS, but anti-GQ1b antibody testing should be considered when Miller Fisher syndrome (MFS) is suspected; nodal–paranodal antibodies should be tested when autoimmune nodopathy is suspected; MRI or ultrasound imaging should be considered in atypical cases; and changing the diagnosis to acute-onset chronic inflammatory demyelinating polyradiculoneuropathy (A-CIDP) should be considered if progression continues after 8 weeks from onset, which occurs in around 5% of patients initially diagnosed with GBS. For treatment, the TF recommends intravenous immunoglobulin (IVIg) 0.4 g/kg for 5 days, in patients within 2 weeks (GPP also within 2–4 weeks) after onset of weakness if unable to walk unaided, or a course of plasma exchange (PE) 12–15 L in four to five exchanges over 1–2 weeks, in patients within 4 weeks after onset of weakness if unable to walk unaided. The TF recommends against a second IVIg course in GBS patients with a poor prognosis; recommends against using oral corticosteroids, and weakly recommends against using IV corticosteroids; does not recommend PE followed immediately by IVIg; weakly recommends gabapentinoids, tricyclic antidepressants or carbamazepine for treatment of pain; does not recommend a specific treatment for fatigue. To estimate the prognosis of individual patients, the TF advises using the modified Erasmus GBS outcome score (mEGOS) to assess outcome, and the modified Erasmus GBS Respiratory Insufficiency Score (mEGRIS) to assess the risk of requiring artificial ventilation. Based on the PICOs, available
格林-巴利综合征(GBS)是一种急性多神经根性神经病。症状的表现和严重程度可能有很大差异。除了虚弱和感觉障碍外,患者还可能有脑神经受累、呼吸功能不全、自主神经功能障碍和疼痛。为了制定GBS诊断和治疗的循证指南,使用建议、评估、发展和评估分级(GRADE)方法,欧洲神经病学学会(EAN)和周围神经学会(PNS)的一个工作组(TF)构建了14个群体/干预/比较/结果问题(PICO),涵盖GBS的诊断、治疗和预后,指导了文献检索。数据被提取并汇总在GRADE发现总结(用于治疗PICO)或证据表(用于诊断和预后PICO)中。根据GRADE决策证据(EtD)框架编制报表。对于六个干预PICO,提出了基于证据的建议。对于其他PICO,制定了良好实践要点。就诊断而言,主要的GP是:如果最近有腹泻或呼吸道感染史,GBS更有可能发生;脑脊液检查是有价值的,尤其是当诊断不太确定时;建议使用电诊断测试来支持诊断;抗神经节苷脂抗体检测在大多数典型运动感觉GBS患者中的临床价值有限,但当怀疑Miller Fisher综合征(MFS)时,应考虑抗GQ1b抗体检测;当怀疑自身免疫性多巴胺时,应检测淋巴结旁抗体;非典型病例应考虑MRI或超声成像;如果8年后病情继续恶化,应考虑将诊断改为急性发作的慢性炎症性脱髓鞘多神经根病变(A-CID) 发病数周后,约5%的最初诊断为GBS的患者出现这种情况。对于治疗,TF建议静脉注射免疫球蛋白(IVIg)0.4 g/kg,适用于5 天,患者在2天内 周(GPP也在2-4内 数周),如果无法独立行走,或进行血浆置换(PE)12-15 L在四到五次交换中超过1-2 周,患者在4周内 虚弱发作后数周,如果无法独立行走。TF建议在预后不良的GBS患者中不要进行第二次IVIg疗程;建议不要使用口服皮质类固醇,并强烈建议不要使用静脉注射皮质类固醇;不建议PE后立即IVIg;弱推荐加巴喷丁类、三环类抗抑郁药或卡马西平用于治疗疼痛;不建议对疲劳进行特殊治疗。为了评估个别患者的预后,TF建议使用改良的伊拉斯谟GBS结果评分(mEGOS)来评估结果,并使用改良的埃拉斯谟-GBS呼吸功能不全评分(mEG RIS)来评估需要人工通气的风险。根据PICO、现有文献和其他讨论,我们提供了流程图,以帮助做出诊断、治疗和重症监护室入院需求的临床决策。
{"title":"European Academy of Neurology/Peripheral Nerve Society Guideline on diagnosis and treatment of Guillain–Barré syndrome","authors":"Pieter A. van Doorn,&nbsp;Peter Y. K. Van den Bergh,&nbsp;Robert D. M. Hadden,&nbsp;Bert Avau,&nbsp;Patrik Vankrunkelsven,&nbsp;Shahram Attarian,&nbsp;Patricia H. Blomkwist-Markens,&nbsp;David R. Cornblath,&nbsp;H. Stephan Goedee,&nbsp;Thomas Harbo,&nbsp;Bart C. Jacobs,&nbsp;Susumu Kusunoki,&nbsp;Helmar C. Lehmann,&nbsp;Richard A. Lewis,&nbsp;Michael P. Lunn,&nbsp;Eduardo Nobile-Orazio,&nbsp;Luis Querol,&nbsp;Yusuf A. Rajabally,&nbsp;Thirugnanam Umapathi,&nbsp;Haluk A. Topaloglu,&nbsp;Hugh J. Willison","doi":"10.1111/jns.12594","DOIUrl":"10.1111/jns.12594","url":null,"abstract":"&lt;p&gt;Guillain–Barré syndrome (GBS) is an acute polyradiculoneuropathy. Symptoms may vary greatly in presentation and severity. Besides weakness and sensory disturbances, patients may have cranial nerve involvement, respiratory insufficiency, autonomic dysfunction and pain. To develop an evidence-based guideline for the diagnosis and treatment of GBS, using Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology, a Task Force (TF) of the European Academy of Neurology (EAN) and the Peripheral Nerve Society (PNS) constructed 14 Population/Intervention/Comparison/Outcome questions (PICOs) covering diagnosis, treatment and prognosis of GBS, which guided the literature search. Data were extracted and summarised in GRADE Summaries of Findings (for treatment PICOs) or Evidence Tables (for diagnostic and prognostic PICOs). Statements were prepared according to GRADE Evidence-to-Decision (EtD) frameworks. For the six intervention PICOs, evidence-based recommendations are made. For other PICOs, good practice points (GPPs) are formulated. For diagnosis, the principal GPPs are: GBS is more likely if there is a history of recent diarrhoea or respiratory infection; CSF examination is valuable, particularly when the diagnosis is less certain; electrodiagnostic testing is advised to support the diagnosis; testing for anti-ganglioside antibodies is of limited clinical value in most patients with typical motor-sensory GBS, but anti-GQ1b antibody testing should be considered when Miller Fisher syndrome (MFS) is suspected; nodal–paranodal antibodies should be tested when autoimmune nodopathy is suspected; MRI or ultrasound imaging should be considered in atypical cases; and changing the diagnosis to acute-onset chronic inflammatory demyelinating polyradiculoneuropathy (A-CIDP) should be considered if progression continues after 8 weeks from onset, which occurs in around 5% of patients initially diagnosed with GBS. For treatment, the TF recommends intravenous immunoglobulin (IVIg) 0.4 g/kg for 5 days, in patients within 2 weeks (GPP also within 2–4 weeks) after onset of weakness if unable to walk unaided, or a course of plasma exchange (PE) 12–15 L in four to five exchanges over 1–2 weeks, in patients within 4 weeks after onset of weakness if unable to walk unaided. The TF recommends against a second IVIg course in GBS patients with a poor prognosis; recommends against using oral corticosteroids, and weakly recommends against using IV corticosteroids; does not recommend PE followed immediately by IVIg; weakly recommends gabapentinoids, tricyclic antidepressants or carbamazepine for treatment of pain; does not recommend a specific treatment for fatigue. To estimate the prognosis of individual patients, the TF advises using the modified Erasmus GBS outcome score (mEGOS) to assess outcome, and the modified Erasmus GBS Respiratory Insufficiency Score (mEGRIS) to assess the risk of requiring artificial ventilation. Based on the PICOs, available","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"28 4","pages":"535-563"},"PeriodicalIF":3.8,"publicationDate":"2023-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jns.12594","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41182968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
PNS Abstracts 2023 PNS摘要2023
IF 3.8 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-10-09 DOI: 10.1111/jns.12585
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引用次数: 0
Mutational screening of Greek patients with axonal Charcot-Marie-Tooth disease using targeted next-generation sequencing: Clinical and molecular spectrum delineation 使用靶向下一代测序对希腊轴索性Charcot-Marie Tooth病患者进行突变筛查:临床和分子谱描绘。
IF 3.8 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-09-25 DOI: 10.1111/jns.12598
Zoi Kontogeorgiou, Chrisoula Kartanou, Michail Rentzos, Panagiotis Kokotis, Evangelos Anagnostou, Thomas Zambelis, Elisabeth Chroni, Argyris Dinopoulos, Marios Panas, Georgios Koutsis, Georgia Karadima

Background and Aims

Axonal forms of Charcot-Marie-Tooth disease (CMT) are classified as CMT2, distal hereditary motor neuropathy (dHMN) or hereditary sensory neuropathy (HSN) and can be caused by mutations in over 100 genes. We presently aimed to investigate for the first time the genetic landscape of axonal CMT in the Greek population.

Methods

Sixty index patients with CMT2, dHMN or HSN were screened by a combination of Sanger sequencing (GJB1) and next-generation sequencing custom-made gene panel covering 24 commonly mutated genes in axonal CMT.

Results

Overall, 20 variants classified as pathogenic or likely pathogenic were identified in heterozygous state in 20 index cases, representing 33.3% of the cohort. Of these, 14 were known pathogenic/likely pathogenic and six were designated as such according to ACMG classification, after in silico evaluation, testing for familial segregation and further literature review. The most frequently involved genes were GJB1 (11.7%), MPZ (5%) and MFN2 (5%), followed by DNM2 (3.3%) and LRSAM1 (3.3%). Single cases were identified with mutations in BSCL2, HSPB1 and GDAP1.

Interpretation

A wide phenotypic variability in terms of severity and age of onset was noted. Given the limited number of genes tested, the diagnostic yield of the present panel compares favourably with studies in other European populations. Our study delineates the genetic and phenotypic variability of inherited axonal neuropathies in the Greek population and contributes to the pathogenicity characterization of further variants linked to axonal neuropathies.

背景和目的:Charcot-Marie Tooth病(CMT)的轴索型分为CMT2、远端遗传性运动神经病(dHMN)或遗传性感觉神经病(HSN),可由100多个基因突变引起。我们目前的目标是首次调查希腊人群中轴突CMT的遗传景观。方法:采用Sanger测序(GJB1)和下一代测序定制基因组相结合的方法对60例CMT2、dHMN或HSN指数患者进行筛选,该基因组涵盖了轴突CMT中24个常见突变基因。其中,14例为已知致病性/可能致病性,6例根据ACMG分类,经过计算机评估、家族分离测试和进一步的文献综述后被指定为已知致病/可能致病。最常见的相关基因是GJB1(11.7%)、MPZ(5%)和MFN2(5%),其次是DNM2(3.3%)和LRSAM1(3.3%)。单个病例被鉴定为BSCL2、HSPB1和GDAP1突变。解释:在严重程度和发病年龄方面存在广泛的表型变异。鉴于测试的基因数量有限,本小组的诊断结果与其他欧洲人群的研究相比是有利的。我们的研究描述了希腊人群中遗传性轴索神经病的遗传和表型变异性,并有助于与轴索神经病相关的进一步变异的致病性表征。
{"title":"Mutational screening of Greek patients with axonal Charcot-Marie-Tooth disease using targeted next-generation sequencing: Clinical and molecular spectrum delineation","authors":"Zoi Kontogeorgiou,&nbsp;Chrisoula Kartanou,&nbsp;Michail Rentzos,&nbsp;Panagiotis Kokotis,&nbsp;Evangelos Anagnostou,&nbsp;Thomas Zambelis,&nbsp;Elisabeth Chroni,&nbsp;Argyris Dinopoulos,&nbsp;Marios Panas,&nbsp;Georgios Koutsis,&nbsp;Georgia Karadima","doi":"10.1111/jns.12598","DOIUrl":"10.1111/jns.12598","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Axonal forms of Charcot-Marie-Tooth disease (CMT) are classified as CMT2, distal hereditary motor neuropathy (dHMN) or hereditary sensory neuropathy (HSN) and can be caused by mutations in over 100 genes. We presently aimed to investigate for the first time the genetic landscape of axonal CMT in the Greek population.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Sixty index patients with CMT2, dHMN or HSN were screened by a combination of Sanger sequencing (<i>GJB1</i>) and next-generation sequencing custom-made gene panel covering 24 commonly mutated genes in axonal CMT.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Overall, 20 variants classified as pathogenic or likely pathogenic were identified in heterozygous state in 20 index cases, representing 33.3% of the cohort. Of these, 14 were known pathogenic/likely pathogenic and six were designated as such according to ACMG classification, after in silico evaluation, testing for familial segregation and further literature review. The most frequently involved genes were <i>GJB1</i> (11.7%), <i>MPZ</i> (5%) and <i>MFN2</i> (5%), followed by <i>DNM2</i> (3.3%) and <i>LRSAM1</i> (3.3%). Single cases were identified with mutations in <i>BSCL2</i>, <i>HSPB1</i> and <i>GDAP1</i>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>A wide phenotypic variability in terms of severity and age of onset was noted. Given the limited number of genes tested, the diagnostic yield of the present panel compares favourably with studies in other European populations. Our study delineates the genetic and phenotypic variability of inherited axonal neuropathies in the Greek population and contributes to the pathogenicity characterization of further variants linked to axonal neuropathies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"28 4","pages":"642-650"},"PeriodicalIF":3.8,"publicationDate":"2023-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jns.12598","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41132239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Diagnostic value of nerve conduction study in NOTCH2NLC-related neuronal intranuclear inclusion disease 神经传导研究对NOTCH2NLC相关神经元核内包涵体疾病的诊断价值。
IF 3.8 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-09-25 DOI: 10.1111/jns.12599
Yun Tian, Xuan Hou, Wanqian Cao, Lu Zhou, Bin Jiao, Sizhe Zhang, Qiao Xiao, Jin Xue, Ying Wang, Ling Weng, Liangjuan Fang, Honglan Yang, Yafang Zhou, Fang Yi, Xiaoyu Chen, Juan Du, Qian Xu, Li Feng, Zhenhua Liu, Sen Zeng, Qiying Sun, Nina Xie, Mengchuan Luo, Mengli Wang, Mengqi Zhang, Qiuming Zeng, Shunxiang Huang, Lingyan Yao, Yacen Hu, Hongyu Long, Yuanyuan Xie, Si Chen, Qing Huang, Junpu Wang, Bin Xie, Lin Zhou, Lili Long, Jifeng Guo, Junling Wang, Xinxiang Yan, Hong Jiang, Hongwei Xu, Ranhui Duan, Beisha Tang, Ruxu Zhang, Lu Shen

Background and Aims

Neuronal intranuclear inclusion disease (NIID) is a rare progressive neurodegenerative disorder mainly caused by abnormally expanded GGC repeats within the NOTCH2NLC gene. Most patients with NIID show polyneuropathy. Here, we aim to investigate diagnostic electrophysiological markers of NIID.

Methods

In this retrospective dual-center study, we reviewed 96 patients with NOTCH2NLC-related NIID, 94 patients with genetically confirmed Charcot–Marie-Tooth (CMT) disease, and 62 control participants without history of peripheral neuropathy, who underwent nerve conduction studies between 2018 and 2022.

Results

Peripheral nerve symptoms were presented by 53.1% of patients with NIID, whereas 97.9% of them showed peripheral neuropathy according to electrophysiological examinations. Patients with NIID were characterized by slight demyelinating sensorimotor polyneuropathy; some patients also showed mild axonal lesions. Motor nerve conduction velocity (MCV) of the median nerve usually exceeded 35 m/s, and were found to be negatively correlated with the GGC repeat sizes. Regarding the electrophysiological differences between muscle weakness type (n = 27) and non-muscle weakness type (n = 69) of NIID, nerve conduction abnormalities were more severe in the muscle weakness type involving both demyelination and axonal impairment. Notably, specific DWI subcortical lace sign was presented in only 33.3% of muscle weakness type, thus it was difficult to differentiate them from CMT. Combining age of onset, distal motor latency, and compound muscle action potential of the median nerve showed the optimal diagnostic performance to distinguish NIID from major CMT (AUC = 0.989, sensitivity = 92.6%, specificity = 97.4%).

Interpretation

Peripheral polyneuropathy is common in NIID. Our study suggest that nerve conduction study is useful to discriminate NIID.

背景和目的:神经元核内包涵体病(NIID)是一种罕见的进行性神经退行性疾病,主要由NOTCH2NLC基因内GGC重复序列异常扩增引起。大多数NIID患者表现为多发性神经病。在这里,我们的目的是研究NIID的诊断电生理标志物。方法:在这项回顾性双中心研究中,我们回顾了96名NOTCH2NLC相关NIID患者、94名遗传证实的Charcot-Marie Tooth(CMT)疾病患者和62名无周围神经病变史的对照参与者,他们在2018年至2022年间接受了神经传导研究。结果:53.1%的NIID患者出现了周围神经症状,而根据电生理检查,97.9%的患者表现为周围神经病变。NIID患者的特点是轻度脱髓鞘感觉运动性多发性神经病;一些患者还表现出轻微的轴索损伤。正中神经的运动神经传导速度(MCV)通常超过35 m/s,并且被发现与GGC重复大小呈负相关。关于肌无力类型(n = 27)和非肌无力型(n = 69),神经传导异常在涉及脱髓鞘和轴突损伤的肌无力型中更为严重。值得注意的是,只有33.3%的肌无力类型出现了特定的DWI皮质下系带征,因此很难将其与CMT区分开来。结合发病年龄、远端运动潜伏期和正中神经的复合肌肉动作电位,显示出区分NIID和主要CMT的最佳诊断性能(AUC = 0.989,灵敏度 = 92.6%,特异性 = 97.4%)。解释:周围性多发性神经病在NIID中很常见。我们的研究表明,神经传导研究有助于鉴别NIID。
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引用次数: 0
期刊
Journal of the Peripheral Nervous System
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