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Nodes of Ranvier in health and disease 朗维耶淋巴结在健康和疾病中的作用
IF 3.8 3区 医学 Q1 Medicine Pub Date : 2023-06-05 DOI: 10.1111/jns.12568
Yael Eshed-Eisenbach, Peter J. Brophy, Elior Peles

Action potential propagation along myelinated axons depends on the geometry of the myelin unit and the division of the underlying axon to specialized domains. The latter include the nodes of Ranvier (NOR), the paranodal junction (PNJ) flanking the nodes, and the adjacent juxtaparanodal region that is located below the compact myelin of the internode. Each of these domains contains a unique composition of axoglial adhesion molecules (CAMs) and cytoskeletal scaffolding proteins, which together direct the placement of specific ion channels at the nodal and juxtaparanodal axolemma. In the last decade it has become increasingly clear that antibodies to some of these axoglial CAMs cause immune-mediated neuropathies. In the current review we detail the molecular composition of the NOR and adjacent membrane domains, describe the function of different CAM complexes that mediate axon-glia interactions along the myelin unit, and discuss their involvement and the underlying mechanisms taking place in peripheral nerve pathologies. This growing group of pathologies represent a new type of neuropathies termed “nodopathies” or “paranodopathies” that are characterized by unique clinical and molecular features which together reflect the mechanisms underlying the molecular assembly and maintenance of this specialized membrane domain.

沿着有髓鞘轴突的动作电位传播取决于髓鞘单位的几何形状和潜在轴突向特殊结构域的划分。后者包括兰维尔结(NOR)、位于结两侧的节旁结(PNJ)以及位于节间致密髓鞘下方的邻近的颈旁区。这些结构域中的每一个都包含一种独特的轴珠粘附分子(CAM)和细胞骨架支架蛋白组成,它们共同指导特定离子通道在淋巴结和颈旁轴上的位置。在过去的十年里,越来越清楚的是,针对其中一些轴突CAM的抗体会导致免疫介导的神经病变。在目前的综述中,我们详细介绍了NOR和相邻膜结构域的分子组成,描述了介导髓鞘单元轴突-神经胶质相互作用的不同CAM复合物的功能,并讨论了它们在外周神经病理中的参与和潜在机制。这一不断增长的病理组代表了一种新型的神经病理学,称为“多巴胺”或“副多巴胺”,其特征是独特的临床和分子特征,这些特征共同反映了分子组装和维持这一特殊膜结构域的机制。
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引用次数: 0
The autoimmune vulnerability of the node of Ranvier Ranvier淋巴结的自身免疫易感性
IF 3.8 3区 医学 Q1 Medicine Pub Date : 2023-06-05 DOI: 10.1111/jns.12570
Luis Querol, Emilien Delmont, Cinta Lleixà

The nodes of Ranvier (NoR) are essential domains for nerve conduction and their disruption plays a key role in the pathophysiology of immune-mediated neuropathies. Our understanding of the specialized nodal regions and the immune mechanisms that affect them is growing and has led to the update of peripheral neuropathy classification to include the autoimmune nodopathies, defined by the site of the autoimmune attack. Autoantibodies directed against molecules of the nodal region (as neurofascin-140/186, neurofascin-155, contactin-1, contactin-associated protein 1, contactin-associated protein 2, gangliosides, LGI4, or myelin-associated glycoprotein), macrophage-induced paranodal demyelination, and phenotypic changes of the nodal domains of Schwann cells have been identified as key mechanisms in the pathogenesis of the autoimmune neuropathies. This review explores the current knowledge of the autoimmune vulnerability of the NoR, including the underlying mechanisms leading to dysfunction in the diverse autoimmune disorders.

Ranvier淋巴结(NoR)是神经传导的重要区域,其破坏在免疫介导的神经病变的病理生理中起着关键作用。我们对特殊淋巴结区域和影响它们的免疫机制的理解正在增长,并导致周围神经病变分类的更新,包括自身免疫结节病,由自身免疫攻击部位定义。针对结区分子的自身抗体(如神经束蛋白140/186、神经束蛋白155、接触蛋白1、接触蛋白相关蛋白1、接触蛋白相关蛋白2、神经节苷、LGI4或髓鞘相关糖蛋白)、巨噬细胞诱导的旁结脱髓鞘以及雪旺细胞结域的表型改变已被确定为自身免疫性神经病变发病的关键机制。这篇综述探讨了目前对NoR自身免疫性易感性的认识,包括导致各种自身免疫性疾病功能障碍的潜在机制。
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引用次数: 1
Autoimmune nodo-paranodopathies 10 years later: Clinical features, pathophysiology and treatment 10年后自身免疫性淋巴结副病:临床特征、病理生理和治疗
IF 3.8 3区 医学 Q1 Medicine Pub Date : 2023-06-05 DOI: 10.1111/jns.12569
Antonino Uncini

Background and Aims

Autoimmune neuropathies are classified, on the basis of pathophysiology, as demyelinating or axonal. The term nodo-paranodopathy, introduced in 2013 to better categorize the neuropathies with antiganglioside antibodies and later expanded to include neuropathies with antibodies to nodal and paranodal axoglial complexes, characterizes disorders in which the nodal region is critical in the pathogenesis. These neuropathies, although presenting electrophysiologic demyelinating features do not show pathologic evidence of segmental demyelination, or, although being classified as axonal, can show reversible nerve conduction failure and rapid recovery contrary with the communal concept of an axonal neuropathy.

Methods

In this personal view is reported, with a splitting approach, an update on autoimmune nodo-paranodopathies, classified according to the domains of peripheral nerve fiber, the target antigens and the antibody class and subclass involved. The clinical features, the electrophysiologic findings, the results of the immunopathological and ultrastructural studies, the pathophysiology and treatment are also described.

Results and Interpretation

The nodo-paranodopathy category integrates the clinical classification of autoimmune neuropathies and expands the traditional dichotomous demyelinating and axonal classification. It helps to a better systematization pointing to the domain and target antigens of the autoimmune process, it resolves conflicting pathologic and electrophysiologic findings, reconciles the contradiction that axonal neuropathies may be rapidly reversible, avoids taxonomical confusion and possible misdiagnoses. Finally this categorization, through the identification of the specific antibody and its prevalent class and subclass, clarifies the pathophysiological mechanisms and addresses to a more targeted therapeutic approach.

背景和目的基于病理生理学,自身免疫性神经病分为脱髓鞘性和轴突性。2013年,为了更好地对含有抗神经节苷脂抗体的神经病进行分类,引入了“淋巴结-副神经节病”这一术语,后来扩大到包括含有针对淋巴结和副神经节轴胶质复合物抗体的神经病,这一术语描述了淋巴结区域在发病机制中起关键作用的疾病。这些神经病变,虽然表现出电生理脱髓鞘特征,但没有表现出节段性脱髓鞘的病理证据,或者,虽然被归类为轴突性,但可以表现出可逆的神经传导障碍和快速恢复,这与轴突性神经病变的普遍概念相反。方法根据周围神经纤维、靶抗原、所涉及的抗体类别和亚类别对自身免疫性结节-副病理进行分类,采用分裂方法报道自身免疫性结节-副病理的最新进展。并对其临床特点、电生理表现、免疫病理及超微结构检查结果、病理生理及治疗进行了叙述。结果与解释结节-副神经病变分类整合了自身免疫性神经病变的临床分类,扩展了传统的脱髓鞘和轴突分类。它有助于更好地系统化指出自身免疫过程的域和靶抗原,它解决了相互矛盾的病理和电生理发现,调和了轴突神经病变可能迅速可逆的矛盾,避免了分类混乱和可能的误诊。最后,通过鉴定特异性抗体及其流行类和亚类,这种分类澄清了病理生理机制,并提出了更有针对性的治疗方法。
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引用次数: 0
Recruiting for an International Rare Disease Clinical Trial Readiness Study during the COVID-19 pandemic: Challenges and solutions COVID-19大流行期间招募国际罕见病临床试验准备研究:挑战和解决方案
IF 3.8 3区 医学 Q1 Medicine Pub Date : 2023-06-04 DOI: 10.1111/jns.12559
Katy Eichinger, Steffen Behrens-Spraggins, Janet E. Sowden, Davide Pareyson, Mary M. Reilly, Steven S. Scherer, Michael E. Shy, David N. Herrmann, the ACT-CMT Study Group
The Accelerate Clinical Trials in
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引用次数: 0
Toxic medications in Charcot–Marie–Tooth patients: A systematic review Charcot-Marie-Tooth患者的毒性药物:系统回顾
IF 3.8 3区 医学 Q1 Medicine Pub Date : 2023-05-30 DOI: 10.1111/jns.12566
Guido Cavaletti, Katherine Forsey, Paola Alberti

Background and Aims

Several widely used medications, with a relevant efficacy profile, are toxic to the peripheral nervous system and an even larger number of agents are suspected to be neurotoxic. There are concerns about the use of these drugs in patients with Charcot–Marie–Tooth disease (CMT), a hereditary motor and sensory neuropathy. This review provides evidence-based updated recommendations on this clinically relevant topic.

Methods

A systematic review of the available studies/reports written in English was performed from July to September 2022 including in the search string all reported putative neurotoxic drugs.

Results

The results of our systematic review provide evidence-based support for the statement that use of vincristine, and possibly paclitaxel, can occasionally induce an atypical, and more severe, course of drug-related peripheral neurotoxicity in CMT patients. It is therefore reasonable to recommend caution in the use of these compounds in CMT patients. However, no convincing evidence for a similar recommendation could be found for all other drugs.

Interpretation

It is important that patients with CMT are not denied effective treatments that may prolong life expectancy for cancer or improve their health status if affected by non-oncological diseases. Accurate monitoring of peripheral nerve function in CMT patients treated with any neurotoxic agent remains mandatory to detect the earliest signs of neuropathy worsening and atypical clinical courses. Neurologists monitoring CMT patients as part of their normal care package or for natural history studies should keep detailed records of exposures to neurotoxic medications and support reporting of accelerated neuropathy progression if observed.

背景和目的一些广泛使用的药物,具有相关的疗效,对周围神经系统有毒性,甚至更多的药物被怀疑是神经毒性的。这些药物在患有腓骨肌萎缩症(CMT)(一种遗传性运动和感觉神经病变)患者中的应用令人担忧。本综述就这一临床相关主题提供了基于证据的最新建议。方法对2022年7月至9月已有的英文研究/报告进行系统回顾,检索字符串中包括所有报道的推定神经毒性药物。结果本系统综述的结果为以下观点提供了证据支持:长春新碱,可能还有紫杉醇,在CMT患者中偶尔会诱发非典型的、更严重的药物相关周围神经毒性病程。因此,建议在CMT患者中谨慎使用这些化合物是合理的。然而,没有令人信服的证据表明类似的建议适用于所有其他药物。重要的是,CMT患者不应被拒绝接受有效的治疗,这些治疗可能延长癌症的预期寿命,或改善非肿瘤疾病患者的健康状况。在接受任何神经毒性药物治疗的CMT患者中,准确监测周围神经功能仍然是必要的,以发现神经病变恶化的早期迹象和非典型临床病程。作为常规护理包或自然史研究的一部分,神经科医生监测CMT患者时,应详细记录神经毒性药物的暴露情况,并支持观察到的神经病变加速进展的报告。
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引用次数: 1
Clinical features of a family with late-onset distal hereditary motor neuropathy harboring p.Pro39Leu variant of HSPB1 携带HSPB1 p.Pro39Leu变异的迟发性远端遗传性运动神经病家族的临床特征
IF 3.8 3区 医学 Q1 Medicine Pub Date : 2023-05-30 DOI: 10.1111/jns.12567
Hiroya Naruse, So Okubo, Atsushi Sudo, Jun Mitsui, Takashi Mikata, Hiroyuki Ishiura, Shinichi Morishita, Shoji Tsuji, Tatsushi Toda

Background and Aims

Pathogenic variants of HSPB1, the gene encoding the small heat shock protein 27, have been reported to cause autosomal dominant distal hereditary motor neuropathy (dHMN) type II and autosomal dominant Charcot–Marie-Tooth (CMT) disease with minimal sensory involvement (CMT2F). This study aimed to describe the clinical features of patients in a family with late-onset dHMN carrying the Pro39Leu variant of HSPB1.

Methods

Whole-exome sequence analysis identified a heterozygous pathogenic variant (Pro39Leu) of HSPB1 in the proband. The presence of the HSPB1 Pro39Leu variant in two affected individuals was confirmed using direct nucleotide sequence analysis.

Results

Both patients exhibited distal muscle weakness with lower extremity predominance and no obvious sensory deficits, leading to a clinical diagnosis of late-onset dHMN. Nerve conduction studies (NCSs) revealed a subclinical complication of sensory disturbance in one of the patients. The clinical and electrophysiological findings of patients with the HSPB1 Pro39Leu variant in this study and previous reports are summarized.

Interpretation

This study suggests that the clinical spectrum of patients carrying HSPB1 Pro39Leu variants, especially the disease onset, might be broader than expected, and HSPB1 variants should be considered in patients diagnosed with late-onset dHMN. Furthermore, patients with dHMN may have concomitant sensory deficits that should be evaluated using NCSs.

背景和目的编码小热休克蛋白27的HSPB1基因的致病性变异已被报道导致常染色体显性远端遗传性运动神经病变(dHMN) II型和常染色体显性夏科-玛丽-图斯病(CMT)伴最小感觉受累(CMT2F)。本研究旨在描述携带HSPB1 Pro39Leu变异体的迟发型dHMN家族患者的临床特征。方法先证者HSPB1基因杂合致病变异(Pro39Leu)的全外显子组序列分析。HSPB1 Pro39Leu变异存在于两个受影响的个体中,通过直接核苷酸序列分析证实。结果两例患者均表现为下肢远端肌无力为主,无明显感觉障碍,临床诊断为迟发性dHMN。神经传导研究(NCSs)显示一个亚临床并发症的感觉障碍的一个病人。本文总结了本研究和以往报道的HSPB1 Pro39Leu变异患者的临床和电生理结果。本研究提示携带HSPB1 Pro39Leu变异体的患者的临床谱,尤其是发病谱可能比预期的更广,在诊断为晚发型dHMN的患者中应考虑HSPB1变异体。此外,dHMN患者可能伴有感觉缺陷,应使用ncs进行评估。
{"title":"Clinical features of a family with late-onset distal hereditary motor neuropathy harboring p.Pro39Leu variant of HSPB1","authors":"Hiroya Naruse,&nbsp;So Okubo,&nbsp;Atsushi Sudo,&nbsp;Jun Mitsui,&nbsp;Takashi Mikata,&nbsp;Hiroyuki Ishiura,&nbsp;Shinichi Morishita,&nbsp;Shoji Tsuji,&nbsp;Tatsushi Toda","doi":"10.1111/jns.12567","DOIUrl":"10.1111/jns.12567","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Pathogenic variants of <i>HSPB1</i>, the gene encoding the small heat shock protein 27, have been reported to cause autosomal dominant distal hereditary motor neuropathy (dHMN) type II and autosomal dominant Charcot–Marie-Tooth (CMT) disease with minimal sensory involvement (CMT2F). This study aimed to describe the clinical features of patients in a family with late-onset dHMN carrying the Pro39Leu variant of <i>HSPB1</i>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Whole-exome sequence analysis identified a heterozygous pathogenic variant (Pro39Leu) of <i>HSPB1</i> in the proband. The presence of the <i>HSPB1</i> Pro39Leu variant in two affected individuals was confirmed using direct nucleotide sequence analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Both patients exhibited distal muscle weakness with lower extremity predominance and no obvious sensory deficits, leading to a clinical diagnosis of late-onset dHMN. Nerve conduction studies (NCSs) revealed a subclinical complication of sensory disturbance in one of the patients. The clinical and electrophysiological findings of patients with the <i>HSPB1</i> Pro39Leu variant in this study and previous reports are summarized.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>This study suggests that the clinical spectrum of patients carrying <i>HSPB1</i> Pro39Leu variants, especially the disease onset, might be broader than expected, and <i>HSPB1</i> variants should be considered in patients diagnosed with late-onset dHMN. Furthermore, patients with dHMN may have concomitant sensory deficits that should be evaluated using NCSs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2023-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jns.12567","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10537201","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
Caspr1 antibodies autoimmune paranodopathy with severe tetraparesis: Potential relevance of antibody titers in monitoring treatment response Caspr1抗体自身免疫性副病伴严重四全:抗体滴度监测治疗反应的潜在相关性
IF 3.8 3区 医学 Q1 Medicine Pub Date : 2023-05-29 DOI: 10.1111/jns.12565
Lorenzo Bresciani, Alessandro Salvalaggio, Elisa Vegezzi, Andrea Visentin, Andrea Fortuna, Mariagiulia Anglani, Mario Cacciavillani, Stefano Masciocchi, Silvia Scaranzin, Miryam Carecchio, Andrea Martinuzzi, Matteo Gastaldi, Chiara Briani

Aim

Nodopathies and paranodopathies are autoimmune neuropathies associated with antibodies to nodal–paranodal antigens (neurofascin 140/186 and 155, contactin-1, contactin-associated protein 1 [Caspr1]) characterized by peculiar clinical features, poor response to standard immunotherapies (e.g., intravenous immunoglobulins, IVIg). Improvement after anti-CD20 monoclonal antibody therapy has been reported. Data on Caspr1 antibodies pathogenicity are still preliminary, and longitudinal titers have been poorly described.

Methods

We report on a young woman who developed a disabling neuropathy with antibodies to the Caspr1/contactin-1 complex showing a dramatic improvement after rituximab therapy, mirrored by the decrease of antibody titers.

Results

A 26-year-old woman presented with ataxic-stepping gait, severe motor weakness at four limbs, and low frequency postural tremor. For neurophysiological evidence of demyelinating neuropathy, she was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy and treated with IVIg without benefit. MRI showed symmetrical hypertrophy and marked signal hyperintensity of brachial and lumbosacral plexi. Cerebrospinal fluid showed 710 mg/dL protein. Despite intravenous methylprednisolone, the patient progressively worsened, and became wheelchair-bound. Antibodies to nodal–paranodal antigens were searched for by ELISA and cell-based assay. Anticontactin/Caspr1 IgG4 antibodies resulted positive. The patient underwent rituximab therapy with slow progressive improvement that mirrored the antibodies titer, measured throughout the disease course.

Conclusions

Our patient had a severe progressive course with early disability and axonal damage, and slow recovery starting only a few months after antibody-depleting therapy. The close correlation between titer, disability, and treatment, supports the pathogenicity of Caspr1 antibodies, and suggest that their longitudinal evaluation might provide a potential biomarker to evaluate treatment response.

目的淋巴结病变和副淋巴结病变是与淋巴结-副淋巴结抗原(神经束蛋白140/186和155,接触蛋白1,接触蛋白相关蛋白1 [Caspr1])抗体相关的自身免疫性神经病变,其临床特征特殊,对标准免疫疗法(如静脉注射免疫球蛋白,IVIg)反应差。抗cd20单克隆抗体治疗后改善已有报道。关于Caspr1抗体致病性的数据仍然是初步的,纵向滴度的描述也很差。方法:我们报告了一位患有Caspr1/contactin-1复合物抗体的年轻女性,她在接受美罗华治疗后出现了显著的改善,抗体滴度下降。结果1例26岁女性患者表现为步态共济失调,四肢严重运动无力,伴有低频体位性震颤。由于脱髓鞘神经病变的神经生理学证据,她被诊断为慢性炎症性脱髓鞘性多根神经病变,并接受IVIg治疗,但没有效果。MRI显示臂丛、腰骶丛对称性肥大,信号明显增高。脑脊液显示蛋白710 mg/dL。尽管静脉注射甲基强的松龙,患者病情仍逐渐恶化,并成为轮椅。采用酶联免疫吸附试验(ELISA)和细胞法寻找结旁抗原抗体。抗接触蛋白/Caspr1 IgG4抗体阳性。患者接受了利妥昔单抗治疗,进展缓慢,反映了整个疾病过程中测量的抗体滴度。结论该患者病程严重,早期残疾,轴突损伤,抗体消耗治疗数月后恢复缓慢。滴度、致残性和治疗之间的密切相关性支持了Caspr1抗体的致病性,并提示其纵向评估可能为评估治疗反应提供潜在的生物标志物。
{"title":"Caspr1 antibodies autoimmune paranodopathy with severe tetraparesis: Potential relevance of antibody titers in monitoring treatment response","authors":"Lorenzo Bresciani,&nbsp;Alessandro Salvalaggio,&nbsp;Elisa Vegezzi,&nbsp;Andrea Visentin,&nbsp;Andrea Fortuna,&nbsp;Mariagiulia Anglani,&nbsp;Mario Cacciavillani,&nbsp;Stefano Masciocchi,&nbsp;Silvia Scaranzin,&nbsp;Miryam Carecchio,&nbsp;Andrea Martinuzzi,&nbsp;Matteo Gastaldi,&nbsp;Chiara Briani","doi":"10.1111/jns.12565","DOIUrl":"10.1111/jns.12565","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Nodopathies and paranodopathies are autoimmune neuropathies associated with antibodies to nodal–paranodal antigens (neurofascin 140/186 and 155, contactin-1, contactin-associated protein 1 [Caspr1]) characterized by peculiar clinical features, poor response to standard immunotherapies (e.g., intravenous immunoglobulins, IVIg). Improvement after anti-CD20 monoclonal antibody therapy has been reported. Data on Caspr1 antibodies pathogenicity are still preliminary, and longitudinal titers have been poorly described.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We report on a young woman who developed a disabling neuropathy with antibodies to the Caspr1/contactin-1 complex showing a dramatic improvement after rituximab therapy, mirrored by the decrease of antibody titers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A 26-year-old woman presented with ataxic-stepping gait, severe motor weakness at four limbs, and low frequency postural tremor. For neurophysiological evidence of demyelinating neuropathy, she was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy and treated with IVIg without benefit. MRI showed symmetrical hypertrophy and marked signal hyperintensity of brachial and lumbosacral plexi. Cerebrospinal fluid showed 710 mg/dL protein. Despite intravenous methylprednisolone, the patient progressively worsened, and became wheelchair-bound. Antibodies to nodal–paranodal antigens were searched for by ELISA and cell-based assay. Anticontactin/Caspr1 IgG4 antibodies resulted positive. The patient underwent rituximab therapy with slow progressive improvement that mirrored the antibodies titer, measured throughout the disease course.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our patient had a severe progressive course with early disability and axonal damage, and slow recovery starting only a few months after antibody-depleting therapy. The close correlation between titer, disability, and treatment, supports the pathogenicity of Caspr1 antibodies, and suggest that their longitudinal evaluation might provide a potential biomarker to evaluate treatment response.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2023-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jns.12565","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10554929","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
Mitofusin 1 overexpression rescues the abnormal mitochondrial dynamics caused by the Mitofusin 2 K357T mutation in vitro Mitofusin 1过表达可在体外修复Mitofusin 2 K357T突变引起的线粒体动力学异常
IF 3.8 3区 医学 Q1 Medicine Pub Date : 2023-05-23 DOI: 10.1111/jns.12564
Filippos Stavropoulos, Elena Georgiou, Natasa Schiza, Shaughn Bell, Robert H. Baloh, Kleopas A. Kleopa, Irene Sargiannidou

Background and aims

Mitofusin 1 (MFN1) and MFN2 are outer mitochondrial membrane fusogenic proteins regulating mitochondrial network morphology. MFN2 mutations cause Charcot-Marie-Tooth type 2A (CMT2A), an axonal neuropathy characterized by mitochondrial fusion defects, which in the case of a GTPase domain mutant, were rescued following wild-type MFN1/2 (MFN1/2WT) overexpression. In this study, we compared the therapeutic efficiency between MFN1WT and MFN2WT overexpression in correcting mitochondrial defects induced by the novel MFN2K357T mutation located in the highly conserved R3 region.

Methods

Constructs expressing either MFN2K357T, MFN2WT, or MFN1WT under the ubiquitous chicken β-actin hybrid (CBh) promoter were generated. Flag or myc tag was used for their detection. Differentiated SH-SY5Y cells were single transfected with MFN1WT, MFN2WT, or MFN2K357T, as well as double transfected with MFN2K357T/MFN2WT or MFN2K357T/MFN1WT.

Results

SH-SY5Y cells transfected with MFN2K357T exhibited severe perinuclear mitochondrial clustering with axon-like processes devoid of mitochondria. Single transfection with MFN1WT resulted in a more interconnected mitochondrial network than transfection with MFN2WT, accompanied by mitochondrial clusters. Double transfection of MFN2K357T with either MFN1WT or MFN2WT resolved the mutant-induced mitochondrial clusters and led to detectable mitochondria throughout the axon-like processes. MFN1WT showed higher efficacy than MFN2WT in rescuing these defects.

Interpretation

These results further demonstrate the higher potential of MFN1WT over MFN2WT overexpression to rescue CMT2A-induced mitochondrial network abnormalities due to mutations outside the GTPase domain. This higher phenotypic rescue conferred by MFN1WT, possibly due to its higher m

背景与目的Mitofusin 1 (MFN1)和MFN2是调节线粒体网络形态的线粒体外膜融合蛋白。MFN2突变导致Charcot-Marie-Tooth型2A (CMT2A),这是一种以线粒体融合缺陷为特征的轴突神经病变,在GTPase结构域突变的情况下,在野生型MFN1/2 (MFN1/2WT)过表达后被拯救。在这项研究中,我们比较了MFN1WT和MFN2WT过表达在纠正位于高度保守的R3区域的新型MFN2K357T突变诱导的线粒体缺陷方面的治疗效果。方法在普遍存在的鸡β-肌动蛋白杂交(CBh)启动子下构建表达MFN2K357T、MFN2WT或MFN1WT的构建体。标记或myc标记用于检测它们。分化后的SH-SY5Y细胞分别单转染MFN1WT、MFN2WT、MFN2K357T,双转染MFN2K357T/MFN2WT或MFN2K357T/MFN1WT。结果转染MFN2K357T的SH-SY5Y细胞表现出严重的核周线粒体聚集,轴突样过程缺乏线粒体。与转染MFN2WT相比,单个转染MFN1WT导致线粒体网络更加相互连接,并伴有线粒体簇。MFN2K357T与MFN1WT或MFN2WT的双重转染解决了突变诱导的线粒体簇,并导致在整个轴突样过程中检测到线粒体。MFN1WT对这些缺陷的修复效果优于MFN2WT。这些结果进一步证明MFN1WT比MFN2WT过表达更有可能挽救cmt2a诱导的由于GTPase结构域外突变引起的线粒体网络异常。这种由MFN1WT带来的更高的表型拯救,可能是由于其更高的线粒体融合能力,可能适用于不同的CMT2A病例,而不管MFN2突变类型如何。
{"title":"Mitofusin 1 overexpression rescues the abnormal mitochondrial dynamics caused by the Mitofusin 2 K357T mutation in vitro","authors":"Filippos Stavropoulos,&nbsp;Elena Georgiou,&nbsp;Natasa Schiza,&nbsp;Shaughn Bell,&nbsp;Robert H. Baloh,&nbsp;Kleopas A. Kleopa,&nbsp;Irene Sargiannidou","doi":"10.1111/jns.12564","DOIUrl":"10.1111/jns.12564","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and aims</h3>\u0000 \u0000 <p>Mitofusin 1 (MFN1) and MFN2 are outer mitochondrial membrane fusogenic proteins regulating mitochondrial network morphology. <i>MFN2</i> mutations cause Charcot-Marie-Tooth type 2A (CMT2A), an axonal neuropathy characterized by mitochondrial fusion defects, which in the case of a GTPase domain mutant, were rescued following wild-type <i>MFN1/2</i> (<i>MFN1/2</i><sup><i>WT</i></sup>) overexpression. In this study, we compared the therapeutic efficiency between <i>MFN1</i><sup><i>WT</i></sup> and <i>MFN2</i><sup><i>WT</i></sup> overexpression in correcting mitochondrial defects induced by the novel <i>MFN2</i><sup><i>K357T</i></sup> mutation located in the highly conserved R3 region.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Constructs expressing either <i>MFN2</i><sup><i>K357T</i></sup>, <i>MFN2</i><sup><i>WT</i></sup>, or <i>MFN1</i><sup><i>WT</i></sup> under the ubiquitous chicken <i>β</i>-actin hybrid (<i>CBh</i>) promoter were generated. Flag or myc tag was used for their detection. Differentiated SH-SY5Y cells were single transfected with <i>MFN1</i><sup><i>WT</i></sup>, <i>MFN2</i><sup><i>WT</i></sup>, or <i>MFN2</i><sup><i>K357T</i></sup>, as well as double transfected with <i>MFN2</i><sup><i>K357T</i></sup>/<i>MFN2</i><sup><i>WT</i></sup> or <i>MFN2</i><sup><i>K357T</i></sup>/<i>MFN1</i><sup><i>WT</i></sup>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>SH-SY5Y cells transfected with <i>MFN2</i><sup><i>K357T</i></sup> exhibited severe perinuclear mitochondrial clustering with axon-like processes devoid of mitochondria. Single transfection with <i>MFN1</i><sup><i>WT</i></sup> resulted in a more interconnected mitochondrial network than transfection with <i>MFN2</i><sup><i>WT</i></sup>, accompanied by mitochondrial clusters. Double transfection of <i>MFN2</i><sup><i>K357T</i></sup> with either <i>MFN1</i><sup><i>WT</i></sup> or <i>MFN2</i><sup><i>WT</i></sup> resolved the mutant-induced mitochondrial clusters and led to detectable mitochondria throughout the axon-like processes. <i>MFN1</i><sup><i>WT</i></sup> showed higher efficacy than <i>MFN2</i><sup><i>WT</i></sup> in rescuing these defects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>These results further demonstrate the higher potential of <i>MFN1</i><sup><i>WT</i></sup> over <i>MFN2</i><sup><i>WT</i></sup> overexpression to rescue CMT2A-induced mitochondrial network abnormalities due to mutations outside the GTPase domain. This higher phenotypic rescue conferred by <i>MFN1</i><sup><i>WT</i></sup>, possibly due to its higher m","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2023-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jns.12564","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10175098","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
Changes in axonal and clinical function during intravenous and subcutaneous immunoglobulin therapy in chronic inflammatory demyelinating polyneuropathy 静脉注射和皮下免疫球蛋白治疗慢性炎性脱髓鞘性多发性神经病期间轴突和临床功能的变化
IF 3.8 3区 医学 Q1 Medicine Pub Date : 2023-05-22 DOI: 10.1111/jns.12563
Peter N. Hansen, Abdullahi A. Mohammed, Lars K. Markvardsen, Henning Andersen, Hatice Tankisi, Søren H. Sindrup, Thomas Krøigård

Background and Aims

Intravenous immunoglobulin (IVIg) has a rapid clinical effect which cannot be explained by remyelination during each treatment cycle in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). This study aimed to investigate axonal membrane properties during the IVIg treatment cycle and their potential correlation with clinically relevant functional measurements.

Methods

Motor nerve excitability testing (NET) of the median nerve was performed before and 4 and 18 days after initiation of an IVIg treatment cycle in 13 treatment-naïve (early) CIDP patients and 24 CIDP patients with long term (late) IVIg treatment, 12 CIDP patients treated with subcutaneous immunoglobulin (SCIg) and 55 healthy controls. Clinical function was measured extensively using the Six Spot Step test, 10-Meter Walk test, 9-Hole Peg test, grip strength, MRC sum score, Overall Neuropathy Limitations Score and Patient Global Impression of Change.

Results

Superexcitability and S2 accommodation decreased significantly in the early treatment group from baseline to day 4 and returned to baseline levels at day 18, suggesting temporary depolarization of the axonal membrane. A similar trend was observed for the late IVIg group. Substantial clinical improvement was observed in both early and late IVIg groups during the entire treatment cycle. No statistically significant correlation was found between clinical and NET changes. No change was found in NET or clinical function in the SCIg group or controls.

Interpretation

NET suggested temporary depolarization of the axonal membrane during IVIg treatment in treatment naïve CIDP patients. The relation to clinical improvement, however, remains speculative.

背景与目的静脉注射免疫球蛋白(IVIg)对慢性炎症性脱髓鞘性多神经病变(CIDP)患者的临床疗效迅速,但不能用每个治疗周期的髓鞘再生来解释。本研究旨在探讨IVIg治疗周期中轴突膜的特性及其与临床相关功能测量的潜在相关性。方法对13例treatment-naïve(早期)CIDP患者和24例长期(晚期)IVIg治疗的CIDP患者,12例皮下免疫球蛋白(SCIg)治疗的CIDP患者和55名健康对照者,在IVIg治疗周期开始前、4天和18 d进行正中神经兴奋性测试(NET)。临床功能广泛测量使用六点步测试,10米步行测试,9孔Peg测试,握力,MRC总评分,整体神经病变限制评分和患者整体印象的变化。结果早期治疗组的超兴奋性和S2调节从基线到第4天显著下降,并在第18天恢复到基线水平,提示轴突膜暂时去极化。在IVIg晚期组也观察到类似的趋势。在整个治疗周期中,早期和晚期IVIg组均观察到显著的临床改善。临床与NET变化无统计学意义相关。SCIg组或对照组的NET或临床功能未见变化。解释网提示,在治疗naïve CIDP患者的IVIg治疗期间,轴突膜暂时去极化。然而,与临床改善的关系仍然是推测性的。
{"title":"Changes in axonal and clinical function during intravenous and subcutaneous immunoglobulin therapy in chronic inflammatory demyelinating polyneuropathy","authors":"Peter N. Hansen,&nbsp;Abdullahi A. Mohammed,&nbsp;Lars K. Markvardsen,&nbsp;Henning Andersen,&nbsp;Hatice Tankisi,&nbsp;Søren H. Sindrup,&nbsp;Thomas Krøigård","doi":"10.1111/jns.12563","DOIUrl":"10.1111/jns.12563","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Intravenous immunoglobulin (IVIg) has a rapid clinical effect which cannot be explained by remyelination during each treatment cycle in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). This study aimed to investigate axonal membrane properties during the IVIg treatment cycle and their potential correlation with clinically relevant functional measurements.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Motor nerve excitability testing (NET) of the median nerve was performed before and 4 and 18 days after initiation of an IVIg treatment cycle in 13 treatment-naïve (early) CIDP patients and 24 CIDP patients with long term (late) IVIg treatment, 12 CIDP patients treated with subcutaneous immunoglobulin (SCIg) and 55 healthy controls. Clinical function was measured extensively using the Six Spot Step test, 10-Meter Walk test, 9-Hole Peg test, grip strength, MRC sum score, Overall Neuropathy Limitations Score and Patient Global Impression of Change.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Superexcitability and S2 accommodation decreased significantly in the early treatment group from baseline to day 4 and returned to baseline levels at day 18, suggesting temporary depolarization of the axonal membrane. A similar trend was observed for the late IVIg group. Substantial clinical improvement was observed in both early and late IVIg groups during the entire treatment cycle. No statistically significant correlation was found between clinical and NET changes. No change was found in NET or clinical function in the SCIg group or controls.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>NET suggested temporary depolarization of the axonal membrane during IVIg treatment in treatment naïve CIDP patients. The relation to clinical improvement, however, remains speculative.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2023-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jns.12563","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10182049","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
Macrophages influence Schwann cell myelin autophagy after nerve injury and in a model of Charcot-Marie-Tooth disease 巨噬细胞影响神经损伤后雪旺细胞髓磷脂自噬和腓骨肌病模型
IF 3.8 3区 医学 Q1 Medicine Pub Date : 2023-05-20 DOI: 10.1111/jns.12561
Eva Maria Weiß, Miriam Geldermann, Rudolf Martini, Dennis Klein

Background and Aims

The complex cellular and molecular interactions between Schwann cells (SCs) and macrophages during Wallerian degeneration are a prerequisite to allow rapid uptake and degradation of myelin debris and axonal regeneration after peripheral nerve injury. In contrast, in non-injured nerves of Charcot-Marie-Tooth 1 neuropathies, aberrant macrophage activation by SCs carrying myelin gene defects is a disease amplifier that drives nerve damage and subsequent functional decline. Consequently, targeting nerve macrophages might be a translatable treatment strategy to mitigate disease outcome in CMT1 patients. Indeed, in previous approaches, macrophage targeting alleviated the axonopathy and promoted sprouting of damaged fibers. Surprisingly, this was still accompanied by robust myelinopathy in a model for CMT1X, suggesting additional cellular mechanisms of myelin degradation in mutant peripheral nerves. We here investigated the possibility of an increased SC-related myelin autophagy upon macrophage targeting in Cx32def mice.

Methods

Combining ex vivo and in vivo approaches, macrophages were targeted by PLX5622 treatment. SC autophagy was investigated by immunohistochemical and electron microscopical techniques.

Results

We demonstrate a robust upregulation of markers for SC autophagy after injury and in genetically-mediated neuropathy when nerve macrophages are pharmacologically depleted. Corroborating these findings, we provide ultrastructural evidence for increased SC myelin autophagy upon treatment in vivo.

Interpretation

These findings reveal a novel communication and interaction between SCs and macrophages. This identification of alternative pathways of myelin degradation may have important implications for a better understanding of therapeutic mechanisms of pharmacological macrophage targeting in diseased peripheral nerves.

背景和目的在Wallerian变性过程中,雪旺细胞(SCs)和巨噬细胞之间复杂的细胞和分子相互作用是周围神经损伤后髓鞘碎片快速摄取和降解和轴突再生的先决条件。相反,在Charcot-Marie-Tooth 1型神经病的未损伤神经中,携带髓磷脂基因缺陷的SCs异常激活巨噬细胞是一种疾病放大器,可导致神经损伤和随后的功能下降。因此,靶向神经巨噬细胞可能是缓解CMT1患者疾病结局的一种可翻译的治疗策略。事实上,在先前的方法中,巨噬细胞靶向减轻了轴索病,促进了受损纤维的发芽。令人惊讶的是,在CMT1X模型中,这仍然伴随着强烈的髓鞘病,这表明在突变的周围神经中髓鞘降解的其他细胞机制。我们在这里研究了Cx32def小鼠巨噬细胞靶向后sc相关髓磷脂自噬增加的可能性。方法采用离体和体内相结合的方法,利用PLX5622靶向巨噬细胞。采用免疫组织化学和电镜技术观察SC自噬。研究结果表明,损伤后和遗传介导的神经病变中,当神经巨噬细胞在药理学上被耗尽时,SC自噬标志物显著上调。为了证实这些发现,我们提供了在体内治疗后SC髓磷脂自噬增加的超微结构证据。这些发现揭示了SCs和巨噬细胞之间的一种新的交流和相互作用。这种髓磷脂降解替代途径的鉴定可能对更好地理解巨噬细胞靶向病变周围神经的治疗机制具有重要意义。
{"title":"Macrophages influence Schwann cell myelin autophagy after nerve injury and in a model of Charcot-Marie-Tooth disease","authors":"Eva Maria Weiß,&nbsp;Miriam Geldermann,&nbsp;Rudolf Martini,&nbsp;Dennis Klein","doi":"10.1111/jns.12561","DOIUrl":"10.1111/jns.12561","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>The complex cellular and molecular interactions between Schwann cells (SCs) and macrophages during Wallerian degeneration are a prerequisite to allow rapid uptake and degradation of myelin debris and axonal regeneration after peripheral nerve injury. In contrast, in non-injured nerves of Charcot-Marie-Tooth 1 neuropathies, aberrant macrophage activation by SCs carrying myelin gene defects is a disease amplifier that drives nerve damage and subsequent functional decline. Consequently, targeting nerve macrophages might be a translatable treatment strategy to mitigate disease outcome in CMT1 patients. Indeed, in previous approaches, macrophage targeting alleviated the axonopathy and promoted sprouting of damaged fibers. Surprisingly, this was still accompanied by robust myelinopathy in a model for CMT1X, suggesting additional cellular mechanisms of myelin degradation in mutant peripheral nerves. We here investigated the possibility of an increased SC-related myelin autophagy upon macrophage targeting in Cx32def mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Combining ex vivo and in vivo approaches, macrophages were targeted by PLX5622 treatment. SC autophagy was investigated by immunohistochemical and electron microscopical techniques.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We demonstrate a robust upregulation of markers for SC autophagy after injury and in genetically-mediated neuropathy when nerve macrophages are pharmacologically depleted. Corroborating these findings, we provide ultrastructural evidence for increased SC myelin autophagy upon treatment in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>These findings reveal a novel communication and interaction between SCs and macrophages. This identification of alternative pathways of myelin degradation may have important implications for a better understanding of therapeutic mechanisms of pharmacological macrophage targeting in diseased peripheral nerves.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2023-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jns.12561","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10187248","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: 1
期刊
Journal of the Peripheral Nervous System
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