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Genetic and clinical profile of 15 Chinese families with GDAP1-related Charcot–Marie–Tooth disease and identification of H256R as a frequent mutation 15个中国GDAP1相关夏科-玛丽-牙病家族的遗传和临床概况,以及H256R作为一种常见突变的鉴定。
IF 3.9 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-05-05 DOI: 10.1111/jns.12628
Zhongzheng Li, Sen Zeng, Yongzhi Xie, Xiaobo Li, Shunxiang Huang, Huadong Zhao, Wanqian Cao, Lei Liu, Mengli Wang, Qiaoyu Gong, Jun Liu, Pengfei Rong, Ruxu Zhang

Background and Aims

Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause axonal or demyelinating Charcot–Marie–Tooth disease (CMT) with autosomal dominant or recessive inheritance. In this study, we aim to report the genotypic and phenotypic features of GDAP1-related CMT in a Chinese cohort.

Methods

Clinical, neurophysiological, genetic data, and available muscle/brain imaging information of 28 CMT patients with GDAP1 variants were retrospectively collected.

Results

We identified 16 GDAP1 pathogenic variants, among which two novel variants c.980dup(p.L328FfsX25) and c.480+4T>G were first reported. Most patients (16/28) presented with AR or AD CMT2K phenotype. Clinical characteristics in our cohort demonstrated that the AR patients presented earlier onset, more severe phenotype compared with the AD patients. Considerable intra-familial phenotypic variability was observed among three AD families. Muscle atrophy and fatty infiltration in the lower extremity were detected by Muscle magnetic resonance imaging (MRI) scans in four patients. MRI showed two AR patients showed more severe muscle involvement of the posterior compartment than those of the anterolateral compartment in the calf. One patient carrying Q38*/H256R variants accompanied with mild periventricular leukoaraiosis.

Conclusions

In this study, we conducted an analysis of clinical features of the GDAP1-related CMT patients, expanded the mutation spectrum in GDAP1 by reporting two novel variants, and presented the prevalent occurrence of the H256R mutation in China. The screening of GDAP1 should be particularly emphasized in Chinese patients with CMT2, given the incomplete penetrance and pathogenic inheritance patterns involving dominant and recessive modes.

背景和目的:神经节苷脂诱导分化相关蛋白1(GDAP1)突变会导致轴索型或脱髓鞘型夏科-玛丽-牙病(CMT),具有常染色体显性或隐性遗传性。本研究旨在报告中国人群中 GDAP1 相关 CMT 的基因型和表型特征:方法:我们回顾性地收集了28例GDAP1变异型CMT患者的临床、神经电生理、遗传学数据以及现有的肌肉/脑成像信息:结果:我们发现了16个GDAP1致病变异,其中两个新变异c.980dup(p.L328FfsX25)和c.480+4T>G为首次报道。大多数患者(16/28)表现为 AR 或 AD CMT2K 表型。我们队列中的临床特征显示,与 AD 患者相比,AR 患者发病更早,表型更严重。在三个 AD 家系中观察到了相当大的家族内表型差异。四名患者的肌肉磁共振成像(MRI)扫描发现了下肢肌肉萎缩和脂肪浸润。核磁共振成像显示,两名AR患者的小腿后部肌肉受累比前外侧肌肉受累更严重。一名携带 Q38*/H256R 变体的患者伴有轻度脑室周围白化病:本研究对 GDAP1 相关 CMT 患者的临床特征进行了分析,报告了两个新的变异体,扩大了 GDAP1 的突变谱,并介绍了 H256R 突变在中国的流行情况。鉴于GDAP1的不完全渗透性以及显性和隐性遗传模式,中国的CMT2患者应特别重视GDAP1的筛查。
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引用次数: 0
Cutaneous biomarkers of therapeutic efficacy in early treatment of hereditary ATTR amyloid polyneuropathy with tafamidis 使用他伐米迪早期治疗遗传性 ATTR 淀粉样多发性神经病的疗效皮肤生物标志物。
IF 3.9 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-05-05 DOI: 10.1111/jns.12624
Karla Cárdenas-Soto, Xel-Ha Dominguez, Giovanni Cortes, Felix Tsai, Maria del Mar Saniger, Paola Guraieb-Chahin, Benjamín Torres-Ocatvo, Christopher Gibbons, Jeffery W. Kelly, Roy Freeman, Alejandra González-Duarte
<div> <section> <h3> Background</h3> <p>ATTR (ATTRv) amyloidosis neuropathy is characterized by progressive sensorimotor and autonomic nerve degeneration secondary to amyloid deposition caused by a misfolded transthyretin protein (TTR). Small nerve fiber neuropathy is an early clinical manifestation of this disease resulting from the dysfunction of the Aδ and C small nerve fibers. Tafamidis, a selective TTR stabilizer, has proven its efficacy in the earlier stages of hATTR.</p> </section> <section> <h3> Objectives</h3> <p>To evaluate the clinical course and utility of cutaneous pathological biomarkers in patients with ATTR amyloidosis treated with tafamidis compared to control patients.</p> </section> <section> <h3> Methods</h3> <p>Forty patients diagnosed with early stages of ATTRv amyloidosis (polyneuropathy disability [PND] scores 0-II) underwent small and large nerve fiber neurological evaluations, and annual skin biopsies for intraepidermal nerve fiber density (IENFD) and amyloid deposition index (ADI) estimation. Thirty patients were allocated to receive tafamidis, and 10 patients served as controls. Tafamidis pharmacokinetics analysis was performed in patients who received the treatment.</p> </section> <section> <h3> Results</h3> <p>At baseline, 12% of patients in stage PND 0 and 28% in PND I displayed small nerve fiber denervation in the distal thigh, whereas 23% and 38%, respectively, in the distal leg. Similarly, 72% and 84% had amyloid deposition in the distal thigh and 56% and 69% in the distal leg. Following 1 year of treatment, the tafamidis group showed significant clinical improvement compared to the control group, revealed by the following mean differences (1) −9.3 versus −4 points (<i>p</i> = <.00) in the patient's neuropathy total symptom score 6 (NTSS-6) questionnaire, (2) −2.5 versus +2.8 points (<i>p</i> = <.00) in the Utah Early Neuropathy Score (UENS), and (3) +1.2°C versus −0.6 (<i>p</i> = .01) in cold detection thresholds. Among the patients who received tafamidis, 65% had stable or increased IENFD in their distal thigh and 27% in the distal leg. In contrast, all patients in the control group underwent denervation. The ADI either decreased or remained constant in 31% of the biopsies in the distal thigh and in 24% of the biopsies in the distal leg of the tafamidis-treated patients, whereas it rose across all the biopsies in the control group. At the 4-year follow-up, the tafamidis group continued to display less denervation in the distal thigh (mean difference [MD] of −3.0 vs. −9.3 fibers/mm) and the distal leg (mean difference [MD] −4.9 vs. −8.6 fibers/mm). ADI in tafamidis-treated patients was also
背景:ATTR(ATTRv)淀粉样变性神经病的特点是,由于转淀粉蛋白(TTR)折叠错误导致淀粉样沉积,从而引起进行性感觉运动和自主神经变性。小神经纤维神经病变是这种疾病的早期临床表现,由 Aδ 和 C 小神经纤维功能障碍引起。Tafamidis 是一种选择性 TTR 稳定剂,已证明对 hATTR 的早期阶段具有疗效:与对照组患者相比,评估接受他法米迪治疗的 ATTR 淀粉样变性患者的临床过程和皮肤病理生物标志物的效用:40名被诊断为ATTRv淀粉样变性早期患者(多发性神经病残疾[PND]评分0-II)接受了小神经纤维和大神经纤维神经学评估,并每年进行皮肤活检,以估算表皮内神经纤维密度(IENFD)和淀粉样沉积指数(ADI)。30名患者被分配接受他法米迪治疗,10名患者作为对照组。对接受治疗的患者进行了他法米迪药代动力学分析:基线时,12% 的 PND 0 期患者和 28% 的 PND I 期患者的大腿远端出现小神经纤维变性,而小腿远端则分别为 23% 和 38%。同样,72% 和 84% 的患者大腿远端有淀粉样蛋白沉积,56% 和 69% 的患者腿部远端有淀粉样蛋白沉积。治疗一年后,他法米地斯组与对照组相比临床症状明显改善,其平均差异如下:(1) -9.3分对 -4分(P = 2),腿远端(23个淀粉样蛋白/平方毫米对 40个淀粉样蛋白/平方毫米)与对照组患者相比明显改善。IENFD改善的患者和淀粉样蛋白沉积减少的患者血浆中他法米迪浓度较高。基线时腿部远端无淀粉样蛋白沉积的患者在4年后疾病进展有所延迟:大腿远端和小腿远端皮肤的皮肤IENFD和淀粉样蛋白沉积评估是早期诊断ATTR淀粉样变性和衡量小神经纤维神经病进展的重要生物标志物。早期使用他伐米迪治疗可减缓疾病的临床进展、皮肤神经支配和皮肤中的淀粉样蛋白沉积。较高的他法米地血浆浓度与较好的疾病预后相关,这表明增加药物剂量可以获得更好的血浆浓度和反应率。本研究描述了使用塔法米地治疗小神经纤维神经病的最长时间试验,也是首次将小神经纤维症状、功能和结构评估作为结果进行报告。
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引用次数: 0
Cytokines and chemokines in patients with chronic inflammatory demyelinating polyradiculoneuropathy and multifocal motor neuropathy: A systematic review 慢性炎症性脱髓鞘多发性神经病和多灶性运动神经病患者体内的细胞因子和趋化因子:系统综述
IF 3.9 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-10 DOI: 10.1111/jns.12622
Claudia Cutellè, Alberto De Lorenzo, Pietro Emiliano Doneddu, Maria Francesca Creta, Carlo Selmi, Giuseppe Liberatore, Andrea Giordano, Francesco Gentile, Gian Luca Erre, Eduardo Nobile-Orazio

Advances in the understanding of cytokines have revolutionized mechanistic treatments for chronic inflammatory and autoimmune diseases, as exemplified by rheumatoid arthritis. We conducted a systematic literature review on the role of cytokines and chemokines in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN). Ovid Medline, EMBASE and Web of Science were searched until August 31, 2022 for human studies investigating cytokines levels in CIDP or MMN. Fifty-five articles on 1061 CIDP patients and 86 MMN patients were included, with a median of 18 patients per study (range 3–71). Studies differed in the inclusion criteria, type of assay, manufacturer, control subjects, and tested biological material. Only a minority of studies reported data on disease activity. Interleukin (IL)-6, IL-17, CXCL10, and tumor necrosis factor alpha (TNF-α), were elevated in CIDP compared to controls in most of the studies. IL-6 and TNF-α levels are also correlated with disability. In MMN patients, IL-1Ra was elevated in the majority of the reports. While acknowledging the challenges in comparing studies and the various limitations of the studies, including small patient numbers, particularly in MMN, our review suggests that IL-6, IL-17, CXCL10, and TNF-α might play a role in CIDP pathogenesis. Larger studies are needed in MMN.

对细胞因子认识的进步彻底改变了慢性炎症和自身免疫性疾病的机理治疗,类风湿性关节炎就是一例。我们对细胞因子和趋化因子在慢性炎症性脱髓鞘多发性神经病(CIDP)和多灶性运动神经病(MMN)中的作用进行了系统的文献综述。截至 2022 年 8 月 31 日,我们检索了 Ovid Medline、EMBASE 和 Web of Science 上有关 CIDP 或 MMN 中细胞因子水平的人类研究。共收录了 55 篇文章,涉及 1061 名 CIDP 患者和 86 名 MMN 患者,每项研究的中位数为 18 名患者(范围在 3-71 之间)。这些研究在纳入标准、检测类型、生产商、对照受试者和检测的生物材料等方面存在差异。只有少数研究报告了疾病活动性数据。在大多数研究中,与对照组相比,白细胞介素(IL)-6、IL-17、CXCL10 和肿瘤坏死因子α(TNF-α)在 CIDP 中升高。IL-6 和 TNF-α 的水平也与残疾相关。在大多数报告中,MMN 患者的 IL-1Ra 均升高。我们承认在比较研究和研究的各种局限性(包括患者人数少,尤其是在 MMN 中)方面存在挑战,但我们的综述表明,IL-6、IL-17、CXCL10 和 TNF-α 可能在 CIDP 发病机制中发挥作用。对 MMN 还需要进行更大规模的研究。
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引用次数: 0
Conduction slowing, conduction block and temporal dispersion in demyelinating, dysmyelinating and axonal neuropathies: Electrophysiology meets pathology 脱髓鞘、髓鞘发育不良和轴索神经病中的传导减慢、传导阻滞和时间弥散:电生理学与病理学的结合
IF 3.9 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-10 DOI: 10.1111/jns.12625
Antonino Uncini, Tiziana Cavallaro, Gian Maria Fabrizi, Fiore Manganelli, Jean-Michel Vallat

Nerve conduction studies are usually the first diagnostic step in peripheral nerve disorders and their results are the basis for planning further investigations. However, there are some commonplaces in the interpretation of electrodiagnostic findings in peripheral neuropathies that, although useful in the everyday practice, may be misleading: (1) conduction block and abnormal temporal dispersion are distinctive features of acquired demyelinating disorders; (2) hereditary neuropathies are characterized by uniform slowing of conduction velocity; (3) axonal neuropathies are simply diagnosed by reduced amplitude of motor and sensory nerve action potentials with normal or slightly slow conduction velocity. In this review, we reappraise the occurrence of uniform and non-uniform conduction velocity slowing, conduction block and temporal dispersion in demyelinating, dysmyelinating and axonal neuropathies attempting, with a translational approach, a correlation between electrophysiological and pathological features as derived from sensory nerve biopsy in patients and animal models. Additionally, we provide some hints to navigate in this complex field.

神经传导检查通常是诊断周围神经疾病的第一步,其结果是计划进一步检查的基础。然而,在对周围神经病电诊断结果的解释中存在一些常识,虽然在日常实践中很有用,但可能会产生误导:(1) 传导阻滞和异常时间弥散是获得性脱髓鞘疾病的显著特征;(2) 遗传性神经病的特征是传导速度均匀减慢;(3) 轴索神经病的简单诊断是运动和感觉神经动作电位振幅降低,传导速度正常或稍慢。在这篇综述中,我们重新评估了脱髓鞘、髓鞘发育不良和轴索性神经病中出现的均匀和非均匀传导速度减慢、传导阻滞和时间弥散,并尝试用转化的方法将患者和动物模型感觉神经活检得出的电生理学特征和病理学特征联系起来。此外,我们还提供了一些在这一复杂领域中的导航提示。
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引用次数: 0
A study concept of expeditious clinical enrollment for genetic modifier studies in Charcot–Marie–Tooth neuropathy 1A 针对 Charcot-Marie-Tooth 神经病 1A 基因改变因子研究的快速临床注册研究理念
IF 3.9 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-04-05 DOI: 10.1111/jns.12621
Isaac R. L. Xu, Matt C. Danzi, Ariel Ruiz, Jacquelyn Raposo, Yeisha Arcia De Jesus, Mary M. Reilly, Andrea Cortese, Michael E. Shy, Steven S. Scherer, David N. Herrmann, Vera Fridman, Jonathan Baets, Mario Saporta, Reza Seyedsadjadi, Tanya Stojkovic, Kristl G. Claeys, Pooja Patel, Shawna Feely, Adriana P. Rebelo, Inherited Neuropathy Consortium, Maike F. Dohrn, Stephan Züchner

Background

Caused by duplications of the gene encoding peripheral myelin protein 22 (PMP22), Charcot–Marie–Tooth disease type 1A (CMT1A) is the most common hereditary neuropathy. Despite this shared genetic origin, there is considerable variability in clinical severity. It is hypothesized that genetic modifiers contribute to this heterogeneity, the identification of which may reveal novel therapeutic targets. In this study, we present a comprehensive analysis of clinical examination results from 1564 CMT1A patients sourced from a prospective natural history study conducted by the RDCRN-INC (Inherited Neuropathy Consortium). Our primary objective is to delineate extreme phenotype profiles (mild and severe) within this patient cohort, thereby enhancing our ability to detect genetic modifiers with large effects.

Methods

We have conducted large-scale statistical analyses of the RDCRN-INC database to characterize CMT1A severity across multiple metrics.

Results

We defined patients below the 10th (mild) and above the 90th (severe) percentiles of age-normalized disease severity based on the CMT Examination Score V2 and foot dorsiflexion strength (MRC scale). Based on extreme phenotype categories, we defined a statistically justified recruitment strategy, which we propose to use in future modifier studies.

Interpretation

Leveraging whole genome sequencing with base pair resolution, a future genetic modifier evaluation will include single nucleotide association, gene burden tests, and structural variant analysis. The present work not only provides insight into the severity and course of CMT1A, but also elucidates the statistical foundation and practical considerations for a cost-efficient and straightforward patient enrollment strategy that we intend to conduct on additional patients recruited globally.

夏科-玛丽-图斯病 1A 型(CMT1A)是由编码外周髓鞘蛋白 22(PMP22)的基因重复引起的,是最常见的遗传性神经病。尽管具有共同的遗传起源,但临床严重程度却有相当大的差异。据推测,遗传修饰因子是造成这种异质性的原因之一,识别这些修饰因子可能会发现新的治疗靶点。在本研究中,我们对来自 RDCRN-INC(遗传性神经病联盟)前瞻性自然史研究的 1564 名 CMT1A 患者的临床检查结果进行了全面分析。我们的主要目标是在该患者群中划分出极端表型特征(轻度和重度),从而提高我们检测具有巨大效应的遗传修饰因子的能力。
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引用次数: 0
Lack of effect from genetic deletion of Hdac6 in a humanized mouse model of CMT2D 在人源化的 CMT2D 小鼠模型中,基因缺失 Hdac6 缺乏影响。
IF 3.9 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-03-29 DOI: 10.1111/jns.12623
Abigail L. D. Tadenev, Courtney L. Hatton, Robert W. Burgess

Background

Inhibition of HDAC6 has been proposed as a broadly applicable therapeutic strategy for Charcot–Marie–Tooth disease (CMT). Inhibition of HDAC6 increases the acetylation of proteins important in axonal trafficking, such as α-tubulin and Miro, and has been shown to be efficacious in several preclinical studies using mouse models of CMT.

Aims

Here, we sought to expand on previous preclinical studies by testing the effect of genetic deletion of Hdac6 on mice carrying a humanized knockin allele of Gars1, a model of CMT-type 2D.

Methods

Gars1ΔETAQ mice were bred to an Hdac6 knockout strain, and the resulting offspring were evaluated for clinically relevant outcomes.

Results

The genetic deletion of Hdac6 increased α-tubulin acetylation in the sciatic nerves of both wild-type and Gars1ΔETAQ mice. However, when tested at 5 weeks of age, the Gars1ΔETAQ mice lacking Hdac6 showed no changes in body weight, muscle atrophy, grip strength or endurance, sciatic motor nerve conduction velocity, compound muscle action potential amplitude, or peripheral nerve histopathology compared to Gars1ΔETAQ mice with intact Hdac6.

Interpretation

Our results differ from those of two previous studies that demonstrated the benefit of the HDAC6 inhibitor tubastatin A in mouse models of CMT2D. While we cannot fully explain the different outcomes, our results offer a counterexample to the benefit of inhibiting HDAC6 in CMT2D, suggesting additional research is necessary.

背景:抑制 HDAC6 被认为是治疗夏科-玛丽-牙病(CMT)的一种广泛适用的策略。目的:在此,我们试图通过测试遗传性 Hdac6 基因缺失对携带 Gars1 人源化基因敲除等位基因(一种 CMT 型 2D 模型)小鼠的影响来扩展之前的临床前研究:方法:将Gars1ΔETAQ小鼠与Hdac6基因敲除品系杂交,并对所产生的后代进行临床相关结果评估:结果:Hdac6基因缺失增加了野生型小鼠和Gars1ΔETAQ小鼠坐骨神经中的α-微管蛋白乙酰化。然而,在 5 周龄时进行测试,与具有完整 Hdac6 的 Gars1ΔETAQ 小鼠相比,缺乏 Hdac6 的 Gars1ΔETAQ 小鼠在体重、肌肉萎缩、握力或耐力、坐骨神经运动神经传导速度、复合肌肉动作电位振幅或周围神经组织病理学方面没有变化:我们的研究结果不同于之前的两项研究,前者证明了 HDAC6 抑制剂管司他丁 A 在 CMT2D 小鼠模型中的益处。虽然我们无法完全解释不同的结果,但我们的结果为抑制 HDAC6 对 CMT2D 的益处提供了一个反例,表明有必要进行更多的研究。
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引用次数: 0
A 21-bp deletion in the complement regulator CD55 promotor region is associated with multifocal motor neuropathy and its disease course 补体调节因子 CD55 启动子区域的 21-bp 缺失与多灶性运动神经病变及其病程有关。
IF 3.9 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-03-25 DOI: 10.1111/jns.12620
Jeroen W. Bos, Ewout J. N. Groen, Henny G. Otten, Kevin Budding, Ruben P. A. van Eijk, Chantall Curial, Tineke Kardol-Hoefnagel, H. Stephan Goedee, Leonard H. van den Berg, W. Ludo van der Pol

Background and Aims

To further substantiate the role of antibody-mediated complement activation in multifocal motor neuropathy (MMN) immunopathology, we investigated the distribution of promotor polymorphisms of genes encoding the membrane-bound complement regulators CD46, CD55, and CD59 in patients with MMN and controls, and evaluated their association with disease course.

Methods

We used Sanger sequencing to genotype five common polymorphisms in the promotor regions of CD46, CD55, and CD59 in 133 patients with MMN and 380 controls. We correlated each polymorphism to clinical parameters.

Results

The genotype frequencies of rs28371582, a 21-bp deletion in the CD55 promotor region, were altered in patients with MMN as compared to controls (p .009; Del/Del genotype 16.8% vs. 7.7%, p .005, odds ratio: 2.43 [1.27–4.58]), and patients carrying this deletion had a more favorable disease course (mean difference 0.26 Medical Research Council [MRC] points/year; 95% confidence interval [CI]: 0.040–0.490, p .019). The presence of CD59 rs141385724 was associated with less severe pre-diagnostic disease course (mean difference 0.940 MRC point/year; 95% CI: 0.083–1.80, p .032).

Interpretation

MMN susceptibility is associated with a 21-bp deletion in the CD55 promotor region (rs2871582), which is associated with lower CD55 expression. Patients carrying this deletion may have a more favorable long-term disease outcome. Taken together, these results point out the relevance of the pre-C5 level of the complement cascade in the inflammatory processes underlying MMN.

背景和目的:为进一步证实抗体介导的补体激活在多灶性运动神经病(MMN)免疫病理中的作用,我们研究了MMN患者和对照组中编码膜结合补体调节因子CD46、CD55和CD59的基因启动子多态性的分布情况,并评估了它们与病程的关系:我们使用桑格测序法对133名MMN患者和380名对照者中CD46、CD55和CD59启动子区域的5个常见多态性进行了基因分型。我们将每个多态性与临床参数相关联:与对照组相比,MMN 患者 CD55 启动子区 21-bp 缺失 rs28371582 的基因型频率发生了改变(P .009;Del/Del 基因型 16.8% vs. 7.7%,P .005,几率比:2.43 [1.27-4.58]),携带该缺失的患者病程更有利(平均差异为 0.26 医学研究委员会 [MRC] 分/年;95% 置信区间 [CI]:0.040-0.490):0.040-0.490, p .019).CD59 rs141385724 的存在与较轻的诊断前病程有关(平均差异为 0.940 MRC 点/年;95% 置信区间 [CI]:0.083-1.80,P .032):MMN易感性与CD55启动子区域的21-bp缺失(rs2871582)有关,该缺失与较低的CD55表达有关。携带该缺失的患者可能会有更有利的长期疾病预后。综上所述,这些结果表明,补体级联的前 C5 水平在 MMN 的炎症过程中具有相关性。
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引用次数: 0
Development of a functional outcome measure for riboflavin transporter deficiency 开发核黄素转运体缺乏症的功能结果测量方法。
IF 3.9 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-03-06 DOI: 10.1111/jns.12619
Jack R. Fennessy, Gabrielle A. Donlevy, Marnee J. McKay, Joshua Burns, Kayla M. D. Cornett, Manoj P. Menezes
<div> <section> <h3> Background and Aims</h3> <p>Riboflavin transporter deficiency (RTD) is a progressive inherited neuropathy of childhood onset, characterised clinically by pontobulbar palsy, sensory ataxia, sensorineural deafness, muscle weakness, optic atrophy and respiratory failure. A robust and responsive functional outcome measure is essential for future clinical trials of disease-modifying therapies including genetic therapies. The Charcot–Marie–Tooth disease Pediatric Scale (CMTPedS) is a well-validated outcome measure for CMT and related neuropathies, and might have utility for measuring disease progression in individuals with RTD. However, the CMTPedS requires modifications to account for phenotypic differences between children with CMT and RTD. The aim of this study was to develop a functional outcome measure based on the CMTPedS for specific use in individuals with RTD.</p> </section> <section> <h3> Methods</h3> <p>The CMTPedS data collected over the last 10 years in individuals with RTD attending the Peripheral Neuropathy Management Clinic at the Children's Hospital at Westmead (Sydney, Australia) were reviewed to evaluate each item within the CMTPedS. A literature review of articles published until September 2021 for functional outcome measures generated an item pool for pilot testing. The results of this pilot testing, alongside analysis of existing CMTPedS item scores in the RTD cohort, informed the modification of the CMTPedS.</p> </section> <section> <h3> Results</h3> <p>CMTPedS data were reviewed for eight individuals over the past 10 years. Two items were identified as requiring modification or removal and additional items of proximal strength and function needed to be considered. Six studies were identified in the literature review, and five items were selected for pilot testing. ‘Shoulder internal rotation’ and the ‘30-s sit to stand test’ were added as proximal measures of strength and function. The composite balance item comprising nine tasks in the CMTPedS showed a ceiling effect and was replaced with the single ‘Feet apart on a line eyes open’ balance item. ‘Pinprick sensation’ was removed due to a floor effect.</p> </section> <section> <h3> Interpretation</h3> <p>This study provides preliminary evidence that the Riboflavin Transporter Deficiency Pediatric Scale (RTDPedS) is a functional outcome measure covering strength, upper and lower limb function, balance and mobility for individuals with RTD to assess disease severity and progression in clinical trials and cohort studies.</p> </section> <
背景和目的:核黄素转运体缺乏症(RTD)是一种儿童期发病的进行性遗传神经病,临床表现为桥脑麻痹、感觉性共济失调、感音神经性耳聋、肌无力、视神经萎缩和呼吸衰竭。对于未来包括基因疗法在内的疾病改变疗法的临床试验而言,一个可靠且反应灵敏的功能结果测量指标至关重要。Charcot-Marie-Tooth病儿科量表(CMTPedS)是针对CMT和相关神经病的一种经过充分验证的结果测量方法,可能对测量RTD患者的疾病进展有用。然而,CMTPedS 需要根据 CMT 和 RTD 儿童的表型差异进行修改。本研究的目的是在 CMTPedS 的基础上开发一种功能结果测量方法,专门用于 RTD 患者:方法:对过去 10 年中收集的在韦斯特米德儿童医院(澳大利亚悉尼)周围神经病变管理诊所就诊的 RTD 患者的 CMTPedS 数据进行回顾,以评估 CMTPedS 中的每个项目。通过对 2021 年 9 月之前发表的有关功能结果测量的文章进行文献回顾,建立了一个用于试点测试的项目库。试点测试的结果以及对 RTD 队列中现有 CMTPedS 项目得分的分析为 CMTPedS 的修改提供了依据:对过去 10 年中 8 人的 CMTPedS 数据进行了审查。发现有两个项目需要修改或删除,另外还需要考虑近端力量和功能项目。在文献回顾中确定了六项研究,并选择了五个项目进行试点测试。增加了 "肩内旋 "和 "30 秒坐立测试 "作为近端力量和功能测量项目。在 CMTPedS 中,由九项任务组成的综合平衡项目出现了天花板效应,因此被 "双脚分开站在一条线上,眼睛睁开 "的单一平衡项目所取代。而 "针刺感 "则因出现地板效应而被删除:本研究提供了初步证据,证明核黄素转运体缺乏症儿科量表(RTDPedS)是一种功能性结果测量方法,适用于核黄素转运体缺乏症患者的力量、上下肢功能、平衡和活动能力,可用于评估临床试验和队列研究中疾病的严重程度和进展情况。
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引用次数: 0
Laura Feltri: In memoriam 劳拉-费尔特里:悼念。
IF 3.8 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-02-25 DOI: 10.1111/jns.12618
Stefano C. Previtali, Carla Taveggia
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引用次数: 0
Genetic diversity in hereditary axonal neuropathy: Analyzing 53 Brazilian children 遗传性轴索神经病的遗传多样性:分析 53 名巴西儿童
IF 3.8 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-02-20 DOI: 10.1111/jns.12617
Fernanda Barbosa Figueiredo, Pedro José Tomaselli, Jaime Hallak, Ana Cláudia Mattiello-Sverzut, Anna Paula Paranhos Miranda Covaleski, Cláudia Ferreira da Rosa Sobreira, Silmara de Paula Gouvêa, Wilson Marques Jr

Background and Aims

The genetic epidemiology of inherited neuropathies in children remains largely unknown. In this study, we specifically investigated the genetic profile of a Brazilian cohort of pediatric patients with pure or complex axonal neuropathies, a crucial knowledge in the near future for establishing treatment priorities and perspectives for this group of patients.

Methods

Fifty-three pediatric patients who were assessed prior to reaching the age of 20, and who had clinical diagnoses of axonal hereditary neuropathy or presented with axonal neuropathy as the primary clinical feature, were included in the study. The recruitment of these cases took place from January 1, 2018, to December 31, 2020.

The diagnosis was based on clinical and electrophysiological data. A molecular assessment was made using target-gene panel or whole-exome sequencing. Subsequently, segregation analysis was performed on available family members, and all candidate variants found were confirmed through Sanger.

Results

A molecular diagnosis was reached in 68% of the patients (n = 36/53), considering only pathogenic and probably pathogenic variants. Variants in MFN2 (n = 15) and GJB1 (n = 3) accounted for half of the genetically confirmed patients (50%; n = 18/36). The other 18 genetically diagnosed patients had variants in several less common genes.

Interpretation

Apart from MFN2 and GJB1 genes, universally recognized as a frequent cause of axonal neuropathies in most studied population, our Brazilian cohort of children with axonal neuropathies showed an important genetic heterogeneity, probably reflecting the multi ethnicity of the Brazilian population. Diagnostic, counseling, and future interventions should consider this characteristic.

背景和目的:儿童遗传性神经病的遗传流行病学在很大程度上仍不为人所知。在这项研究中,我们专门调查了巴西纯合性或复杂性轴索神经病儿科患者的遗传特征,这对于在不久的将来确定这类患者的治疗重点和前景至关重要:本研究共纳入 53 名儿童患者,这些患者在 20 岁之前接受过评估,临床诊断为轴索遗传性神经病或以轴索神经病为主要临床特征。这些病例的招募时间为 2018 年 1 月 1 日至 2020 年 12 月 31 日。诊断基于临床和电生理数据。分子评估采用靶基因面板或全外显子组测序。随后,对可用的家庭成员进行了分离分析,并通过 Sanger 确认了发现的所有候选变异:结果:仅考虑致病变异和可能致病变异,68%的患者(n = 36/53)获得了分子诊断。在基因确诊的患者中,MFN2(n = 15)和 GJB1(n = 3)变异占一半(50%;n = 18/36)。其他18名基因确诊患者的变异涉及几个不太常见的基因:除了MFN2和GJB1基因是大多数研究人群中公认的轴突性神经病的常见病因外,我们的巴西轴突性神经病患儿队列还显示出重要的遗传异质性,这可能反映了巴西人口的多种族性。诊断、咨询和未来的干预措施都应考虑这一特点。
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引用次数: 0
期刊
Journal of the Peripheral Nervous System
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