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Imbalance and lower limb tremor in chronic inflammatory demyelinating polyradiculoneuropathy: Reply to Letter to the Editor 慢性炎症性脱髓鞘多发性神经病的失衡和下肢震颤:回复致编辑的信
IF 3.8 3区 医学 Q1 Medicine Pub Date : 2023-09-04 DOI: 10.1111/jns.12592
Matthew Silsby, Steve Vucic
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引用次数: 2
Corneal confocal microscopy in small and mixed fiber neuropathy—Comparison with skin biopsy and cold detection in a large prospective cohort 小纤维和混合纤维神经病的角膜共焦显微镜与大型前瞻性队列中的皮肤活检和冷检测的比较。
IF 3.8 3区 医学 Q1 Medicine Pub Date : 2023-08-31 DOI: 10.1111/jns.12595
Asger Bjørnkær, Laura M. Gaist, Jakob V. Holbech, David Gaist, Martin Wirenfeldt, Søren H. Sindrup, Thomas Krøigård

Background and Aims

The diagnosis of small fiber neuropathy (SFN) is supported by reduced intraepidermal nerve fiber density (IENFD). The noninvasive method corneal confocal microscopy (CCM) has the potential to be a practical alternative. We aimed to estimate the diagnostic accuracy of CCM compared with IENFD and cold detection thresholds (CDT) in SFN and mixed fiber neuropathy (MFN).

Methods

CCM was performed in an unselected prospective cohort of patients with a clinical suspicion of polyneuropathy. Predefined criteria were used to classify SFN and MFN. Neuropathy scores, including the Utah early neuropathy scale (UENS), were used to describe severity. Patients with established other diagnoses were used for diagnostic specificity calculations.

Results

Data were taken from 680 patients, of which 244 had SFN or MFN. There was no significant difference in sensitivities [95%CI] of CCM (0.44 [0.38–0.51]), IEFND (0.43 [0.36–0.49]), and CDT (0.34 [0.29–0.41]). CCM specificity (0.75 [0.69–0.81]) was lower (p = .044) than for IENFD (0.99 [0.96–1.00]) but not than for CDT (0.81 [0.75–0.86]). The AUCs of the ROC curves of 0.63, 0.63 and 0.74 respectively, was lower for corneal nerve fiber density (p = .0012) and corneal nerve fiber length (p = .0015) compared with IENFD. While UENS correlated significantly with IENFD (p = .0016; R2 = .041) and CDT (p = .0002; R2 = .056), it did not correlate with CCM measures.

Interpretation

The diagnostic utility of CCM in SNF and MFN is limited by the low specificity compared with skin biopsy. Further, CCM is less suitable than skin biopsy and CDT as a marker for neuropathy severity.

背景和目的:表皮内神经纤维密度降低(IENFD)支持小纤维神经病(SFN)的诊断。非侵入性角膜共聚焦显微镜(CCM)有可能成为一种实用的替代方法。我们旨在评估CCM与IENFD和冷检测阈值(CDT)相比对SFN和混合纤维神经病(MFN)的诊断准确性。方法:在临床怀疑为多发性神经病的未经选择的前瞻性队列中进行CCM。使用预定义的标准对SFN和MFN进行分类。神经病变评分,包括犹他州早期神经病变量表(UENS),用于描述严重程度。已确定其他诊断的患者用于诊断特异性计算。结果:数据取自680名患者,其中244名患者患有SFN或MFN。CCM(0.44[0.38-0.51])、IEFND(0.43[0.36-0.49])和CDT(0.34[0.29-0.41])的敏感性[95%CI]没有显著差异。CCM特异性(0.75[0.69-0.81])较低(p = .044),而不是CDT(0.81[0.75-0.86])。ROC曲线的AUC分别为0.63、0.63和0.74,角膜神经纤维密度的AUC较低(p = .0012)和角膜神经纤维长度(p = .0015)与IENFD相比。UENS与IENFD显著相关(p = .0016;R2 = .041)和CDT(p = .0002;R2 = .056),它与CCM测量没有相关性。解释:CCM在SNF和MFN中的诊断作用受到与皮肤活检相比特异性低的限制。此外,CCM不如皮肤活检和CDT适合作为神经病变严重程度的标志物。
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引用次数: 0
Expanding the genetic and clinical spectrum of SORD-related peripheral neuropathy by reporting a novel variant c.210T>G and evidence of subclinical muscle involvement 通过报告一种新型变体 c.210T>G 和亚临床肌肉受累的证据,扩展了 SORD 相关周围神经病变的遗传和临床范围
IF 3.8 3区 医学 Q1 Medicine Pub Date : 2023-08-16 DOI: 10.1111/jns.12591
Lu Li, Yongzhi Xie, Sen Zeng, Xiaobo Li, Zhiqiang Lin, Shunxiang Huang, Huadong Zhao, Wanqian Cao, Lei Liu, Jun Liu, Pengfei Rong, Ruxu Zhang

Background and Aims

Biallelic variants in the sorbitol dehydrogenase (SORD) gene have been identified as the genetic cause of autosomal recessive (AR) peripheral neuropathy (PN) manifesting as Charcot–Marie–Tooth disease type 2 (CMT2) or distal hereditary motor neuropathy (dHMN). We aim to observe the genetic and clinical spectrum of a cohort of patients with SORD-related PN (SORD-PN).

Methods

A total of 107 patients with AR or sporadic CMT2/dHMN underwent molecular diagnosis by whole-exome sequencing and subsequent Sanger sequencing validation. Available phenotypic data for SORD-PN were collected and analyzed.

Results

Eleven (10.28%) of 107 patients were identified as SORD-PN, including four with CMT2 and seven with dHMN. The SORD variant c.210 T > G;p.His70Gln in F-d3 was firstly reported and subsequent analysis showed that it resulted in loss of SORD enzyme function. Evidence of subclinical muscle involvement was frequently detected in patients with SORD-PN, including mildly to moderately elevated serum creatine kinase (CK) levels in 10 patients, myogenic electrophysiological changes in one patient, and muscle edema in five patients undergoing lower extremity MRI. Fasting serum sorbitol level was 88-fold higher in SORD-PN patients (9.69 ± 1.07 mg/L) than in healthy heterozygous subjects (0.11 ± 0.01 mg/L) and 138-fold higher than in healthy controls (0.07 ± 0.02 mg/L).

Interpretation

The novel SORD variant c.210 T > G;p.His70Gln and evidence of subclinical muscle involvement were identified, which expanded the genetic and clinical spectrum of SORD-PN. Subclinical muscle involvement might be a common but easily overlooked clinical feature. The serum CK and fasting serum sorbitol levels were expected to be sensitive biomarkers confirmed by follow-up cohort study.

背景和目的 已发现山梨醇脱氢酶(SORD)基因的双叶变体是常染色体隐性(AR)周围神经病(PN)的遗传病因,表现为夏科-玛丽-牙病 2 型(CMT2)或远端遗传性运动神经病(dHMN)。我们的目的是观察一组 SORD 相关 PN(SORD-PN)患者的遗传和临床谱系。 方法 共有 107 名 AR 或散发性 CMT2/dHMN 患者接受了全外显子组测序的分子诊断和随后的 Sanger 测序验证。收集并分析了 SORD-PN 的表型数据。 结果 107 例患者中有 11 例(10.28%)被确定为 SORD-PN,其中包括 4 例 CMT2 患者和 7 例 dHMN 患者。F-d3 中的 SORD 变异 c.210 T > G;p.His70Gln 最早被报道,随后的分析表明该变异导致 SORD 酶功能丧失。在 SORD-PN 患者中经常发现亚临床肌肉受累的证据,包括 10 例患者血清肌酸激酶(CK)水平轻度至中度升高,1 例患者出现肌源性电生理改变,5 例患者在接受下肢核磁共振成像检查时出现肌肉水肿。SORD-PN 患者的空腹血清山梨醇水平(9.69 ± 1.07 mg/L)是健康杂合子受试者(0.11 ± 0.01 mg/L)的 88 倍,是健康对照组(0.07 ± 0.02 mg/L)的 138 倍。 解释 发现了新型 SORD 变异 c.210 T > G;p.His70Gln 和亚临床肌肉受累的证据,这扩大了 SORD-PN 的遗传和临床范围。亚临床肌肉受累可能是一种常见但容易被忽视的临床特征。随访队列研究证实,血清肌酸激酶和空腹血清山梨醇水平有望成为敏感的生物标志物。
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引用次数: 0
Genetic, electrophysiological, and pathological studies on patients with SCN9A-related pain disorders 对 SCN9A 相关疼痛疾病患者的遗传学、电生理学和病理学研究
IF 3.8 3区 医学 Q1 Medicine Pub Date : 2023-08-09 DOI: 10.1111/jns.12590
Jun-Hui Yuan, Xiaoyang Cheng, Eiji Matsuura, Yujiro Higuchi, Masahiro Ando, Akihiro Hashiguchi, Akiko Yoshimura, Ryo Nakachi, Jun Mine, Takeshi Taketani, Kenichi Maeda, Saori Kawakami, Ryutaro Kira, Shoko Tanaka, Kazuaki Kanai, Fadia Dib-Hajj, Sulayman D. Dib-Hajj, Stephen G. Waxman, Hiroshi Takashima

Background and Aims

Voltage-gated sodium channel Nav1.7, encoded by the SCN9A gene, has been linked to diverse painful peripheral neuropathies, represented by the inherited erythromelalgia (EM) and paroxysmal extreme pain disorder (PEPD). The aim of this study was to determine the genetic etiology of patients experiencing neuropathic pain, and shed light on the underlying pathogenesis.

Methods

We enrolled eight patients presenting with early-onset painful peripheral neuropathies, consisting of six cases exhibiting EM/EM-like disorders and two cases clinically diagnosed with PEPD. We conducted a gene-panel sequencing targeting 18 genes associated with hereditary sensory and/or autonomic neuropathy. We introduced novel SCN9A mutation (F1624S) into a GFP-2A-Nav1.7rNS plasmid, and the constructs were then transiently transfected into HEK293 cells. We characterized both wild-type and F1624S Nav1.7 channels using an automated high-throughput patch-clamp system.

Results

From two patients displaying EM-like/EM phenotypes, we identified two SCN9A mutations, I136V and P1308L. Among two patients diagnosed with PEPD, we found two additional mutations in SCN9A, F1624S (novel) and A1632E. Patch-clamp analysis of Nav1.7-F1624S revealed depolarizing shifts in both steady-state fast inactivation (17.4 mV, p < .001) and slow inactivation (5.5 mV, p < .001), but no effect on channel activation was observed.

Interpretation

Clinical features observed in our patients broaden the phenotypic spectrum of SCN9A-related pain disorders, and the electrophysiological analysis enriches the understanding of genotype–phenotype association caused by Nav1.7 gain-of-function mutations.

背景和目的 由 SCN9A 基因编码的电压门控钠通道 Nav1.7 与多种疼痛性周围神经病有关,其中以遗传性红斑性肢痛症(EM)和阵发性极度疼痛症(PEPD)为代表。本研究旨在确定神经病理性疼痛患者的遗传病因,并揭示其潜在的发病机制。 方法 我们招募了八名早发性疼痛性周围神经病患者,其中六名表现为 EM/EM 类疾病,两名临床诊断为 PEPD。我们对与遗传性感觉和/或自主神经病变相关的18个基因进行了基因组测序。我们将新型 SCN9A 突变(F1624S)导入 GFP-2A-Nav1.7rNS 质粒,然后将构建体瞬时转染到 HEK293 细胞中。我们使用自动高通量膜片钳系统鉴定了野生型和 F1624S Nav1.7 通道。 结果 我们从两名表现出 EM-like/EM 表型的患者中发现了两个 SCN9A 突变,即 I136V 和 P1308L。在两名被诊断为 PEPD 的患者中,我们发现了 SCN9A 的另外两个突变,即 F1624S(新型)和 A1632E。对 Nav1.7-F1624S 的贴片钳分析表明,稳态快速失活(17.4 mV,p < .001)和慢速失活(5.5 mV,p < .001)均有去极化偏移,但对通道激活没有影响。 解释 我们在患者身上观察到的临床特征拓宽了 SCN9A 相关疼痛疾病的表型谱,电生理分析丰富了对 Nav1.7 功能增益突变引起的基因型-表型关联的理解。
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引用次数: 0
Ophthalmological involvement in wild-type transthyretin amyloidosis: A multimodal imaging study 野生型转甲状腺素淀粉样变性的眼科受累:多模态成像研究
IF 3.8 3区 医学 Q1 Medicine Pub Date : 2023-08-08 DOI: 10.1111/jns.12589
Luisa Frizziero, Alessandro Salvalaggio, Eleonora Cosmo, Alberto Cipriani, Edoardo Midena, Chiara Briani

Background and Aims

Ophthalmological abnormalities have been reported in hereditary transthyretin-related amyloidosis (ATTRv, v for variant) but not in wild-type transthyretin-related amyloidosis (ATTRwt).

Methods

Patients with ATTRwt, ATTRv, and light chain amyloidosis (AL) and healthy subjects (controls) underwent complete eye examination, including optical coherence tomography (OCT), OCT angiography (OCTA), and in vivo corneal confocal microscopy (CCM).

Results

Seventeen ATTRwt, nine ATTRv, two ATTRv carriers, and seven AL patients were enrolled. Compared with other groups, ATTRwt patients had 10 letters lower visual acuity and a higher prevalence of glaucoma, cataract, and retinal pigment epithelium alterations. In the whole group of patients, especially in ATTRwt, we observed (1) a reduced corneal nerve fiber length and more tortuous stromal nerves at CCM, (2) a reduced macular volume and peripapillary nerve fiber layer thickness at OCT, and (3) impairment of peripapillary and macular vascularization at OCTA.

Interpretation

Ophthalmological abnormalities are common in ATTRwt, significantly impairing visual acuity. Noninvasive imaging modalities allow for the identification of small nerve fibers and small vessel damage, which may represent further warning signs for early diagnosis of ATTRwt.

背景和目的 据报道,遗传性转甲状腺素相关淀粉样变性病(ATTRv,v表示变异型)会出现眼部异常,而野生型转甲状腺素相关淀粉样变性病(ATTRwt)不会出现眼部异常。 方法 对 ATTRwt、ATTRv 和轻链淀粉样变性(AL)患者以及健康受试者(对照组)进行全面的眼部检查,包括光学相干断层扫描(OCT)、OCT 血管造影术(OCTA)和活体角膜共聚焦显微镜(CCM)。 结果 共纳入 17 名 ATTRwt 患者、9 名 ATTRv 患者、2 名 ATTRv 携带者和 7 名 AL 患者。与其他组别相比,ATTRwt 患者的视力要低 10 个字母,青光眼、白内障和视网膜色素上皮改变的发病率较高。在整组患者中,尤其是在 ATTRwt 患者中,我们观察到:(1)CCM 观察到角膜神经纤维长度减少,基质神经更加迂曲;(2)OCT 观察到黄斑体积和毛细血管周围神经纤维层厚度减少;(3)OCTA 观察到毛细血管周围和黄斑血管受损。 解释 ATTRwt 常见眼科异常,严重影响视力。无创成像模式可识别小神经纤维和小血管损伤,这可能是早期诊断 ATTRwt 的进一步预警信号。
{"title":"Ophthalmological involvement in wild-type transthyretin amyloidosis: A multimodal imaging study","authors":"Luisa Frizziero,&nbsp;Alessandro Salvalaggio,&nbsp;Eleonora Cosmo,&nbsp;Alberto Cipriani,&nbsp;Edoardo Midena,&nbsp;Chiara Briani","doi":"10.1111/jns.12589","DOIUrl":"10.1111/jns.12589","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Ophthalmological abnormalities have been reported in hereditary transthyretin-related amyloidosis (ATTRv, v for variant) but not in wild-type transthyretin-related amyloidosis (ATTRwt).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Patients with ATTRwt, ATTRv, and light chain amyloidosis (AL) and healthy subjects (controls) underwent complete eye examination, including optical coherence tomography (OCT), OCT angiography (OCTA), and in vivo corneal confocal microscopy (CCM).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Seventeen ATTRwt, nine ATTRv, two ATTRv carriers, and seven AL patients were enrolled. Compared with other groups, ATTRwt patients had 10 letters lower visual acuity and a higher prevalence of glaucoma, cataract, and retinal pigment epithelium alterations. In the whole group of patients, especially in ATTRwt, we observed (1) a reduced corneal nerve fiber length and more tortuous stromal nerves at CCM, (2) a reduced macular volume and peripapillary nerve fiber layer thickness at OCT, and (3) impairment of peripapillary and macular vascularization at OCTA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Ophthalmological abnormalities are common in ATTRwt, significantly impairing visual acuity. Noninvasive imaging modalities allow for the identification of small nerve fibers and small vessel damage, which may represent further warning signs for early diagnosis of ATTRwt.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2023-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jns.12589","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10135095","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
Two new mouse models of Gjb1-associated Charcot–Marie–Tooth disease type 1X 两种新的gjb1相关的1X型腓骨肌萎缩症小鼠模型
IF 3.8 3区 医学 Q1 Medicine Pub Date : 2023-08-07 DOI: 10.1111/jns.12588
A. L. D. Tadenev, C. L. Hatton, B. Pattavina, T. Mullins, R. Schneider, L. P. Bogdanik, Robert W. Burgess

Background

Charcot–Marie–Tooth disease type 1X is caused by mutations in GJB1, which is the second most common gene associated with inherited peripheral neuropathy. The GJB1 gene encodes connexin 32 (CX32), a gap junction protein expressed in myelinating glial cells. The gene is X-linked, and the mutations cause a loss of function.

Aims

A large number of disease-associated variants have been identified, and many result in mistrafficking and mislocalization of the protein. An existing knockout mouse lacking Gjb1 expression provides a valid animal model of CMT1X, but the complete lack of protein may not fully recapitulate the disease mechanisms caused by aberrant CX32 proteins. To better represent the spectrum of human CMT1X-associated mutations, we have generated a new Gjb1 knockin mouse model.

Methods

CRISPR/Cas9 genome editing was used to produce mice carrying the R15Q mutation in Gjb1. In addition, we identified a second allele with an early frame shift mutation in codon 7 (del2). Mice were analyzed using clinically relevant molecular, histological, neurophysiological, and behavioral assays.

Results

Both alleles produce protein detectable by immunofluorescence in Schwann cells, with some protein properly localizing to nodes of Ranvier. However, both alleles also result in peripheral neuropathy with thinly myelinated and demyelinated axons, as well as degenerating and regenerating axons, predominantly in distal motor nerves. Nerve conduction velocities were only mildly reduced at later ages and compound muscle action potential amplitudes were not reduced. Levels of neurofilament light chain in plasma were elevated in both alleles. The del2 mice have an onset at ~3 months of age, whereas the R15Q mice had a later onset at 5–6 months of age, suggesting a milder loss of function. Both alleles performed comparably to wild type littermates in accelerating rotarod and grip strength tests of neuromuscular performance.

Interpretation

We have generated and characterized two new mouse models of CMT1X that will be useful for future mechanistic and preclinical studies.

背景:1X型腓骨肌萎缩症是由GJB1突变引起的,GJB1是与遗传性周围神经病变相关的第二大常见基因。GJB1基因编码连接蛋白32 (CX32),这是一种在髓鞘胶质细胞中表达的间隙连接蛋白。该基因是x连锁的,突变会导致功能丧失。目的大量与疾病相关的变异已被发现,其中许多变异导致蛋白质的错误运输和错误定位。现有缺失Gjb1表达的敲除小鼠提供了一种有效的CMT1X动物模型,但完全缺乏蛋白质可能无法完全概括异常CX32蛋白引起的疾病机制。为了更好地代表人类cmt1x相关突变谱,我们建立了一个新的Gjb1敲入小鼠模型。方法采用CRISPR/Cas9基因组编辑技术,制备携带Gjb1基因R15Q突变的小鼠。此外,我们在密码子7 (del2)上发现了第二个等位基因,其早期帧移位突变。使用临床相关的分子、组织学、神经生理学和行为分析小鼠。结果两种等位基因在雪旺细胞中均产生免疫荧光可检测的蛋白,部分蛋白可定位于Ranvier淋巴结。然而,这两种等位基因也会导致周围神经病变,包括髓鞘稀疏和脱髓鞘轴突,以及轴突退化和再生,主要发生在远端运动神经。神经传导速度仅在老年时轻度降低,复合肌肉动作电位振幅未降低。两种等位基因血浆中神经丝轻链水平均升高。del2小鼠在约3个月大时发病,而R15Q小鼠在5-6个月大时发病,表明功能丧失较轻。这两个等位基因在神经肌肉性能的加速旋转和握力测试中表现与野生型幼崽相当。我们已经建立并描述了两种新的CMT1X小鼠模型,这将对未来的机制和临床前研究有用。
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引用次数: 0
Benefit of high-dose oral riboflavin therapy in riboflavin transporter deficiency 大剂量口服核黄素治疗核黄素转运蛋白缺乏的益处
IF 3.8 3区 医学 Q1 Medicine Pub Date : 2023-08-03 DOI: 10.1111/jns.12587
Jack R. Fennessy, Kayla M. D. Cornett, Joshua Burns, Manoj P. Menezes

Riboflavin transporter deficiency (RTD) is a progressive inherited neuropathy of childhood onset, characterised by pontobulbar palsy, sensorineural deafness, sensory ataxia, muscle weakness, optic atrophy and respiratory failure. Riboflavin supplementation is beneficial in short-term reports, but the quantum of benefit in various clinical domains is not well understood. A PubMed search was conducted, which identified 94 genetically confirmed cases of RTD who received riboflavin supplementation and had follow-up assessments. Information on the clinical and functional status before and after riboflavin supplementation was collected and analysed. Seventy-six of the 94 patients (80.9%) showed an overall improvement after riboflavin supplementation, and the remaining (19.1%) were stable, though some patients had deteriorations in individual domains with no reported deaths. The domains that had the highest rates of response to riboflavin supplementation were gross motor function (93.3% improved), bulbar palsy (91.3%) and ataxia (90.0%). Improvements were also seen in limb muscle weakness, audiology, facial nerve palsy and respiratory function. Despite treatment, many patients required assistance to ambulate and had severe or profound hearing loss and some remained gastrostomy or tracheostomy dependent. Riboflavin supplementation is a lifesaving intervention for patients with RTD and results in a profound improvement in several functional domains, with early diagnosis and treatment further improving outcomes. Despite treatment, patients are left with residual disability. There is a need to accurately measure functional outcomes in children with RTD and develop additional disease-modifying therapies.

核黄素转运蛋白缺乏症(RTD)是一种儿童期发病的进行性遗传性神经病变,其特征为桥脑麻痹、感音神经性耳聋、感觉共济失调、肌肉无力、视神经萎缩和呼吸衰竭。补充核黄素在短期报告中是有益的,但在各种临床领域的获益量尚不清楚。PubMed进行了检索,确定了94例基因确诊的RTD病例,他们接受了核黄素补充并进行了随访评估。收集和分析补充核黄素前后的临床和功能状况。94例患者中有76例(80.9%)在补充核黄素后表现出总体改善,其余(19.1%)表现稳定,尽管一些患者在个别领域出现恶化,未报告死亡。补充核黄素反应率最高的领域是大运动功能(改善93.3%)、球性麻痹(改善91.3%)和共济失调(改善90.0%)。肢体肌肉无力、听力学、面神经麻痹和呼吸功能也有改善。尽管进行了治疗,但许多患者需要辅助行走,并有严重或深度听力损失,一些患者仍然依赖胃造口术或气管造口术。补充核黄素对RTD患者来说是一种挽救生命的干预措施,可以显著改善几个功能领域,早期诊断和治疗可以进一步改善预后。尽管进行了治疗,患者仍会留下残障。有必要准确地测量RTD儿童的功能结局,并开发额外的疾病改善疗法。
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引用次数: 0
Quantitative sensory testing and skin biopsy findings in late-onset ATTRv presymptomatic carriers: Relationships with predicted time of disease onset (PADO) 迟发性atv症状前携带者的定量感觉测试和皮肤活检结果:与预测发病时间(PADO)的关系
IF 3.8 3区 医学 Q1 Medicine Pub Date : 2023-08-03 DOI: 10.1111/jns.12586
Luca Leonardi, Rocco Costanzo, Francesca Forcina, Stefania Morino, Giovanni Antonini, Marco Salvetti, Marco Luigetti, Angela Romano, Guido Primiano, Valeria Guglielmino, Laura Fionda, Matteo Garibaldi, Antonio Lauletta, Elena Rossini, Laura Tufano, Marco Ceccanti, Nicoletta Esposito, Pietro Falco, Giuseppe di Pietro, Andrea Truini, Eleonora Galosi
Hereditary transthyretin amyloidosis polyneuropathy (ATTRv‐PN) presymptomatic carriers often show preclinical abnormalities at small fiber‐related diagnostic tests. However, no validated biomarker is currently available to use for presymptomatic carriers' follow‐up, thus helping therapeutic decision making. Our study aimed at assessing nerve conduction study (NCS), quantitative sensory testing (QST), and skin biopsy parameters in a large cohort of late‐onset ATTRv presymptomatic carriers and to evaluate whether they correlated with predicted age of disease onset (PADO).
遗传性甲状腺转蛋白淀粉样变性多神经病变(ATTRv-PN)症状前携带者在小纤维相关诊断试验中经常表现出临床前异常。然而,目前还没有经过验证的生物标志物可用于症状前携带者的随访,从而帮助治疗决策。本研究旨在评估一大批迟发性ATTRv症状前携带者的神经传导研究(NCS)、定量感觉测试(QST)和皮肤活检参数,并评估它们是否与预测发病年龄(PADO)相关。方法连续招募迟发性atv症状前携带者,进行NCS、QST和皮肤活检,并从远端和近端评估表皮内神经纤维密度(IENFD)。采用双神经病变-4 (DN4)和小纤维神经病变-症状量表(SFN-SIQ)评估疼痛和小纤维神经病变相关症状。估计每个携带者的PADO和到达PADO的时间(delta-PADO),并分析与诊断测试措施的相关性。结果入选症状前ATTRv受试者40例。20名携带者(50%)远端IENFD减少,73%的病例具有非长度依赖性分布。11名受试者(27.5%)在QST有冷和/或热检测阈值(CDT和/或WDT)异常。δ - pado与腓肠感觉神经动作电位(SNAP)振幅正相关(r =。416, p = .004),而CDT等QST参数的z值(r =。314, p = 0.028), WDT (r =−。294, p = 0.034),机械检测阈值(MDT;r =−。382, p = .012)。简单线性回归模型显示δ - pado与患者SAP、CDT、MDT呈线性关系。结论:我们的研究结果证实,在ATTRv症状前携带者中,IENFD减少和QST异常可能发生在早期,通常具有非长度依赖模式。然而,只有总体SAP振幅和QST参数与delta-PADO相关,提示连续联合QST和NCS评估可用于atv症状前携带者的随访。
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引用次数: 2
Evidence for spontaneous regulation of the humoral IgM anti-GM1 autoimmune response by IgG antibodies in multifocal motor neuropathy patients 多灶性运动神经病变患者体液IgM抗gm1自身免疫反应自发调节的证据
IF 3.8 3区 医学 Q1 Medicine Pub Date : 2023-07-27 DOI: 10.1111/jns.12583
Marianna Di Egidio, Cristian R. Bacaglio, Rocio Arrejoría, Andrés M. Villa, Gustavo A. Nores, Pablo H. H. Lopez

Background and Aims

Multifocal motor neuropathy (MMN) is a peripheral nerve disorder characterized by slow progressive distal asymmetric weakness with minimal or no sensory impairment. Currently, a vast evidence supports a direct pathogenic role of IgM anti-GM1 antibodies on disease pathogenesis. Patients with MMN seropositive for GM1-specific IgM antibodies have significantly more weakness, disability and axon loss than patients without these antibodies. During the screening for IgM anti-GM1 antibodies in a cohort of patients with neuropathy we noticed an absence or significant reduction of natural IgM anti-GM1 autoreactivity in some patients with MMN, suggesting a mechanism of self-control of autoreactivity. We aim to understand the lack of natural reactivity against GM1 in MMN patients.

Methods

The presence of free IgM anti-GM1 reactivity or its complex to blocking IgG was analysed by combining high performance thin layer chromatography-immunostaining, soluble binding inhibition assays, Protein-G or GM1-affinity columns and dot blot assays.

Results

We identified in MMN patients an immunoregulation of IgM anti-GM1 antibodies mediated by IgG immunoglobulins characterized by: (i) lack of natural IgM anti-GM1 autoreactivity as a result of a immunoregulatory IgG-dependent mechanism; (ii) presence of natural and disease-associated IgM anti-GM1/IgG blocking Ab complexes in sera; and (iii) high levels of IgG blocking against natural IgM anti-GM1 antibodies (Abs.

Interpretation

Our observations unmask a spontaneous IgG-dependent mechanism of immunoregulation against IgM anti-GM1 antibodies that could explain, in part, fluctuations in the usually slowly progressive clinical course that characterizes the disease and, at the same time, allows the identification of an autoimmune response against GM1 ganglioside in seronegative patients.

背景和目的多灶性运动神经病(MMN)是一种以缓慢进行性远端不对称无力为特征的周围神经疾病,伴有轻微或无感觉损伤。目前,大量证据支持IgM抗gm1抗体在疾病发病机制中的直接致病作用。MMN血清中gm1特异性IgM抗体阳性的患者比没有这些抗体的患者有更多的虚弱、残疾和轴突损失。在一组神经病变患者中筛选IgM抗gm1抗体时,我们注意到在一些MMN患者中IgM抗gm1天然自身反应性缺失或显著降低,提示自身反应性的自我控制机制。我们的目的是了解MMN患者缺乏对GM1的天然反应性。方法采用高效薄层色谱-免疫染色法、可溶性结合抑制法、Protein-G或gm1亲和柱法和点印迹法,分析游离IgM抗gm1或其复合物对阻断IgG的反应性。结果我们在MMN患者中发现了IgG免疫球蛋白介导的IgM抗gm1抗体的免疫调节,其特点是:(i)由于免疫调节IgG依赖机制而缺乏天然的IgM抗gm1自身反应性;(ii)血清中存在天然的和与疾病相关的IgM抗gm1 /IgG阻断Ab复合物;(iii)对天然IgM抗gm1抗体(Abs)的高水平IgG阻断。解释我们的观察揭示了针对IgM抗gm1抗体的自发IgG依赖的免疫调节机制,该机制可以部分解释通常缓慢进展的临床过程的波动,这是该疾病的特征。允许在血清阴性患者中识别针对GM1神经节苷脂的自身免疫反应。
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引用次数: 0
Differences in the ultrastructure of neurons in the spinal ganglion and dorsal rootlet between rats treated with cisplatin only versus co-administration with a sphingosine 1-phosphate receptor 2 agonist in attenuating neuropathy and allodynia 单用顺铂与联用鞘氨醇1-磷酸受体2激动剂减轻神经病变和异常性疼痛大鼠脊髓神经节和背根神经元超微结构差异
IF 3.8 3区 医学 Q1 Medicine Pub Date : 2023-07-22 DOI: 10.1111/jns.12582
Kanokporn Chayaburakul, Wei Yi Ong, Deron R. Herr, Phetnarin Kobutree, Kraisri Chantra

Background and Aims

Cisplatin is a chemotherapeutic agent for many types of cancer. The neurotoxicity of cisplatin includes neuropathy and allodynia. We aimed to study structural changes by using CYM54-78, attenuating cisplatin-induced neuropathy and blocking the pathogenesis in neurons, and promoting axonal regeneration.

Methods

TEM (transmission electron microscopy) was used to distinguish ultrastructural changes in dorsal root ganglion (DRG) and dorsal rootlets (DR) between rats treated with cisplatin alone and rats co-treated with cisplatin and sphingosine -1-phosphate receptor2 (S1P2) agonist, CYM-5478.

Results

In DRG of rats treated with cisplatin alone, TEM micrographs showed necrosis and apoptotic cells. Neuronal cytoplasm showed numerous vacuole (stage C) and swelling (stage B➔C) mitochondrial degeneration. Neurons in DRG from cisplatin+CYM-5478 group showed a higher percentage of healthy mitochondria (from 5.3% to 75.6%) than those treated with cisplatin alone. DR of cisplatin only group showed abnormal axoplasm, axolemma, and focal detached myelin sheaths, especially in Aδ (fast pain) and Aβ (touch) fibers, and revealed collateral branches that sprouted from Aβ fibers, which is characteristic of allodynia. Moreover, vasoconstriction was observed in DRG and DR. Rats in cisplatin+CYM-5478 group showed not only fewer abnormal structures than those in cisplatin only group, but also showed Bands of Büngner and onion bulb-like structures, which are characteristic of nerve regeneration.

Interpretation

Together with our previous study, showed that CYM-5478 attenuated neuropathy and allodynia in a rat model of cisplatin-induced neuropathy, these results suggest S1P2 agonists as a potential approach the for treatment of cancer due to the reduction of side effects of cisplatin.

背景与目的顺铂是一种治疗多种癌症的化疗药物。顺铂的神经毒性包括神经病变和异常性疼痛。我们的目的是研究CYM54-78的结构变化,减轻顺铂诱导的神经病变,阻断神经元的发病机制,促进轴突再生。方法采用透射电镜(TEM)观察顺铂单用和与鞘氨醇-1-磷酸受体2 (S1P2)激动剂CYM-5478联用大鼠背根神经节(DRG)和背根小管(DR)超微结构的变化。结果单用顺铂处理大鼠DRG后,透射电镜观察到细胞坏死和凋亡。神经元细胞质显示大量液泡(C期)和肿胀(B期)线粒体变性。顺铂+CYM-5478组DRG神经元的健康线粒体百分比(从5.3%到75.6%)高于单独顺铂组。单用顺铂组DR表现为轴质、轴膜、局灶性髓鞘异常,特别是Aδ(快痛)纤维和Aβ(触)纤维异常,并可见Aβ纤维长出侧支,为异位性痛的特征。同时,DRG和dr血管收缩,顺铂+CYM-5478组大鼠不仅异常结构少于单顺铂组,而且还出现了神经再生特征的带状带状结构和洋葱鳞茎样结构。结合我们之前的研究表明,CYM-5478在顺铂诱导的神经病变大鼠模型中减轻了神经病变和异常性疼痛,这些结果表明,由于减少了顺铂的副作用,S1P2激动剂可能成为治疗癌症的潜在途径。
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引用次数: 0
期刊
Journal of the Peripheral Nervous System
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