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Increase in Full-Length Dystrophin by Exon Skipping in Duchenne Muscular Dystrophy Patients with Single Exon Duplications: An Open-label Study. 单外显子重复的杜兴氏肌肉萎缩症患者通过外显子缺失增加全长肌营养不良蛋白:一项开放标签研究
IF 3.2 4区 医学 Q2 Medicine Pub Date : 2024-01-01 DOI: 10.3233/JND-230107
Stefan Nicolau, Jyoti Malhotra, Maryann Kaler, Pamela Magistrado-Coxen, Megan A Iammarino, Natalie F Reash, Emma C Frair, Saranga Wijeratne, Benjamin J Kelly, Peter White, Linda P Lowes, Megan A Waldrop, Kevin M Flanigan

Single exon duplications account for disease in a minority of Duchenne muscular dystrophy patients. Exon skipping in these patients has the potential to be highly therapeutic through restoration of full-length dystrophin expression. We conducted a 48-week open label study of casimersen and golodirsen in 3 subjects with an exon 45 or 53 duplication. Two subjects (aged 18 and 23 years) were non-ambulatory at baseline. Upper limb, pulmonary, and cardiac function appeared stable in the 2 subjects in whom they could be evaluated. Dystrophin expression increased from 0.94 % ±0.59% (mean±SD) of normal to 5.1% ±2.9% by western blot. Percent dystrophin positive fibers also rose from 14% ±17% at baseline to 50% ±42% . Our results provide initial evidence that the use of exon-skipping drugs may increase dystrophin levels in patients with single-exon duplications.

单外显子重复是少数杜氏肌营养不良症患者患病的原因。通过恢复全长肌营养不良蛋白的表达,这些患者的外显子跳越具有很强的治疗潜力。我们对3名患有外显子45或53重复的受试者进行了为期48周的卡西美森和戈洛迪森开放标签研究。两名受试者(年龄分别为 18 岁和 23 岁)基线时不能行走。在可以进行评估的两名受试者中,上肢、肺部和心脏功能似乎都很稳定。通过 Western 印迹,肌营养不良蛋白的表达从正常值的 0.94% ±0.59%(平均值±SD)增加到 5.1% ±2.9%。肌营养不良蛋白阳性纤维的百分比也从基线时的 14% ±17% 上升到 50% ±42% 。我们的研究结果提供了初步证据,证明使用外显子切割药物可提高单外显子重复患者的肌营养不良素水平。
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引用次数: 0
Break Down of the Complexity and Inconsistency Between Levels of Matriglycan and Disease Phenotype in FKRP-Related Dystroglycanopathies: A Review and Model of Interpretation. 打破 FKRP 相关肌营养不良症中 Matriglycan 水平与疾病表型之间的复杂性和不一致性:回顾与解释模型。
IF 3.3 4区 医学 Q2 Medicine Pub Date : 2024-01-01 DOI: 10.3233/JND-230205
Qi L Lu, Molly C Holbrook, Marcela P Cataldi, Anthony Blaeser

Dystroglycanopathies are a group of muscle degenerative diseases characterized with significant reduction in matriglycan expression critical in disease pathogenesis. Missense point mutations in the Fukutin-related protein (FKRP) gene cause variable reduction in the synthesis of matriglycan on alpha-dystroglycan (α-DG) and a wide range of disease severity. Data analyses of muscle biopsies from patients fail to show consistent correlation between the levels of matriglycan and clinical phenotypes. By reviewing clinical reports in conjunction with analysis of clinically relevant mouse models, we identify likely causes for the confusion. Nearly all missense FKRP mutations retain variable, but sufficient function for the synthesis of matriglycan during the later stage of muscle development and periods of muscle regeneration. These factors lead to a highly heterogenous pattern of matriglycan expression in diseased muscles, depending on age and stages of muscle regeneration. The limited size in clinical biopsy samples from different parts of even a single muscle tissue at different time points of disease progression may well mis-represent the residual function (base-levels) of the mutated FKRPs and phenotypes. We propose to use a simple Multi Point tool from ImageJ to more accurately measure the signal intensity of matriglycan expression on fiber membrane for assessing mutant FKRP function and therapeutic efficacy. A robust and sensitive immunohistochemical protocol would further improve reliability and comparability for the detection of matriglycan.

肌营养不良性疾病是一组肌肉退行性疾病,其特点是在疾病发病机制中关键性的 matriglycan 表达明显减少。Fukutin 相关蛋白(FKRP)基因中的错义点突变会导致α-肌收缩蛋白(α-DG)上的 matriglycan 合成量不同程度地减少,疾病的严重程度也有很大差异。对患者肌肉活检的数据分析未能显示 matriglycan 水平与临床表型之间存在一致的相关性。通过回顾临床报告并结合临床相关小鼠模型的分析,我们找出了造成混淆的可能原因。几乎所有的 FKRP 错义突变都保留了在肌肉发育后期和肌肉再生期合成 matriglycan 的不同但足够的功能。这些因素导致病变肌肉中 matriglycan 的表达具有高度异质性,具体取决于年龄和肌肉再生阶段。即使是在疾病进展的不同时间点从单个肌肉组织的不同部位采集的临床活检样本,其大小也有限,这很可能会错误地反映突变 FKRP 的残余功能(基底水平)和表型。我们建议使用 ImageJ 的简单多点工具来更准确地测量纤维膜上 matriglycan 表达的信号强度,以评估突变 FKRP 的功能和疗效。稳健灵敏的免疫组化方案将进一步提高检测 matriglycan 的可靠性和可比性。
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引用次数: 0
Methodological Quality of Clinical Trials in Amyotrophic Lateral Sclerosis: A Systematic Review. 肌萎缩侧索硬化症临床试验的方法学质量:系统性综述。
IF 3.2 4区 医学 Q2 CLINICAL NEUROLOGY Pub Date : 2024-01-01 DOI: 10.3233/JND-230217
Elisabetta Pupillo, Ammar Al-Chalabi, Serena Sassi, Emilio Arippol, Lorenzo Tinti, Eugenio Vitelli, Massimiliano Copetti, Maurizio A Leone, Elisa Bianchi

Background: More than 200 clinical trials have been performed worldwide in ALS so far, but no agents with substantial efficacy on disease progression have been found.

Objective: To describe the methodological quality of all clinical trials performed in ALS and published before December 31, 2022.

Methods: We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta Analyses.

Results: 213 trials were included. 47.4% manuscripts described preclinical study evaluation, with a positive effect in all. 67.6% of trials were conducted with a parallel-arm design, while 12.7% were cross-over studies; 77% were randomized, while in 5.6% historical-controls were used for comparison. 70% of trials were double blind. Participant inclusion allowed forced vital capacity (or corresponding slow vital capacity)<50% in 15% cases, between 55-65% in 21.6%, between 70-80% in 14.1% reports, and 49.3% of the evaluated manuscripts did not provide a minimum value for respiratory capacity at inclusion. Disease duration was < 6-months in 6 studies, 7-36 months in 68, 37-60 months in 24, 8 trials requested more than 1-month of disease duration, while in 107 reports a disease duration was not described. Dropout rate was ≥20% in 30.5% trials, while it was not reported for 8.5%.

Conclusion: The methodological quality of the included studies was highly variable. Major issues to be addressed in future ALS clinical trials include: the requirement for standard animal toxicology and phase I studies, the resource-intensive nature of phase II-III studies, adequate study methodology and design, a good results reporting.

背景:迄今为止,全球已进行了200多项ALS临床试验,但尚未发现对疾病进展有实质性疗效的药物:描述 2022 年 12 月 31 日之前发表的所有 ALS 临床试验的方法学质量:结果:共纳入 213 项试验。47.4%的手稿描述了临床前研究评估,所有研究均取得了积极效果。67.6%的试验采用平行臂设计,12.7%为交叉研究;77%为随机试验,5.6%采用历史对照进行比较。70%的试验为双盲试验。纳入的参与者均具有强制生命容量(或相应的缓慢生命容量):纳入研究的方法质量差异很大。未来 ALS 临床试验需要解决的主要问题包括:标准动物毒理学和 I 期研究的要求、II-III 期研究的资源密集性、适当的研究方法和设计以及良好的结果报告。
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引用次数: 0
Quantitative muscle MRI in sporadic inclusion body myositis (sIBM): A prospective cohort study. 散发性包涵体肌炎(sIBM)的定量肌肉磁共振成像:前瞻性队列研究
IF 3.2 4区 医学 Q2 CLINICAL NEUROLOGY Pub Date : 2024-01-01 DOI: 10.3233/JND-240053
Lara Schlaffke, Robert Rehmann, Martijn Froeling, Anne-Katrin Güttsches, Matthias Vorgerd, Elena Enax-Krumova, Johannes Forsting

Background: Sporadic inclusion body myositis (sIBM) is the predominant idiopathic inflammatory myopathy (IIM) in older people. Limitations of classical clinical assessments have been discussed as possible explanations for failed clinical trials, underlining the need for more sensitive outcome measures. Quantitative muscle MRI (qMRI) is a promising candidate for evaluating and monitoring sIBM.

Objective: Longitudinal assessment of qMRI in sIBM patients.

Methods: We evaluated fifteen lower extremity muscles of 12 sIBM patients (5 females, mean age 69.6, BMI 27.8) and 12 healthy age- and gender-matched controls. Seven patients and matched controls underwent a follow-up evaluation after one year. Clinical assessment included testing for muscle strength with Quick Motor Function Measure (QMFM), IBM functional rating scale (IBM-FRS), and gait analysis (6-minute walking distance). 3T-MRI scans of the lower extremities were performed, including a Dixon-based sequence, T2 mapping and Diffusion Tensor Imaging. The qMRI-values fat-fraction (FF), water T2 relaxation time (wT2), fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (λ1), and radial diffusivity (RD) were analysed.

Results: Compared to healthy controls, significant differences for all qMRI parameters averaged over all muscles were found in sIBM using a MANOVA (p < 0.001). In low-fat muscles (FF < 10%), a significant increase of wT2 and FA with an accompanying decrease of MD, λ1, and RD was observed (p≤0.020). The highest correlation with clinical assessments was found for wT2 values in thigh muscles (r≤-0.634). Significant changes of FF (+3.0%), wT2 (+0.6 ms), MD (-0.04 10-3mm2/s), λ1 (-0.05 10-3mm2/s), and RD (-0.03 10-3mm2/s) were observed in the longitudinal evaluation of sIBM patients (p≤0.001). FA showed no significant change (p = 0.242).

Conclusion: qMRI metrics correlate with clinical findings and can reflect different ongoing pathophysiological mechanisms. While wT2 is an emerging marker of disease activity, the role of diffusion metrics, possibly reflecting changes in fibre size and intracellular deposits, remains subject to further investigations.

背景:散发性包涵体肌炎(sIBM)是老年人最主要的特发性炎症性肌病(IIM)。传统临床评估的局限性被认为是临床试验失败的可能原因,这强调了对更敏感的结果测量的需求。定量肌肉磁共振成像(qMRI)是评估和监测sIBM的一个有前途的候选方法:方法:我们对 15 名下肢肌肉萎缩症患者进行了评估:我们评估了 12 名 sIBM 患者(5 名女性,平均年龄 69.6 岁,体重指数 27.8)和 12 名年龄和性别匹配的健康对照者的 15 块下肢肌肉。7 名患者和匹配对照组在一年后接受了随访评估。临床评估包括快速运动功能测量法(QMFM)肌力测试、IBM功能评分量表(IBM-FRS)和步态分析(6分钟步行距离)。对下肢进行了 3T-MRI 扫描,包括基于狄克逊序列、T2 映射和弥散张量成像。对qMRI值脂肪分数(FF)、水T2弛豫时间(wT2)、分数各向异性(FA)、平均扩散率(MD)、轴向扩散率(λ1)和径向扩散率(RD)进行了分析:结论:qMRI 指标与临床发现相关,可反映不同的持续病理生理机制。虽然 wT2 是疾病活动性的新兴标志物,但弥散指标的作用可能反映纤维大小和细胞内沉积物的变化,仍有待进一步研究。
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引用次数: 0
Nociceptive Pain in Patients with Neuromuscular Disorders: A Cross-Sectional Clinical Study. 神经肌肉疾病患者的痛觉疼痛--一项横断面临床研究。
IF 3.2 4区 医学 Q2 CLINICAL NEUROLOGY Pub Date : 2024-01-01 DOI: 10.3233/JND-240068
Elena Sagerer, Corinna Wirner-Piotrowski, Marko Mijic, Marcela Arndt, Natalia Garcia-Angarita, Benedikt Schoser, Stephan Wenninger

Background: Muscle pain is a common symptom in patients with neuromuscular disorders (NMD) and accounts for severely reduced quality of life. OBJECTIVE: This clinical study aimed to observe possible differences in pain prevalence among distinct NMDs and to determine whether the patients' nociceptive pain is influenced by gender, muscle strength and psychological factors and to examine potential pain-associated alterations in muscle properties.

Methods: The cross-sectional study on nociceptive pain in various NMDs involved patient-reported outcomes, muscle strength evaluations (dynamometry and quick motor function test (QMFT)), nociceptive pain evaluations (muscular pressure pain threshold (PPT)), and non-invasive measurement of muscle stiffness, frequency, decrement, relaxation, and creep (myotonometry).

Results: Involving 81 NMD patients and a control group, the study found high variability in pain prevalence among the subgroups. Patients with DM2 and FSHD had significantly higher levels of pain prevalence compared to other examined NMD subgroups and the control group. Female gender, high fatigue levels (representing factors such as depression, anxiety, stress, and impairment of quality of life), and low QMFT scores (representing reduced muscle strength) showed an association with increased sensitivity to pressure pain in the arm and leg region. As assessed by myotonometry, less pain is experienced in neck muscles with a high muscle tone, high stiffness, and a short relaxation time highlighting the importance of intrinsic muscular tone for their pressure pain sensitivity.

Conclusion: Individualized therapeutic concepts including psychological and physical approaches in the pain management of patients with NMDs, especially in women, should be considered. Further research in this field is necessary to gain a more detailed insight into the perception of muscle pain.

背景:肌肉疼痛是神经肌肉疾病(NMD)患者的常见症状,严重降低了患者的生活质量。目的:这项临床研究旨在观察不同 NMD 患者的疼痛发生率可能存在的差异,确定患者的痛觉疼痛是否受性别、肌肉力量和心理因素的影响,并检查肌肉特性中可能与疼痛相关的改变:这项关于不同 NMD 患者痛觉疼痛的横断面研究涉及患者报告结果、肌力评估(测力法和快速运动功能测试 (QMFT))、痛觉疼痛评估(肌肉压力痛阈值 (PPT))以及肌肉僵硬度、频率、减弱、松弛和蠕动的非侵入性测量(肌张力测定法):该研究涉及 81 名 NMD 患者和一个对照组,发现不同亚组的疼痛发生率差异很大。与其他接受检查的 NMD 亚组和对照组相比,DM2 和 FSHD 患者的疼痛发生率明显更高。女性性别、高疲劳度(代表抑郁、焦虑、压力和生活质量受损等因素)和低 QMFT 分数(代表肌肉力量减弱)与手臂和腿部对压痛的敏感性增加有关。根据肌张力测定法的评估,肌张力高、僵硬度高、放松时间短的颈部肌肉所感受到的疼痛较轻,这凸显了内在肌肉张力对压痛敏感性的重要性:结论:在对 NMD 患者(尤其是女性患者)进行疼痛治疗时,应考虑包括心理和物理方法在内的个性化治疗理念。有必要在这一领域开展进一步研究,以便更详细地了解肌肉疼痛的感知。
{"title":"Nociceptive Pain in Patients with Neuromuscular Disorders: A Cross-Sectional Clinical Study.","authors":"Elena Sagerer, Corinna Wirner-Piotrowski, Marko Mijic, Marcela Arndt, Natalia Garcia-Angarita, Benedikt Schoser, Stephan Wenninger","doi":"10.3233/JND-240068","DOIUrl":"10.3233/JND-240068","url":null,"abstract":"<p><strong>Background: </strong>Muscle pain is a common symptom in patients with neuromuscular disorders (NMD) and accounts for severely reduced quality of life. OBJECTIVE: This clinical study aimed to observe possible differences in pain prevalence among distinct NMDs and to determine whether the patients' nociceptive pain is influenced by gender, muscle strength and psychological factors and to examine potential pain-associated alterations in muscle properties.</p><p><strong>Methods: </strong>The cross-sectional study on nociceptive pain in various NMDs involved patient-reported outcomes, muscle strength evaluations (dynamometry and quick motor function test (QMFT)), nociceptive pain evaluations (muscular pressure pain threshold (PPT)), and non-invasive measurement of muscle stiffness, frequency, decrement, relaxation, and creep (myotonometry).</p><p><strong>Results: </strong>Involving 81 NMD patients and a control group, the study found high variability in pain prevalence among the subgroups. Patients with DM2 and FSHD had significantly higher levels of pain prevalence compared to other examined NMD subgroups and the control group. Female gender, high fatigue levels (representing factors such as depression, anxiety, stress, and impairment of quality of life), and low QMFT scores (representing reduced muscle strength) showed an association with increased sensitivity to pressure pain in the arm and leg region. As assessed by myotonometry, less pain is experienced in neck muscles with a high muscle tone, high stiffness, and a short relaxation time highlighting the importance of intrinsic muscular tone for their pressure pain sensitivity.</p><p><strong>Conclusion: </strong>Individualized therapeutic concepts including psychological and physical approaches in the pain management of patients with NMDs, especially in women, should be considered. Further research in this field is necessary to gain a more detailed insight into the perception of muscle pain.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380240/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141537937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
GNE Myopathy: Genotype - Phenotype Correlation and Disease Progression in an Indian Cohort. GNE 肌病:印度队列中基因型与表型的相关性和疾病进展
IF 3.2 4区 医学 Q2 CLINICAL NEUROLOGY Pub Date : 2024-01-01 DOI: 10.3233/JND-230130
Dipti Baskar, Nishanth Reddy, Veeramani Preethish-Kumar, Kiran Polavarapu, Vikas Nishadham, Seena Vengalil, Saraswati Nashi, Sai Bhargava Sanka, Mainak Bardhan, Akshata Huddar, Gopikrishnan Unnikrishnan, Ganaraja Valakunja Harikrishna, Swetha Gunasekaran, Priya Treesa Thomas, Muddasu Suhasini Keerthipriya, Manu Santhappan Girija, Gautham Arunachal, Ram Murthy Anjanappa, Ichizo Nishino, Oksana Pogoryelova, Hanns Lochmuller, Atchayaram Nalini

Introduction: GNE myopathy is a rare slowly progressive adult-onset distal myopathy with autosomal recessive inheritance. It has distinctive features of quadriceps sparing with preferential anterior tibial involvement. Most patients eventually become wheelchair bound by 10-20 years after onset. This study analyzes the phenotype-genotype characteristics and disease progression in a large cohort of GNEM patients from India.

Materials and methods: Retrospective observational study on GNEM from a quaternary neurology referral hospital in southern India. Data was collected from clinical phenotyping, serum creatine kinase levels, muscle biopsy histopathology, genetic analysis and functional assessment scales - IBMFRS and MDFRS.

Results: 157 patients were included with mean age at onset and diagnosis: 26.5±6.2 years and 32.8±7.8 years, respectively. M:F ratio was 25 : 13. Most common presenting symptom: foot drop (46.5%) and limb girdle weakness (19.1%). Wasting and weakness of small muscles of hand and finger flexors seen in 66.2% and as an initial symptoms in 5.2%. Though tibialis anterior involvement was most common (89.2%), early quadriceps weakness was noted in 3.2% and Beevor's sign in 59.2%. Rimmed vacuoles were present in 75% of patients with muscle biopsy. Most common variant was the Indian Founder variant identified in 129 patients (c.2179 G>A, p.Val727Met - 82.2%) and most common zygosity being compound heterozygous state (n = 115, 87.5%). Biallelic kinase domain variations predisposed to a more severe phenotype. Wheelchair bound state noted in 8.9% with a mean age and duration of 32.0±7.1 and 6.3±4.9 years respectively, earlier than previous studies on other ethnic groups.

Conclusion: This is the largest GNEM cohort reported from South Asia. The p.Val727Met variant in compound heterozygous state is noted in majority (82.2%) of the cases. Observed relationships between genotype and clinical parameters shows that severity of the disease might be attributable to specific GNE genotype and thus could aid in predicting the disease progression.

导言GNE 肌病是一种罕见的缓慢进展型成人发病远端肌病,具有常染色体隐性遗传性。它的显著特征是股四头肌受累,胫骨前肌优先受累。大多数患者最终会在发病后 10-20 年坐上轮椅。本研究分析了来自印度的一大批 GNEM 患者的表型-基因型特征和疾病进展情况:对印度南部一家四级神经病学转诊医院的 GNEM 患者进行回顾性观察研究。通过临床表型、血清肌酸激酶水平、肌肉活检组织病理学、基因分析和功能评估量表(IBMFRS 和 MDFRS)收集数据:结果:共纳入 157 名患者,发病和确诊时的平均年龄分别为(26.5±6.2)岁和(32.8±7.8)岁。男女比例为 25 :13.最常见的症状:足下垂(46.5%)和四肢无力(19.1%)。66.2%的患者会出现手部小肌肉和屈指肌萎缩和无力,5.2%的患者会以手部小肌肉和屈指肌萎缩和无力为首发症状。胫骨前肌受累最常见(89.2%),3.2%的患者早期出现股四头肌无力,59.2%的患者出现贝弗氏征。75%的肌肉活检患者存在边缘空泡。最常见的变异是在129名患者中发现的印度创始人变异(c.2179 G>A,p.Val727Met-82.2%),最常见的杂合状态是复合杂合状态(n = 115,87.5%)。双复制激酶域变异易导致更严重的表型。8.9%的患者处于坐轮椅状态,平均年龄(32.0±7.1)岁,平均病程(6.3±4.9)年,早于以往对其他种族群体的研究:结论:这是南亚地区报告的最大的 GNEM 群体。大多数病例(82.2%)的p.Val727Met变异为复合杂合状态。基因型与临床参数之间的关系表明,疾病的严重程度可能与特定的 GNE 基因型有关,因此有助于预测疾病的进展。
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引用次数: 0
Gene Distribution in Pediatric-Onset Inherited Peripheral Neuropathy: A Single Tertiary Center in Thailand. 儿童发病遗传性周围神经病变的基因分布:泰国的一个单一的三级中心。
IF 3.3 4区 医学 Q2 Medicine Pub Date : 2024-01-01 DOI: 10.3233/JND-230174
Pimchanok Kulsirichawaroj, Yanin Suksangkharn, Da Eun Nam, Theeraphong Pho-Iam, Chanin Limwongse, Ki Wha Chung, Oranee Sanmaneechai, Stephan L Zuchner, Byung-Ok Choi

Background: Inherited peripheral neuropathy presents a diagnostic and therapeutic challenge due to its association with mutations in over 100 genes. This condition leads to long-term disability and poses a substantial healthcare burden on society.

Objective: This study aimed to investigate the distribution of genes and establish the genotype-phenotype correlations, focusing on pediatric-onset cases.

Methods: Exome sequencing and other analytical techniques were employed to identify pathogenic variants, including duplication analysis of the PMP22 gene. Each patient underwent physical examination and electrophysiological studies. Genotypes were correlated with phenotypic features, such as age at disease onset and ulnar motor nerve conduction velocity.

Results: We identified 35 patients with pediatric-onset inherited peripheral neuropathy. Pathogenic or likely pathogenic variants were confirmed in 24 out of 35 (68.6%) patients, with 4 of these variants being novel. A confirmed molecular diagnosis was achieved in 90.9% (10/11) of patients with demyelinating Charcot-Marie-Tooth disease (CMT) and 56.3% (9/16) of patients with axonal CMT. Among patients with infantile-onset CMT (≤2 years), the most common causative genes were MFN2 and NEFL, while GDAP1 and MFN2 were frequent causes among patients with childhood- or adolescent-onset CMT (3-9 years).

Conclusions: The MFN2 gene was the most commonly implicated gene, and the axonal type was predominant in this cohort of Thai patients with pediatric-onset inherited peripheral neuropathy.

背景:遗传性周围神经病变由于与100多个基因突变有关,在诊断和治疗方面面临挑战。这种情况会导致长期残疾,并给社会带来巨大的医疗负担。目的:本研究旨在研究儿童发病病例的基因分布,建立基因型-表型相关性。方法:采用外显子组测序和其他分析技术鉴定致病性变异,包括PMP22基因的重复分析。每位患者都接受了身体检查和电生理学研究。基因型与表型特征相关,如发病年龄和尺骨运动神经传导速度。结果:我们确定了35例儿童遗传性周围神经病变患者。35名患者中有24名(68.6%)确诊了致病性或可能的致病性变异,其中4名为新变异。90.9%(10/11)的脱髓鞘Charcot-Marie Tooth病(CMT)患者和56.3%(9/16)的轴突CMT患者获得了确诊的分子诊断。在婴儿期CMT(≤2岁)患者中,最常见的致病基因是MFN2和NEFL,而在儿童或青少年期CMT(3-9年)患者中GDAP1和MFN2是最常见的病因,并且轴突型在这组患有儿童遗传性周围神经病变的泰国患者中占主导地位。
{"title":"Gene Distribution in Pediatric-Onset Inherited Peripheral Neuropathy: A Single Tertiary Center in Thailand.","authors":"Pimchanok Kulsirichawaroj, Yanin Suksangkharn, Da Eun Nam, Theeraphong Pho-Iam, Chanin Limwongse, Ki Wha Chung, Oranee Sanmaneechai, Stephan L Zuchner, Byung-Ok Choi","doi":"10.3233/JND-230174","DOIUrl":"10.3233/JND-230174","url":null,"abstract":"<p><strong>Background: </strong>Inherited peripheral neuropathy presents a diagnostic and therapeutic challenge due to its association with mutations in over 100 genes. This condition leads to long-term disability and poses a substantial healthcare burden on society.</p><p><strong>Objective: </strong>This study aimed to investigate the distribution of genes and establish the genotype-phenotype correlations, focusing on pediatric-onset cases.</p><p><strong>Methods: </strong>Exome sequencing and other analytical techniques were employed to identify pathogenic variants, including duplication analysis of the PMP22 gene. Each patient underwent physical examination and electrophysiological studies. Genotypes were correlated with phenotypic features, such as age at disease onset and ulnar motor nerve conduction velocity.</p><p><strong>Results: </strong>We identified 35 patients with pediatric-onset inherited peripheral neuropathy. Pathogenic or likely pathogenic variants were confirmed in 24 out of 35 (68.6%) patients, with 4 of these variants being novel. A confirmed molecular diagnosis was achieved in 90.9% (10/11) of patients with demyelinating Charcot-Marie-Tooth disease (CMT) and 56.3% (9/16) of patients with axonal CMT. Among patients with infantile-onset CMT (≤2 years), the most common causative genes were MFN2 and NEFL, while GDAP1 and MFN2 were frequent causes among patients with childhood- or adolescent-onset CMT (3-9 years).</p><p><strong>Conclusions: </strong>The MFN2 gene was the most commonly implicated gene, and the axonal type was predominant in this cohort of Thai patients with pediatric-onset inherited peripheral neuropathy.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10789325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71482614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Impaired Neurodevelopment in Children with 5q-SMA - 2 Years After Newborn Screening. 新生儿筛查后2年5q SMA患儿的神经发育受损。
IF 3.3 4区 医学 Q2 Medicine Pub Date : 2024-01-01 DOI: 10.3233/JND-230136
Heike Kölbel, Marius Kopka, Laura Modler, Astrid Blaschek, Ulrike Schara-Schmidt, Katharina Vill, Oliver Schwartz, Wolfgang Müller-Felber

Objective: Numerous studies have consistently found that reduced SMN protein expression does not severely affect cognitive function in SMA patients. However, the average intelligence quotient of SMA patients has ranged above to below average in different studies. The cognitive development of SMA patients identified through newborn screening remains largely unknown.

Methods: 40 of 47 eligible SMA patients (23 females/17 males) from 39 families identified through newborn screening between January 2018 and December 2020 underwent developmental testing using Bayley III (BSID) after the 2 years of age. The mean age was 29.25 months (23-42 months). 17 patients had 2, 11 patients had 3 and 12 patients had ≥4 copies of SMN2.

Results: cognitive scale: mean 94.55 (SD 24.01); language scale: mean 86.09 (SD 26.41); motor scale: 81.28 (SD 28.07). Overall, the cognitive scales show that 14 children were below average, 20 children were average and 6 children were above average. 10/14 children with below average scores had 2 SMN2 copies. The post-hoc pairwise comparisons showed that the cognition main scale was significantly more sensitive to the number of SMN2 copies than the motor main scale of the BSID (MΔ= 10.27, p = 0.014). There is also evidence that cognition scored higher than the language main scale (MΔ= 7.11, p = 0.090).

Conclusion: The impaired cognitive development of SMA children with 2 SMN2 copies, despite early initiation of therapy, underscores the critical role of the SMN protein in the early stages of brain development.

目的:大量研究一致发现,SMA患者SMN蛋白表达减少不会严重影响认知功能。然而,在不同的研究中,SMA患者的平均智商从高于平均水平到低于平均水平不等。通过新生儿筛查确定的SMA患者的认知发展在很大程度上仍然未知。方法:在2018年1月至2020年12月期间,通过新生儿筛查确定的39个家庭的47名符合条件的SMA患者中,有40名(23名女性/17名男性)在2岁后使用Bayley III(BSID)进行发育测试。平均年龄29.25个月(23-42个月)。SMN2拷贝数≥4者12例,其中2例17例,3例11例。结果:认知量表:平均94.55(SD 24.01);语言量表:平均86.09(SD 26.41);运动量表:81.28(SD 28.07)。总体而言,认知量表显示,14名儿童低于平均水平,20名儿童处于平均水平,6名儿童高于平均水平。得分低于平均水平的儿童有10/14份SMN2拷贝。事后配对比较表明,认知主量表对SMN2拷贝数的敏感性明显高于运动主量表的BSID(MΔ= 10.27,p = 0.014)。也有证据表明认知得分高于语言主量表(MΔ= 7.11,p = 0.090)。结论:尽管早期开始治疗,但2个SMN2拷贝的SMA儿童的认知发展受损,突显了SMN蛋白在大脑发育早期阶段的关键作用。
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引用次数: 0
Antisense Oligonucleotide-Mediated Downregulation of IGFBPs Enhances IGF-1 Signaling. 反义寡核苷酸介导的 IGFBPs 下调可增强 IGF-1 信号传导。
IF 3.3 4区 医学 Q2 Medicine Pub Date : 2024-01-01 DOI: 10.3233/JND-230118
Alper Yavas, Maaike van Putten, Annemieke Aartsma-Rus

Insulin-like growth factor-1 (IGF-1) has been considered as a therapeutic agent for muscle wasting conditions including Duchenne muscular dystrophy as it stimulates muscle regeneration, growth and function. Several preclinical and clinical studies have been conducted to show the therapeutic potential of IGF-1, however, delivery issues, short half-life and isoform complexity have impose challenges. Antisense oligonucleotides (AONs) are able to downregulate target proteins by interfering with their transcripts. Here, we investigated the feasibility of enhancing IGF-1 signaling by downregulation of IGF-binding proteins. We observed that out of frame exon skipping of Igfbp1 and Igfbp3 downregulated their protein expression, which increased Akt phosphorylation on the downstream IGF-1 signaling in vitro. 3'RNA sequencing analysis revealed the related transcriptome in C2C12 cells in response to IGFBP3 downregulation. The AONs did however not induce any exon skipping or protein knockdown in mdx mice after 6 weeks of systemic treatment. We conclude that IGFBP downregulation could be a good strategy to increase IGF-1 signaling but alternative tools are needed for efficient delivery and knockdown in vivo.

胰岛素样生长因子-1(IGF-1)可刺激肌肉再生、生长和功能,因此被认为是包括杜兴氏肌肉萎缩症在内的肌肉萎缩症的治疗药物。目前已进行了多项临床前和临床研究,以显示 IGF-1 的治疗潜力,然而,给药问题、半衰期短和同工酶的复杂性都给研究带来了挑战。反义寡核苷酸(AONs)能够通过干扰靶蛋白的转录本来下调靶蛋白。在这里,我们研究了通过下调 IGF 结合蛋白来增强 IGF-1 信号转导的可行性。我们观察到,Igfbp1 和 Igfbp3 的缺框外显子跳越下调了它们的蛋白表达,从而增加了体外 IGF-1 信号下游的 Akt 磷酸化。3'RNA测序分析揭示了C2C12细胞中相关转录组对IGFBP3下调的反应。然而,经过 6 周的全身治疗后,AONs 并未在 mdx 小鼠体内诱导任何外显子跳转或蛋白敲除。我们得出的结论是,IGFBP 下调可能是增加 IGF-1 信号传导的一个好策略,但要在体内有效传递和敲除 IGFBP,还需要其他工具。
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引用次数: 0
Clinical and Genetic Heterogeneity of Nuclear Envelopathy Related Muscular Dystrophies in an Indian Cohort. 印度队列中核包膜相关肌营养不良症的临床和遗传异质性
IF 3.2 4区 医学 Q2 CLINICAL NEUROLOGY Pub Date : 2024-01-01 DOI: 10.3233/JND-230172
Dipti Baskar, Veeramani Preethish-Kumar, Kiran Polavarapu, Seena Vengalil, Saraswati Nashi, Deepak Menon, Valakunja Harikrishna Ganaraja, Manu Santhappan Girija, Bevinahalli Nanjegowda Nandeesh, Gautham Arunachal, Atchayaram Nalini

Introduction: Nuclear envelopathies occur due to structural and/or functional defects in various nuclear envelope proteins such as lamin A/C and lamin related proteins. This study is the first report on the phenotype-genotype patterns of nuclear envelopathy-related muscular dystrophies from India.

Methods: In this retrospective study, we have described patients with genetically confirmed muscular dystrophy associated with nuclear envelopathy. Data on clinical, laboratory findings and muscle MRI were collected.

Results: Sixteen patients were included with median age at onset of 3 years (range: 1 month - 17 years). Three genes were involved: LMNA (11, 68.75%), EMD (4, 25%) and SYNE1 (1, 6.25%). The 11 patients with LMNA variants were Congenital muscular dystrophy (MDCL)=4, Limb Girdle Muscular Dystrophy (LGMD1B)=4 and Emery-Dreifuss Muscular Dystrophy (EDMD2)=3. On muscle biopsy, one patient from each laminopathy phenotype (n = 3) revealed focal perivascular inflammatory infiltrate. Other notable features were ophthalmoparesis in one and facial weakness in one. None had cardiac involvement. Patients with EDMD1 had both upper (UL) and lower limb (LL) proximo-distal weakness. Cardiac rhythm disturbances such as sick sinus syndrome and atrial arrhythmias were noted in two patients with EDMD1. Only one patient with variant c.654_658dup (EMD) lost ambulation in the 3rd decade, 18 years after disease onset. Two had finger contractures with EMD and SYNE1 variants respectively. All patients with LMNA and SYNE1 variants were ambulant at the time of evaluation. Mean duration of illness (years) was 11.6±13 (MDCL), 3.2±1.0 (EDMD2), 10.4±12.8 (LGMD1B), 11.8±8.4 (EDMD1) and 3 (EDMD4). One patient had a novel SYNE1 mutation (c.22472dupA, exon 123) and presented with UL phenotype and prominent finger and wrist contractures.

Conclusion: The salient features included ophthalmoparesis and facial weakness in LMNA, prominent finger contractures in EMD and SYNE1 and upper limb phenotype with the novel pathogenic variant in SYNE1.

导言:核包膜病是由于各种核包膜蛋白(如层粘连蛋白A/C和层粘连蛋白相关蛋白)的结构和/或功能缺陷引起的。本研究首次报道了印度核包膜病相关肌营养不良症的表型-基因型模式:在这项回顾性研究中,我们描述了经基因证实与核包膜病变相关的肌肉萎缩症患者。我们收集了有关临床、实验室检查结果和肌肉核磁共振成像的数据:共纳入 16 名患者,发病时的中位年龄为 3 岁(范围:1 个月 - 17 岁)。涉及三个基因:LMNA(11 例,占 68.75%)、EMD(4 例,占 25%)和 SYNE1(1 例,占 6.25%)。这11名LMNA变体患者中,先天性肌营养不良症(MDCL)=4人,肢腰肌营养不良症(LGMD1B)=4人,埃默里-德赖福斯肌营养不良症(EDMD2)=3人。在肌肉活检中,每种板层病表型的一名患者(n = 3)都发现有局灶性血管周围炎症浸润。其他值得注意的特征包括:一名患者眼部瘫痪,一名患者面部无力。没有人累及心脏。EDMD1患者既有上肢(UL)无力,也有下肢(LL)近远端无力。两名 EDMD1 患者出现心律紊乱,如病窦综合征和房性心律失常。只有一名变异型c.654_658dup(EMD)患者在发病18年后的第3个10年失去了行动能力。两名分别患有 EMD 和 SYNE1 变体的患者手指挛缩。所有患有LMNA和SYNE1变异型的患者在接受评估时都能行动自如。平均病程(年)为11.6±13(MDCL)、3.2±1.0(EDMD2)、10.4±12.8(LGMD1B)、11.8±8.4(EDMD1)和3(EDMD4)。其中一名患者存在新型SYNE1突变(c.22472dupA,外显子123),表现为UL表型以及突出的手指和手腕挛缩:结论:LMNA的突出特征包括眼瘫和面部无力,EMD和SYNE1的突出手指挛缩,以及SYNE1新型致病变异的上肢表型。
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引用次数: 0
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Journal of neuromuscular diseases
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