Neuromuscular Disorders最新文献_第5页

SRSF2 is upregulated in Duchenne muscular dystrophy and impairs myoblast autophagy by alternatively splicing HUWE1 SRSF2在杜氏肌营养不良症中上调，并通过选择性剪接HUWE1损害成肌细胞自噬

IF 2.8 4区医学 Q2 CLINICAL NEUROLOGY

Neuromuscular Disorders

Pub Date : 2025-10-24 DOI: 10.1016/j.nmd.2025.106254

Pingping Fang , Jingzhe Han , Yuhao Wu , Di An , Yi Bu , Guang Ji , Mingjuan Liu , Jinliang Deng , Xu Han , Hongran Wu , Shaojuan Ma , Xueqin Song

This study aimed to investigate the effect of serine and arginine rich splicing factor 2 (SRSF2) on myoblast autophagy in Duchenne muscular dystrophy (DMD). Protein expressions of SRSF2 and HUWE1, and mRNA expressions of SRSF2, HUWE1 isoform 1/2/3 (HUWE1-S1/S2/S3) were detected in mdx mice (DMD model). SRSF2, HUWE1-S1 and HUWE1-S2 overexpression plasmids, and SRSF2, HUWE1-S1 and HUWE1-S2 siRNAs were transfected into mouse myoblast C2C12 cells alone or in combination. SRSF2, HUWE1-S1, and HUWE1-S2, but not HUWE1-S3, were upregulated in mdx mice compared with control mice. In myoblasts, SRSF2 positively regulated HUWE1-S1 and HUWE1-S2 but less affected HUWE1-S3. RNA immunoprecipitation confirmed that SRSF2 protein directly bound to HUWE1-S1 and HUWE1-S2, but not HUWE1-S3. SRSF2 overexpression reduced myoblast autophagy reflected by lower LC3B(II/I) expression and autophagic flux, while higher p62 expression; however, SRSF2 siRNA revealed opposite effects. Moreover, SRSF2 overexpression decreased while siRNA increased autophagy in dystrophin-deficient myoblasts. HUWE1-S1 overexpression or siRNA did not alter autophagy or attenuated SRSF2’s effect on autophagy in myoblasts. Notably, HUWE1-S2 siRNA improved autophagy in myoblasts, and attenuated SRSF2 overexpression-mediated myoblast autophagy impairment; meanwhile, HUWE1-S2 overexpression revealed opposite effects. Conclusively, SRSF2 is upregulated in DMD mouse model and impairs myoblast autophagy through alterative splicing HUWE1.

本研究旨在探讨富丝氨酸和精氨酸剪接因子2 （SRSF2）对杜氏肌营养不良症（DMD）成肌细胞自噬的影响。mdx小鼠（DMD模型）检测SRSF2、HUWE1蛋白表达，SRSF2、HUWE1异构体1/2/3 (HUWE1- s1 /S2/S3) mRNA表达。将SRSF2、HUWE1-S1和HUWE1-S2过表达质粒以及SRSF2、HUWE1-S1和HUWE1-S2 sirna单独或联合转染小鼠成肌细胞C2C12。与对照小鼠相比，mdx小鼠的SRSF2、HUWE1-S1和HUWE1-S2表达上调，但HUWE1-S3不表达上调。在成肌细胞中，SRSF2正调控HUWE1-S1和HUWE1-S2，但对HUWE1-S3的影响较小。RNA免疫沉淀证实SRSF2蛋白直接与HUWE1-S1和HUWE1-S2结合，但不与HUWE1-S3结合。SRSF2过表达降低成肌细胞自噬，表现为LC3B（II/I）表达和自噬通量降低，而p62表达升高；然而，SRSF2 siRNA显示出相反的作用。此外，SRSF2过表达减少，而siRNA增加了肌营养不良蛋白缺陷的成肌细胞的自噬。HUWE1-S1过表达或siRNA不改变成肌细胞的自噬，也不减弱SRSF2对自噬的影响。值得注意的是，HUWE1-S2 siRNA改善了成肌细胞的自噬，减轻了SRSF2过表达介导的成肌细胞自噬损伤；而HUWE1-S2过表达则表现出相反的作用。综上所述，SRSF2在DMD小鼠模型中上调，并通过HUWE1的选择性剪接损害成肌细胞自噬。

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引用次数: 0

Surgical correction of foot deformities in Charcot-Marie-Tooth-disease: effects on personal goals and gait capacity charcot - marie - tooth病足部畸形的手术矫正：对个人目标和步态能力的影响

IF 2.8 4区医学 Q2 CLINICAL NEUROLOGY

Neuromuscular Disorders

Pub Date : 2025-10-01 DOI: 10.1016/j.nmd.2025.106213

Heleen van der Wielen , Jorik Nonnekes , Michelle van Mierlo , Christian M.A. Donken , Jan Willem K. Louwerens , Noël L.W. Keijsers

Charcot Marie Tooth disease (CMT) is the most common group of inherited muscular disorders, resulting in foot deformities. Foot and ankle surgical procedures are frequently performed to improve function in persons with CMT. Understanding the patients’ personal goals is crucial for effective counselling. However, there is limited evidence regarding the extent to which personal goals are achieved through surgery, as well as the impact of surgery on balance and gait capacity. A prospective cohort study was conducted in 28 persons with CMT who underwent surgery. A wide range of personal goals was identified using the Canadian Occupational Performance Measure (COPM), with the most common goal being 'less problems during walking on uneven ground with shoes’. Wilcoxon signed-rank revealed a significant improvement in mean COPM scores after surgery for both performance (median difference: 3.0, range: -2 to 8; p < 0.001) and satisfaction (3.5, -2 to 9; p ≤ 0.001). Mini-BESTest (balance capacity) also showed significant improvement (17.0 to 20.3 points, p < 0.001), whereas gait (gait velocity, gait width, and single support time) remained unchanged. This study highlights the variability in personal goals, with an overlap on individual and group levels. After surgery, balance capacity improved, both objectively and subjectively.

Charcot Marie Tooth disease （CMT）是最常见的遗传性肌肉疾病，导致足部畸形。足部和踝关节手术通常用于改善CMT患者的功能。了解病人的个人目标是有效咨询的关键。然而，关于通过手术实现个人目标的程度，以及手术对平衡和步态能力的影响，证据有限。一项前瞻性队列研究对28名接受手术的CMT患者进行了研究。加拿大职业表现评估（COPM）确定了广泛的个人目标，其中最常见的目标是“穿鞋在不平坦的地面上行走时减少问题”。Wilcoxon sign -rank显示，手术后的平均COPM评分在表现（中位差：3.0，范围：-2至8；p < 0.001）和满意度（3.5，-2至9；p≤0.001）两方面均有显著改善。mini - best（平衡能力）也有显著改善（17.0至20.3分，p < 0.001），而步态（步态速度、步态宽度和单次支撑时间）保持不变。这项研究强调了个人目标的可变性，在个人和群体层面上存在重叠。手术后，平衡能力在客观上和主观上都有所改善。

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引用次数: 0

Applying the international rare disease research consortium (IRDiRC) N-of-1 therapy task force eligibility criteria for individualised therapies use case: Duchenne muscular dystrophy 应用国际罕见病研究联盟（IRDiRC） N-of-1治疗工作组个体化治疗用例资格标准：杜氏肌营养不良症。

IF 2.8 4区医学 Q2 CLINICAL NEUROLOGY

Neuromuscular Disorders

Pub Date : 2025-10-01 DOI: 10.1016/j.nmd.2025.106221

Annemieke Aartsma-Rus , Anneliene H. Jonker , Daniel O’Connor

The nucleic acid therapy field is making progress in rare diseases, with multiple regulatory approved therapeutic modalities. As these therapeutic approaches are programmable, they also provide an opportunity for individualized therapy development. Indeed, currently over 30 individuals are being treated with such N-of-1 antisense oligonucleotides. The International Rare Disease Research Consortium (IRDiRC) Task Force of N-of-1 treatments published a roadmap to outline the different steps that are involved, among others, in establishing whether an individual is eligible for N-of-1 treatment development. We have tested these principles, using Duchenne muscular dystrophy as a use case. Our analysis shows that while assessing some eligibility aspects, such as genetic eligibility, is relatively straightforward, assessing other criteria, such as unmet medical need and extrapolation from approved treatments, was more difficult.

核酸治疗领域在罕见疾病方面取得了进展，有多种监管机构批准的治疗方式。由于这些治疗方法是可编程的，它们也为个性化治疗的发展提供了机会。事实上，目前有超过30个人正在接受这种N-of-1反义寡核苷酸的治疗。国际罕见病研究联盟（IRDiRC） N-of-1治疗工作组发布了一份路线图，概述了确定一个人是否有资格接受N-of-1治疗的不同步骤。我们以杜氏肌营养不良症为例，对这些原则进行了测试。我们的分析表明，虽然评估某些方面的资格，如遗传资格，相对简单，但评估其他标准，如未满足的医疗需求和从已批准的治疗中推断，就比较困难。

引用次数: 0

Real-world experience with switch to onasemnogene abeparvovec after initial therapy with nusinersen or risdiplam 现实世界的经验，切换到onasemnogene abparvovec在最初的治疗与nusinersen或risdiplan。

IF 2.8 4区医学 Q2 CLINICAL NEUROLOGY

Neuromuscular Disorders

Pub Date : 2025-10-01 DOI: 10.1016/j.nmd.2025.105454

Magdalena Chrościńska-Krawczyk, Ilona Kozioł, Ewa Zienkiewicz

Spinal muscular atrophy is a progressive neurodegenerative disorder leading to motor neuron loss and muscle weakness. In this retrospective single-center study, we evaluated motor and safety outcomes in 40 children (median age, 18 months; range, 5–107; 60% female) with spinal muscular atrophy who received onasemnogene abeparvovec after initial nusinersen (n=38) or risdiplam (n=2) therapy. Motor function was assessed at baseline and at 1 and 6 months post-infusion using the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND, n=19) or the Hammersmith Functional Motor Scale Expanded (HFMSE, n=21). Six months after onasemnogene abeparvovec, median scores increased from 27 (range, 18–55) to 37 (range, 20–61) on CHOP-INTEND and from 30 (18–56) to 36 (range, 26–63) on HFMSE (p <0.0001). Clinically meaningful improvement was observed in 67.5% of patients at 1 month and 95.0% at 6 months. All patients experienced transient fever, vomiting, and liver enzyme elevation; thrombocytopenia occurred in 32.5%, with no cases of thrombotic microangiopathy or multi-organ failure. These findings indicate that switching to onasemnogene abeparvovec after prior splicing-modifying therapy yields clinically meaningful motor gains and a manageable safety profile.

脊髓性肌萎缩症是一种进行性神经退行性疾病，导致运动神经元丧失和肌肉无力。在这项回顾性单中心研究中，我们评估了40名儿童的运动和安全结局(中位年龄18个月；范围内,5 - 107;60%的女性)患有脊髓性肌萎缩，在最初的nusinersen （n=38）或risdiplam （n=2）治疗后接受onasemnogene abparvovec。使用费城儿童医院婴儿神经肌肉疾病测试（chop - intention, n=19）或Hammersmith功能运动量表扩展（HFMSE, n=21）在基线和输液后1和6个月评估运动功能。在onasemnogene abparvovec治疗6个月后，chop - intention的中位得分从27分（范围18-55分）上升到37分（范围20-61分），HFMSE的中位得分从30分（18-56分）上升到36分（范围26-63分）

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引用次数: 0

ENMC Themed Workshops ENMC主题工作坊

IF 2.8 4区医学 Q2 CLINICAL NEUROLOGY

Neuromuscular Disorders

Pub Date : 2025-10-01 DOI: 10.1016/S0960-8966(25)00998-8

引用次数: 0

Marion or the metamorphosis: a journey of self-reconstruction and hope in the face of FSHD 玛丽昂或变形：面对FSHD的自我重建和希望之旅

IF 2.8 4区医学 Q2 CLINICAL NEUROLOGY

Neuromuscular Disorders

Pub Date : 2025-10-01 DOI: 10.1016/j.nmd.2025.106218

M. Sellenet , A. Belayew , R. de Haas , B.G.M. van Engelen , N.C. Voermans

This Patients’ Forum centers on the testimonial of visual artist Marion Sellenet, who lives with facioscapulohumeral muscular dystrophy (FSHD). In her film Marion or the metamorphosis, co-created with Laëtitia Moreau, she documents her dual journey: coping with the physical manifestations of FSHD and overcoming a "second illness" of fear, despair, and stigma induced by the diagnosis. By relinquishing the hope of cure, she found renewed meaning and a sense of wholeness, advocating for collaborative approaches that integrate medical, philosophical, and experiential knowledge. Her account is complemented by reflections from Alexandra Belayew, who underscores the importance of patient education and accessible communication of research; Baziel van Engelen, who highlights the need to bracket biomedical knowledge to address lived experience; and Ria de Haas and Nicol Voermans, who emphasize patient engagement in care and research. Together, these perspectives illustrate the transformative potential of patient narratives and underline the value of patient-centered, holistic approaches in FSHD.

本次患者论坛以视觉艺术家Marion Sellenet的证词为中心，她患有面部肩胛骨肱肌营养不良症（FSHD）。在她与Laëtitia Moreau共同创作的电影《Marion or the metamorphosis》中，她记录了她的双重旅程：应对FSHD的身体表现，克服由诊断引起的恐惧、绝望和耻辱的“第二种疾病”。通过放弃治愈的希望，她找到了新的意义和整体感，倡导整合医学，哲学和经验知识的合作方法。亚历山德拉·贝莱尤（Alexandra Belayew）的反思补充了她的叙述，她强调了患者教育和无障碍研究交流的重要性；巴齐尔·范·恩格尔（Baziel van Engelen）强调了将生物医学知识与生活经验结合起来的必要性；以及强调患者参与护理和研究的Ria de Haas和Nicol Voermans。总之，这些观点说明了患者叙述的变革潜力，并强调了以患者为中心的FSHD整体方法的价值。

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引用次数: 0

KLHL9-linked distal myopathy: a second family suggesting broad phenotypic variability 与klhl9相关的远端肌病：第二个家族表明广泛的表型变异性。

IF 2.8 4区医学 Q2 CLINICAL NEUROLOGY

Neuromuscular Disorders

Pub Date : 2025-10-01 DOI: 10.1016/j.nmd.2025.105450

Rumiko Izumi , Isao Fukasaka , Tsuyoshi Matsumura , Naoko Nakamura , Toshiaki Takahashi , Naoki Suzuki , Yukako Nishimori , Kazuma Sugie , Tetsuya Niihori , Masashi Aoki

Distal myopathies comprise a clinically and genetically diverse group of muscle disorders characterized by initial involvement of the distal extremities. We describe siblings who developed progressive weakness in the ankle plantar flexors from adolescence to early adulthood. By their 50s, the lower legs exhibited severe fatty degeneration with pronounced involvement of the gastrocnemius and soleus. Genetic analysis identified a heterozygous p.L95F variant in KLHL9, previously associated with an early-onset autosomal dominant form of distal myopathy featuring tibialis anterior atrophy and sensory deficits. Though considering himself unaffected, the father harbored the same variant and exhibited an extremely mild phenotype. Muscle biopsy revealed chronic myopathic changes with normal expression of KLHL9. This may represent the second reported family with a KLHL9 variant, and is worth establishing KLHL9-linked distal myopathy. The combination of shared and distinct findings from the original family broadens the clinical phenotype and provides insight into the disease.

远端肌病包括一组临床和遗传多样化的肌肉疾病，其特征是最初累及远端肢体。我们描述了从青春期到成年早期踝关节跖屈肌进行性无力的兄弟姐妹。到50多岁时，小腿表现出严重的脂肪变性，腓肠肌和比目鱼肌明显受累。遗传分析确定了KLHL9的杂合p.L95F变异，该变异先前与以胫前肌萎缩和感觉缺陷为特征的早发常染色体显性远端肌病有关。尽管认为自己没有受到影响，但父亲携带了相同的变体，并表现出极其温和的表型。肌肉活检显示慢性肌病改变，KLHL9表达正常。这可能是第二个报道的KLHL9变异家族，值得建立与KLHL9相关的远端肌病。来自原始家族的共同和独特发现的结合拓宽了临床表型，并提供了对疾病的深入了解。

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引用次数: 0

Prevalence of pediatric neuromuscular disorders in the Southwest region of France 法国西南地区儿童神经肌肉疾病的患病率

IF 2.8 4区医学 Q2 CLINICAL NEUROLOGY

Neuromuscular Disorders

Pub Date : 2025-10-01 DOI: 10.1016/j.nmd.2025.106214

Maelle Biotteau , Claude Messiaen , Elisabeth Wallach , François Rivier , Ulrike Walther-Louvier , Lea Thevenet , Caroline Espil , Anne-Sophie Jannot , Claude Cances

Around the world, epidemiological data on neuromuscular disorders (NMD) in the pediatric population are very limited. Through medical and genetic hospital records in expert NMD centers (Toulouse, Montpellier, Bordeaux), from May 2001 to June 2022, NMD pediatric prevalence and the epidemiological profile of these disorders were investigated. We performed a retrospective cohort study with data from the French National Rare Disease Databank, which gathers a minimal dataset on all patients. The prevalence by diagnosis and age group or by year and survival from birth for muscular disorders by sub-group were analyzed. 1621 children were included with 62 % males. We estimated the regional prevalence at 37.9 (CI95 % = 35.3 − 40.7)/100,000 inhabitants under 18 years old. For the muscular disorder sub-cohort analysis, we estimated regional prevalence for Duchenne, Becker, Charcot-Marie-Tooth type 1 and Spinal Muscular Atrophy at 5 (CI95 % = 4.1 − 6.1), 1.3 (CI95 % = 0.9 − 1.9), 6.2 (CI95 % = 0.1 − 7.3) and 3.2 (CI95 % = 2.5 − 4.1), respectively. Our findings seem in accordance with other previous but scarce data. Together, these data may reflect a consensus across countries. This epidemiological study is the first robust estimation of the French pediatric prevalence of neuromuscular disorders and presents a strong starting point to be confirmed by analyses extended to all French expert centers.

在世界范围内，关于小儿神经肌肉疾病（NMD）的流行病学数据非常有限。通过NMD专家中心（图卢兹、蒙彼利埃、波尔多）2001年5月至2022年6月的医疗和遗传医院记录，调查了NMD儿科患病率和这些疾病的流行病学概况。我们对来自法国国家罕见病数据库的数据进行了回顾性队列研究，该数据库收集了所有患者的最小数据集。分析各亚组肌肉疾病的诊断、年龄、年龄、出生后生存率。共纳入1621名儿童，其中62%为男性。我们估计18岁以下的地区患病率为37.9 /100,000 （CI95 % = 35.3−40.7）。对于肌肉疾病亚队列分析，我们估计Duchenne、Becker、charco - marie - tooth型和脊髓性肌萎缩症的区域患病率分别为5 （ci95% = 4.1 - 6.1）、1.3 （ci95% = 0.9 - 1.9）、6.2 （ci95% = 0.1 - 7.3）和3.2 （ci95% = 2.5 - 4.1）。我们的发现似乎与其他以往的数据一致，但缺乏数据。总之，这些数据可能反映了各国的共识。这项流行病学研究是对法国儿童神经肌肉疾病患病率的第一个可靠估计，并提出了一个强有力的起点，可以通过扩展到所有法国专家中心的分析来证实。

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引用次数: 0

279th ENMC international workshop: Classification, clinical care, outcome measures and biomarkers in childhood onset facioscapulohumeral dystrophy: towards standardizing clinical care and ensuring clinical trial readiness. Hoofddorp, The Netherlands, 1-3 November 2024 第279届ENMC国际研讨会：儿童期面部肩周骨营养不良的分类、临床护理、结果测量和生物标志物：标准化临床护理和确保临床试验准备。荷兰胡夫多普，2024年11月1日至3日。

IF 2.8 4区医学 Q2 CLINICAL NEUROLOGY

Neuromuscular Disorders

Pub Date : 2025-10-01 DOI: 10.1016/j.nmd.2025.106236

Jildou N. Dijkstra , Bettina C. Henzi , Katherine D. Mathews , Corrie E. Erasmus , Renatta Knox , Tracey Willis , Katy de Valle , ENMC 279th Workshop Study Group

The 279th ENMC workshop on childhood-onset facioscapulohumeral dystrophy (FSHD) was held on November 1–3, 2024. The workshop aimed to standardize classification based on disease severity, address implications for clinical trials and patient access, and improve clinical management of children and adolescents with FSHD. Key priorities included establishing a working party to address knowledge gaps in clinical management and outcome measures, defining a standardized minimal dataset in both research and clinical environments, and enhancing pharmaceutical engagement. Childhood-onset FSHD presents a spectrum, from early-onset progressive cases to later adolescent onset with a classical phenotype. Standardized care, including psychological support and transition planning, is needed. Challenges in trial design, such as disease heterogeneity and ethical considerations, were highlighted. Consensus that childhood-onset FSHD forms part of a disease continuum was reached. Two task forces were established to define minimal outcome measure datasets and paediatric-specific care guidelines, marking a crucial step toward improved clinical care and trial readiness.

第279届ENMC儿童性面肩肱骨营养不良（FSHD）研讨会于2024年11月1日至3日举行。该研讨会旨在标准化基于疾病严重程度的分类，解决临床试验和患者可及性的影响，并改善儿童和青少年FSHD的临床管理。关键优先事项包括建立一个工作组，以解决临床管理和结果衡量方面的知识差距，在研究和临床环境中定义标准化的最小数据集，以及加强制药企业的参与。儿童期发病的FSHD呈现出一个谱系，从早期发病的进行性病例到后来青春期发病的典型表型。需要标准化护理，包括心理支持和过渡规划。强调了试验设计中的挑战，如疾病异质性和伦理考虑。人们一致认为，儿童期发病的FSHD是疾病连续体的一部分。建立了两个工作组来定义最小结果测量数据集和儿科特定护理指南，标志着朝着改善临床护理和试验准备迈出了关键一步。

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引用次数: 0

283rd ENMC international workshop: Establishing expert care recommendations for LAMA2-RD: A prototype for the development of congenital muscular dystrophy subtype-specific care guidelines. Hoofddorp, The Netherlands, January 17th-19th 2025 第283届ENMC国际研讨会：为LAMA2-RD建立专家护理建议：先天性肌肉萎缩症亚型特异性护理指南的雏形。霍夫多普，荷兰，2025年1月17日至19日。

IF 2.8 4区医学 Q2 CLINICAL NEUROLOGY

Neuromuscular Disorders

Pub Date : 2025-10-01 DOI: 10.1016/j.nmd.2025.106220

Alberto Andrea Zambon , Andrea Klein , Anna Sarkozy , A. Reghan Foley , Workshop participants

LAMA2-related dystrophies (LAMA2-RDs) are among the most frequent congenital muscular dystrophies, caused by pathogenic variants in the LAMA2 gene. They typically present in infancy with severe muscle weakness but span a wide clinical spectrum, from neonatal onset to milder, later-onset forms. Complications include respiratory insufficiency, nutritional difficulties, joint contractures, scoliosis, and central nervous system involvement. No specific internationally agreed standards of care (SoC) exist, leading to variability in diagnosis, monitoring, and access to multidisciplinary management and care. The 283rd ENMC International Workshop gathered international stakeholders to review current evidence, suggest expert care recommendations and reach an agreement on the best methods to develop diagnostic and care guidelines for LAMA2-RD. Key outcomes included consensus care recommendations across major clinical domains, strategies for dissemination through a dynamic, open-access resource, and a framework to guide development of SoC for other genetic forms of congenital muscular dystrophies.

LAMA2相关营养不良症（LAMA2- rd）是最常见的先天性肌肉营养不良症之一，由LAMA2基因的致病变异引起。它们通常出现在婴儿期，伴有严重的肌肉无力，但临床范围很广，从新生儿发病到较轻的晚发病形式。并发症包括呼吸功能不全、营养困难、关节挛缩、脊柱侧凸和中枢神经系统受累。目前没有具体的国际商定的护理标准（SoC），导致诊断、监测和获得多学科管理和护理方面存在差异。第283届ENMC国际研讨会汇集了国际利益攸关方，审查现有证据，提出专家护理建议，并就制定LAMA2-RD诊断和护理指南的最佳方法达成协议。主要成果包括主要临床领域的共识护理建议，通过动态开放获取资源的传播策略，以及指导其他遗传形式先天性肌营养不良症SoC发展的框架。

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引用次数: 0