From the Department of Neurology (R.S., V.P.-M.), Massachusetts General Hospital, Harvard Medical School, Boston; Centre for Neuromuscular Diseases (J.M.M., M.M.R.), Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom; Department of Neurology (D.T.), and Department of Radiology (P.A.D.), University of Iowa Health Care, Carver College of Medicine, Iowa City; Michigan Neuroscience Institute (B.A.M.), University of Michigan, Ann Arbor; Unit of Medical Genetics and Neurogenetics (D.P.), Department of Diagnostics and Technology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; Department of Neurology (D.N.H.), University of Rochester, NY; Department of Neurology (J.L.), Houston Methodist Research Institute; Neurology & Neuromuscular Care Center/Neurology Rare Disease Center (D.C.), Denton, TX; and Department of Molecular Physiology and Biophysics (M.E.S.), University of Iowa Health Care, Carver College of Medicine, Iowa City.
Neurology. 2024 Sep 10;103(5):e209763. doi: 10.1212/WNL.0000000000209763. Epub 2024 Aug 12.
Charcot-Marie-Tooth disease type 4J (CMT4J) is caused by autosomal recessive variants in the () gene. Recent preclinical work has demonstrated the feasibility of adeno-associated virus serotype 9-FIG4 gene therapy. This study aimed to further characterize the CMT4J phenotype and evaluate feasibility of validated CMT-related outcome measures for future clinical trials.
This cross-sectional study enrolled children and adults with genetically confirmed CMT4J, with 2 documented disease-causing variants in the gene. Patients were recruited through the Inherited Neuropathy Consortium network. Disease severity was assessed using standardized CMT-specific outcome measures and exploratory biomarkers including muscle MRI fat fraction, electrophysiology, and neurofilament light chain levels. Descriptive statistics and correlation analyses were conducted to explore relationships between variables.
We recruited a total of 19 patients, including 14 pediatric patients (mean age 10.9 ± 3.9 years) and 5 adults (mean age 40.0 ± 13.9 years). The most frequent symptoms were gross motor delay and distal more than proximal muscle weakness, which were observed in 14 of 19 patients. The most common non-neuromuscular symptoms were cognitive and respiratory deficits, each seen in 8 of 19 patients. We denoted asymmetric weakness in 2 patients and nonuniform slowing of conduction velocities in 6 patients. Charcot-Marie-Tooth Disease Pediatric Scale (CMTPedS), Pediatric Quality of Life Inventory, and Vineland Adaptive Behavior Scale scores were affected in most patients. We observed a significant positive correlation between neurofilament light chain levels and CMTPedS, but the study was underpowered to observe a correlation between CMTPedS and MRI fat fraction.
We obtained baseline clinical and biomarker data in a broad cohort with CMT4J in pediatric and adult patients. Motor delay, muscle weakness, and respiratory and cognitive difficulties were the most common clinical manifestations of CMT4J. Many patients had nerve conduction studies with nonuniform slowing, and 2 had an asymmetric pattern of muscle weakness. We observed that the neurofilament light chain levels correlated with the CMTPedS in the pediatric population. This study showed feasibility of clinical outcomes including CMTPedS in assessment of disease severity in the pediatric patient population and provided baseline characteristics of exploratory biomarkers, neurofilament light chain levels, and muscle MRI fat fraction. The coronavirus disease 2019 pandemic affected some of the visits, resulting in a reduced number of some of the assessments.
Charcot-Marie-Tooth 病 4J（CMT4J）是由常染色体隐性变体引起的 () 基因。最近的临床前研究已经证明了腺相关病毒血清型 9-FIG4 基因治疗的可行性。本研究旨在进一步描述 CMT4J 表型，并评估经过验证的 CMT 相关结局测量指标在未来临床试验中的可行性。
本横断面研究纳入了经基因证实的 CMT4J 儿童和成人患者，这些患者均携带 2 个 () 基因的致病性变异。患者通过遗传性神经病变联合会网络招募。使用标准化的 CMT 特异性结局测量指标和探索性生物标志物（包括肌肉 MRI 脂肪分数、电生理学和神经丝轻链水平）评估疾病严重程度。进行描述性统计和相关性分析以探讨变量之间的关系。
我们共招募了 19 名患者，包括 14 名儿科患者（平均年龄 10.9 ± 3.9 岁）和 5 名成人（平均年龄 40.0 ± 13.9 岁）。最常见的症状是粗大运动发育迟缓以及远端重于近端的肌肉无力，19 名患者中有 14 名出现这些症状。最常见的非神经肌肉症状是认知和呼吸功能缺陷，19 名患者中有 8 名出现这些症状。我们注意到 2 名患者存在不对称性肌无力，6 名患者存在传导速度不均匀减慢。大多数患者的 Charcot-Marie-Tooth 疾病儿科量表（CMTPedS）、儿科生活质量量表和 Vineland 适应行为量表评分受到影响。我们观察到神经丝轻链水平与 CMTPedS 呈显著正相关，但本研究尚不足以观察到 CMTPedS 与 MRI 脂肪分数之间的相关性。
我们在儿科和成年患者中获得了 CMT4J 广泛队列的基线临床和生物标志物数据。运动发育迟缓、肌肉无力以及呼吸和认知困难是 CMT4J 最常见的临床表现。许多患者的神经传导研究显示传导速度不均匀减慢，2 名患者存在不对称性肌无力模式。我们观察到神经丝轻链水平与儿科人群中的 CMTPedS 相关。本研究显示，包括 CMTPedS 在内的临床结局评估在儿科患者人群中具有评估疾病严重程度的可行性，并提供了神经丝轻链水平和肌肉 MRI 脂肪分数等探索性生物标志物的基线特征。2019 年冠状病毒病大流行影响了部分就诊，导致部分评估的患者数量减少。
