Natural History of the Inherited Neuropathies (Project 1)

遗传性神经病的自然史（项目 1）

• 批准号: 10652519
• 负责人: MICHAEL E. SHY
• 金额: $ 26.02万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10652519
• 关键词: 17p11.2; Adult; Advisory Committees; Affect; Award; Biological Markers; Biopsy; Candidate Disease Gene; Charcot-Marie-Tooth Disease; Child; Childhood; Chromosomes; Chronic; Clinical Research; Clinical Trials; Collaborations; Cross-Sectional Studies; Data; Disease; Ensure; Fatty acid glycerol esters; Genes; Genetic; Goals; Health; Heritability; Individual; International; Intramuscular; Iowa; Leg; Light; London; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Messenger RNA; Muscle; Muscle denervation procedure; Mutation; National Institute of Neurological Disorders and Stroke; Natural History; Neuromuscular Diseases; Neuropathy; Outcome Measure; PMP22 gene; Pathogenesis; Patient Outcomes Assessments; Patients; Peripheral Nervous System Diseases; Phenotype; Plasma; Recurrence; Research Personnel; Research Project Grants; Schwann Cells; Severities; Site; Skin; Therapeutic Studies; Time; Universities; Wisconsin; autosome; axonal degeneration; burden of illness; clinical candidate; clinical effect; clinical outcome assessment; clinical predictors; college; comparison control; design; functional outcomes; gene replacement; hereditary neuropathy; indexing; longitudinal analysis; loss of function; member; neurofilament; novel; novel marker; participant enrollment; trial readiness

Abstract Charcot Marie Tooth diseases (CMT) are heritable peripheral neuropathies and are the most common genetic neuromuscular disease, affecting 1:2500 individuals. CMT1A is the most common subtype, affecting approximately 1:4000 patients with CMT, caused by a recurring 1.4 Mb duplication within chromosome 17p11.2 in the region containing the PMP22 gene. CMTX1 (1:25,000), CMT1B (1:36,000) and CMT2A (1:36,000) are the next most frequent forms and are caused by many different mutations in the GJB1, MPZ and MFN2 genes respectively. Recent progress on these four forms of CMT has led to clinical trials that have begun or will be ready to begin in the upcoming RDCRN cycle. Although the severity may vary in between patients, individual CMT patients often progress slowly, so that sensitive outcome measures and biomarkers are needed for clinical trials. The Inherited Neuropathy Consortium (INC) has developed clinical outcome assessments (COAs) - including the Rasch modified CMT Neuropathy or Exam Scores (CMTNS-R/CMTES-R) and the CMT Pediatric Score (CMTPedS) - that can measure progression in adults and children with CMT1A within a two-year interval. The INC has recently developed patient reported outcomes (PROs) to measure disease burden (CMT Health Index; CMT-HI) and functional outcome measures (CMT-FOM) in adults. INC sites have also shown that the intramuscular fat accumulation (IMFA) fraction of calf muscles measured by MRI increases over 12 months in patients with CMT1A, as a sensitive marker of chronic denervation of muscle, and this has been confirmed in a collaboration between our London and Iowa sites. The London site also demonstrated that plasma levels of neurofilament light (NFL), a measure of axonal degeneration, are elevated and correlate with severity in CMT1A. In collaboration with Dr. Svaren, a member of the INC External Advisory Committee (EAC) from the University of Wisconsin, our Iowa site demonstrated that PMP22 mRNA and other Schwann cell genes are increased in skin biopsies from patients with CMT1A compared to controls. We believe that the INC is uniquely situated to now integrate these various COAs in longitudinal studies, and that this will enable high quality clinical trials in CMT1A, CMTX1 CMT1B, and CMT2A as well as in rarer forms of CMT, all of which may be amenable to therapy in the upcoming RDCRN cycle. In Clinical Research Project 1 we propose to (1) Complete the longitudinal analysis of COA and biomarkers in adults and children with CMT1A, (2) Determine the relative responsiveness of our prior and novel COAs CMTES-R, CMT-FOM and CMT-HI on a yearly basis for subjects with CMTX1, CMT1B and CMT2A, and (3) Determine the relative responsiveness of the COA CMTES-R, CMT-FOM and CMT-HI on a yearly basis for subjects with rare forms of CMT. We believe that completion of these aims will enable clinical trials for the more common as well as rare forms of CMT.

抽象的 腓骨肌萎缩症 (CMT) 是一种遗传性周围神经病，是最常见的疾病 遗传性神经肌肉疾病，影响 1:2500 人。 CMT1A 是最常见的亚型，影响 约 1:4000 患者患有 CMT，由染色体内重复出现的 1.4 Mb 重复引起 17p11.2中含有PMP22基因的区域。 CMTX1 (1:25,000)、CMT1B (1:36,000) 和 CMT2A (1:36,000) 是第二常见的形式，由 GJB1、MPZ 中的许多不同突变引起 和MFN2基因分别。这四种形式的 CMT 的最新进展导致了临床试验 在即将到来的 RDCRN 周期中开始或准备开始。 尽管患者之间的严重程度可能有所不同，但个别 CMT 患者通常进展缓慢，因此 临床试验需要敏感的结果测量和生物标志物。遗传性神经病 联盟 (INC) 开发了临床结果评估 (COA) - 包括 Rasch 改良 CMT 神经病变或考试分数 (CMTNS-R​​/CMTES-R) 和 CMT 儿科分数 (CMTPedS) - 可以 测量成人和儿童 CMT1A 在两年内的进展情况。最近，INC 制定患者报告结果 (PRO) 来衡量疾病负担（CMT 健康指数；CMT-HI）和 成人功能结果测量（CMT-FOM）。 INC 网站还表明，肌内脂肪 MRI 测量的小腿肌肉累积 (IMFA) 分数在 12 个月内增加 CMT1A，作为肌肉慢性去神经支配的敏感标记，这一点已在合作中得到证实 我们的伦敦和爱荷华站点之间。伦敦站点还证明，神经丝的血浆水平 light (NFL) 是轴突变性的一种测量指标，在 CMT1A 中升高并与严重程度相关。在 与来自University of University的INC外部咨询委员会（EAC）成员Svaren博士合作 威斯康星州，我们爱荷华州的站点证明 PMP22 mRNA 和其他施万细胞基因在皮肤中增加 与对照组相比，CMT1A 患者的活检结果。我们相信 INC 迄今为止处于独特的位置 将这些不同的 COA 整合到纵向研究中，这将使高质量的临床试验成为可能 CMT1A、CMTX1、CMT1B 和 CMT2A 以及罕见形式的 CMT，所有这些都可能适用于 即将到来的 RDCRN 周期中的治疗。 在临床研究项目1中，我们建议（1）完成COA和的纵向分析 患有 CMT1A 的成人和儿童的生物标志物，(2) 确定我们先前和 每年为患有 CMTX1、CMT1B 和 CMT2A，以及 (3) 确定 COA CMTES-R、CMT-FOM 和 CMT-HI 在 患有罕见形式 CMT 的受试者每年为基础。我们相信，这些目标的完成将使临床 针对更常见和罕见形式的 CMT 的试验。