Natural History of the Inherited Neuropathies (Project 1)

摘要 Charcot Marie Tooth疾病(CMT)是遗传性周围神经疾病，也是最常见的 遗传性神经肌肉疾病，影响1：2500人。CMT1a是最常见的亚型，影响 大约1：4000名CMT患者，由染色体内反复出现的1.4Mb重复引起 17p11.2，位于PMP22基因区域。CMTX1(1：25,000)、CMT1B(1：36,000)和CMT2A (1：36,000)是其次最常见的形式，由GJB1、MPZ的许多不同突变引起 和Mfn2基因。最近在这四种形式的CMT上的进展导致了临床试验 在即将到来的RDCRN周期中开始或将准备开始。 尽管不同患者的严重程度可能不同，但个别CMT患者往往进展缓慢，因此 临床试验需要敏感的结果指标和生物标记物。遗传性神经病 财团(Inc.)已经开发了临床结果评估(COA)-包括RASCH修改的CMT 神经病或考试分数(CMTNS-R/CMTES-R)和CMT儿科评分(CMTPedS)-可以 测量成人和患有CMT1A的儿童在两年间隔内的进展。The Inc.最近 用于衡量疾病负担的已开发患者报告结果(PRO)(CMT Health Index；CMT-HI)和 成人功能结果测量(CMT-FOM)。Inc.网站还表明，肌肉内脂肪 MRI测量的小腿肌肉积聚分数(IMFA)在12个月内增加 CMT1a作为肌肉慢性失神经的敏感标志物，这一点已在一项合作中得到证实 在我们的伦敦和爱荷华州之间。伦敦的网站还表明，血浆中神经丝的水平 轻度(NFL)是轴突变性的一个指标，在CMT1a中升高，并与严重程度相关。在……里面 与加州大学INC外部咨询委员会(EAC)成员斯瓦伦博士合作 威斯康星州，我们的爱荷华州网站证明，皮肤中PMP22 mRNA和其他雪旺细胞基因增加 CMT1A患者的活组织检查与对照组的比较。我们相信，到目前为止，Inc.的位置是独一无二的 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 CMT1A、CMTX1、CMT1B和CMT2A以及更罕见的CMT形式，所有这些都可能符合 在即将到来的RDCRN周期中进行治疗。 在临床研究项目1中，我们建议(1)完成COA和 患有CMT1a的成人和儿童中的生物标记物，(2)决定了我们以前和 CMTX1、CMT1B和CMT1B受试者每年的新COAS CMTES-R、CMT-FOM和CMT-HI CMT2A，以及(3)确定COA CMTES-R、CMT-FOM和CMT-HI对 对于患有罕见形式的CMT的受试者，每年的基准。我们相信，完成这些目标将使临床 对更常见和罕见形式的CMT的试验。

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.