Natural History of the Inherited Neuropathies (Project 1)

摘要 Charcot玛丽牙病（CMT）是遗传性周围神经病变，是最常见的 遗传性神经肌肉疾病，影响1：2500人。CMT 1A是最常见的亚型，影响 约1：4000例CMT患者，由染色体内重复的1.4 Mb重复引起 17p11.2在含有PMP 22基因的区域。CMTX 1（1：25，000）、CMT 1B（1：36，000）和CMT 2A （1：36，000）是下一个最常见的形式，由GJB 1，MPZ 和MFN 2基因。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。 虽然严重程度可能因患者而异，但个体CMT患者通常进展缓慢，因此 临床试验需要敏感的结果指标和生物标志物。遗传性神经病 联盟（INC）已开发了临床结局评估（COA）-包括Rasch改良CMT 神经病变或检查评分（CMTNS-R/CMTES-R）和CMT儿科评分（CMTPedS）-可以 在两年内测量CMT 1A成人和儿童的进展情况。INC最近 开发了患者报告结局（PRO）来衡量疾病负担（CMT健康指数; CMT-HI）， 功能结果测量（CMT-FOM）。INC网站还表明，肌内脂肪 MRI测量的小腿肌肉的IMFA分数在12个月内增加 CMT 1A作为肌肉慢性去神经支配的敏感标志物，这一点已在一项合作研究中得到证实。 在我们的伦敦和爱荷华州之间。伦敦研究中心还证实， 光（NFL），轴突变性的量度，升高并与CMT 1A的严重程度相关。在 Svaren博士是INC外部咨询委员会（EAC）的成员，来自哥伦比亚大学， 威斯康星州，我们的爱荷华州网站证明，在皮肤中， 与对照组相比，CMT 1A患者的活检组织。我们相信，到目前为止， 在纵向研究中整合这些不同的COA，这将使高质量的临床试验， CMT 1A、CMTX 1、CMT 1B和CMT 2A以及更罕见形式的CMT，所有这些都可能适合于 在即将到来的RDCRN周期治疗。 在临床研究项目1中，我们建议（1）完成COA的纵向分析， CMT 1A成人和儿童中的生物标志物，（2）确定我们先前和 CMTX 1、CMT 1B和CMT 1B受试者每年接受一次新COA CMTES-R、CMT-FOM和CMT-HI， CMT 2A，和（3）确定COA CMTES-R、CMT-FOM和CMT-HI对CMT 2A的相对响应性。 罕见CMT受试者的年度基础。我们相信，这些目标的实现将使临床 更常见和罕见的CMT形式的试验。

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.