From the Department of Neurology (B.A.M.), University of Michigan Medical School, Ann Arbor; and Department of Neurology (V.F.), University of Colorado Anschutz Medical Campus, Aurora.
Neurology. 2024 Dec 24;103(12):e210120. doi: 10.1212/WNL.0000000000210120. Epub 2024 Nov 25.
Charcot-Marie-Tooth disease (CMT) encompasses a diverse group of genetic forms of inherited peripheral neuropathy and stands as the most common hereditary neurologic disease worldwide. At present, no disease-modifying treatments exist for any form of CMT. However, promising therapeutic strategies are rapidly emerging, necessitating careful consideration of clinical outcome assessments (COAs) and clinical trial design. In this review, we discuss the challenges and successes over the past 2 decades in efforts to design and validate COAs and disease biomarkers of CMT. Natural history studies and completed clinical trials have underscored the limitations of early clinical scales for CMT, including the neuropathy impairment score, overall neuropathy limitation scale, and CMT neuropathy score. These studies prompted the development of newer, psychometrically supported scales including the CMT neuropathy score version 2, CMT pediatric scale, CMT infant scale, CMT functional outcome measure, and CMT health index. Although promising, many of these scales have yet to be formally tested in longitudinal studies. Given inherent challenges of relying solely on COAs in slowly progressive forms of CMT, there is growing recognition of the need for objective disease biomarkers that could serve as surrogate end points in clinical trials. Among these, MRI muscle fat fraction in the lower extremities has proven the most responsive biomarker to date, although its relationship to functional outcomes and its performance in treatment trials remain uncertain. Serum biomarkers including neurofilament light, transmembrane protease serine 5, specific microRNAs, neural cell adhesion molecule 1, and growth and differentiation factor 15 reliably distinguish patients with CMT from controls, but their responsiveness to effective therapies also remains unknown. Although the optimal combination of outcome measures in CMT has yet to be established, many of the most promising COAs and biomarkers are now being put to the test in ongoing clinical trials. These early studies will also help address other critical clinical trial considerations, such as patient selection and enrollment targets, which will become increasingly important in this exciting new era of bringing the first disease-modifying treatments to people living with CMT.
腓骨肌萎缩症（CMT）包括一组遗传性周围神经病的遗传形式，是世界上最常见的遗传性神经疾病。目前，尚无针对任何形式 CMT 的疾病修正治疗方法。然而，有前途的治疗策略正在迅速出现，这就需要仔细考虑临床结局评估（COA）和临床试验设计。在这篇综述中，我们讨论了在过去 20 年中设计和验证 CMT 的 COA 和疾病生物标志物方面所面临的挑战和取得的成功。自然史研究和已完成的临床试验强调了早期 CMT 临床量表的局限性，包括神经病变损伤评分、总体神经病变限制量表和 CMT 神经病变评分。这些研究促使开发了更新的、具有心理测量学支持的量表，包括 CMT 神经病变评分 2.0 版、CMT 儿科量表、CMT 婴儿量表、CMT 功能结局测量和 CMT 健康指数。尽管很有前景，但这些量表中的许多尚未在纵向研究中进行正式测试。鉴于在进展缓慢的 CMT 形式中仅依赖 COA 存在固有挑战，人们越来越认识到需要客观的疾病生物标志物，这些标志物可以作为临床试验中的替代终点。在这些标志物中，下肢 MRI 肌肉脂肪分数是迄今为止最敏感的生物标志物，尽管其与功能结局的关系及其在治疗试验中的表现仍不确定。包括神经丝轻链、跨膜蛋白酶丝氨酸 5、特定 microRNA、神经细胞黏附分子 1 和生长分化因子 15 在内的血清生物标志物可靠地区分 CMT 患者和对照者，但它们对有效治疗的反应性也尚不清楚。尽管 CMT 的最佳组合结局测量尚未确定，但许多最有前途的 COA 和生物标志物现在正在进行中的临床试验中进行测试。这些早期研究还将有助于解决其他关键的临床试验考虑因素，例如患者选择和入组目标，这些因素在将首个疾病修正治疗方法带给 CMT 患者的这个令人兴奋的新时代将变得越来越重要。
