Abstract
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.