Charcot-Marie-Tooth disease (CMT), the most common hereditary neurologic disease worldwide, is witnessing advancements in clinical outcome assessments (COAs) and biomarkers, crucial for the development of disease-modifying treatments. With no existing cures, the focus is shifting towards identifying reliable measures for clinical trials.
Challenges with Early Clinical Scales
Early clinical scales for CMT, including the neuropathy impairment score, overall neuropathy limitation scale, and CMT neuropathy score, have shown limitations in natural history studies and completed clinical trials. These shortcomings have spurred the development of newer, psychometrically supported scales such as the CMT neuropathy score version 2 (CMTNSv2), CMT pediatric scale, CMT infant scale, CMT functional outcome measure (CMT-FOM), and CMT health index.
Promising Newer Scales
While these newer scales show promise, many have yet to be formally tested in longitudinal studies. The need for objective disease biomarkers that could serve as surrogate endpoints in clinical trials is increasingly recognized, especially given the inherent challenges of relying solely on COAs in slowly progressive forms of CMT.
MRI Muscle Fat Fraction as a Biomarker
Among potential biomarkers, MRI muscle fat fraction in the lower extremities has emerged as the most responsive to date. However, its relationship to functional outcomes and its performance in treatment trials remain uncertain. This highlights the ongoing need for validation and correlation with clinical measures.
Serum Biomarkers
Serum biomarkers, including neurofilament light, transmembrane protease serine 5, specific microRNAs, neural cell adhesion molecule 1, and growth and differentiation factor 15, can reliably distinguish patients with CMT from controls. However, their responsiveness to effective therapies remains unknown, posing a challenge for their use as surrogate endpoints.
Ongoing Clinical Trials
The optimal combination of outcome measures in CMT is yet to be established. Many of the most promising COAs and biomarkers are currently being tested in ongoing clinical trials. These early studies will help address critical clinical trial considerations, such as patient selection and enrollment targets, which will become increasingly important in bringing the first disease-modifying treatments to people living with CMT.
