Abstract

Objective: To determine the rate of disease progression in a longitudinal natural history study of children with Charcot-Marie-Tooth disease (CMT).

Methods: 206 (103 female) participants aged 3-20 years enrolled in the Inherited Neuropathies Consortium were assessed at baseline and 2-years. Demographic, anthropometric, and diagnostic information were collected. Disease progression was assessed with the CMT Pediatric Scale (CMTPedS), a reliable Rasch-built linearly weighted disability scale evaluating fine and gross motor function, strength, sensation, and balance.

Results: On average CMTPedS Total scores progressed at a rate of 2.4±4.9 over 2-years (14% change from baseline, p<0.001). There was no difference between males and females (mean difference 0.5, 95%CI -0.9 to 1.9, p=0.49). The most responsive CMTPedS items were dorsiflexion strength (z-score change: -0.3, 95% CI -0.6 to -0.05, p=0.02), balance (z-score change: -1.0, 95% CI -1.9 to -0.09, p=0.03), and long jump (z-score change: -0.4, 95% CI -0.7 to -0.02, p=0.04). Of the most common genetic subtypes, 111 participants with CMT1A/PMP22 duplication progressed by 1.8±4.2 (12% change from baseline, p<0.001), nine participants with CMT1B/MPZ mutation progressed by 2.2±5.1 (11% change), six participants with CMT2A/MFN2 mutation progressed by 6.2±7.9 (23% change), and seven participants with CMT4C/SH3TC2 mutations progressed by 3.0±4.5 (12% change). Participants with CMT2A progressed faster than CMT1A (mean difference -4.4, 95%CI -8.1 to -0.8, p=0.02). Children with CMT1A progressed consistently through early childhood (3-10 years) and adolescence (11-20 years) (mean difference 1.1, 95%CI -0.6 to 2.7, p=0.19) while CMT2A appeared to progress faster during early childhood than adolescence (mean difference 10.0, 95%CI -2.2 to 22.2, p=0.08).

Interpretation: Using the CMTPedS as an outcome measure of disease severity, children with CMT progress at a significant rate over 2-years. Understanding the rate at which children with CMT deteriorate is essential for adequately powering trials of disease-modifying interventions. This article is protected by copyright. All rights reserved.

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