Magnetic resonance imaging of the anterior compartment of the lower leg is a biomarker for weakness, disability, and impaired gait in childhood Charcot-Marie-Tooth disease.

INTRODUCTION: Biomarkers of disease severity in Charcot-Marie-Tooth disease (CMT) are required to evaluate early responses to treatment. In this study we used magnetic resonance imaging (MRI) to evaluate the relationship between muscle volume and intramuscular fat accumulation with weakness, disability, and impaired gait in affected children and adolescents. METHODS: Fifty-five participants underwent MRI of the anterior compartment of the lower leg. Muscle and fat volumes were calculated. Strength was measured using hand-held dynamometry, disability using the CMT Pediatric Scale, and 3-dimensional gait analysis using an 8-camera Vicon Nexus motion capture system. RESULTS: Lower muscle volume was significantly associated with reduced dorsiflexion strength, increased disability, impaired gait profile score, and foot drop. Intramuscular fat accumulation was associated with reduced dorsiflexion strength and impaired gait profile score. DISCUSSION: The MRI protocol described was feasible, reliable, and sensitive to the magnitude of weakness, disability, and walking difficulties in children with CMT. Muscle Nerve 59:213-217, 2019.

Safety and efficacy of progressive resistance exercise for Charcot-Marie-Tooth disease in children: a randomised, double-blind, sham-controlled trial.

BACKGROUND: Exercise is potentially therapeutic for neuromuscular disorders, but a risk of harm exists due to overwork weakness. We aimed to assess the safety and efficacy of progressive resistance exercise for foot dorsiflexion weakness in children with Charcot-Marie-Tooth disease. METHODS: We did this randomised, double-blind, sham-controlled trial across the Sydney Children's Hospitals Network (NSW, Australia). Children aged 6-17 years with Charcot-Marie-Tooth disease were eligible if they had foot dorsiflexion weakness (negative Z score based on age-matched and sex-matched normative reference values). We randomly allocated (1:1) children, with random block sizes of 4, 6, and 8 and stratification by age, to receive 6 months (three times per week on non-consecutive days; 72 sessions in total) of progressive resistance training (from 50% to 70% of the most recent one repetition maximum) or sham training (negligible non-progressed intensity), using an adjustable exercise cuff to exercise the dorsiflexors of each foot. The primary efficacy outcome was the between-group difference in dorsiflexion strength assessed by hand-held dynamometry (expressed as a Z score) from baseline to months 6, 12, and 24. The primary safety outcome was the between-group difference in muscle and intramuscular fat volume of the anterior compartment of the lower leg assessed by MRI (expressed as a scaled volume) from baseline to 6 months and 24 months. Participants, parents, outcome evaluators, and investigators other than the treatment team were masked to treatment assignment. Analysis was by intention to treat. The trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12613000552785. FINDINGS: From Sept 2, 2013, to Dec 11, 2014, we randomly assigned 60 children to receive progressive resistance exercise (n=30) or sham training (n=30), and 55 (92%) children completed the trial. ANCOVA-adjusted Z score differences in dorsiflexion strength between groups were 0 (95% CI -0·37 to 0·42; p=0·91) at 6 months, 0·3 (-0·23 to 0·81; p=0·27) at 12 months, and 0·6 (95% CI 0·03 to 1·12; p=0·041) at 24 months. Scaled muscle and fat volume was comparable between groups at 6 months (ANCOVA-adjusted muscle volume difference 0, 95% CI -0·03 to 0·10, p=0·24; and fat volume difference 0, 95% CI -0·01 to 0·05, p=0·25) and 24 months (0, -0·08 to 0·12, p=0·67; and 0, -0·05 to 0·03, p=0·58). No serious adverse events were reported. INTERPRETATION: 6 months of targeted progressive resistance exercise attenuated long-term progression of dorsiflexion weakness without detrimental effect on muscle morphology or other signs of overwork weakness in paediatric patients with Charcot-Marie-Tooth disease. FUNDING: Muscular Dystrophy Association and Australian National Health and Medical Research Council.

Randomised controlled trial protocol of foot and ankle exercise for children with Charcot-Marie-Tooth disease.

INTRODUCTION: Charcot-Marie-Tooth disease (CMT) is one of the most commonly inherited neuromuscular diseases--there is no effective treatment. Foot and ankle weakness is a major problem for children with CMT, thus interventions that focus on maintaining and increasing strength may provide a solution. RESEARCH QUESTION: Is progressive resistance strength training an effective and safe intervention to improve strength, disability, gait and quality of life of children with CMT? PARTICIPANTS AND SETTING: Sixty children (6 to 17 years) with confirmed CMT who reside in Sydney, Australia will be recruited via referral from a paediatric neurologist, advertisements or the Australasian Paediatric CMT Registry. INTERVENTION: Participants will be randomised to undergo a 24-week, thrice weekly, high-intensity progressive resistance foot and ankle exercise programme (HIGH) or low-intensity foot and ankle exercise control programme (LOW). MEASUREMENTS: Out-come measures will be conducted at baseline, 6, 12 and 24 months.The primary outcome is isometric dorsiflexion strength measured by hand-held dynamometry. Secondary outcomes include disability, gait, quality of life, functional ankle instability and muscle volume and fatty infiltration of the anterior compartment of the lower leg (determined by MRI). PROCEDURE: Randomisation and allocation will be by a computer-generated algorithm, maintained and assigned by an external phone-based system, concealed to the investigators. Participants, parents and the outcome assessors will be blinded to group assignment. ANALYSIS: Treatment effect between groups is by intention-to-treat with a linear regression approach to analysis of covariance using 95% CI and p < 0.05. DISCUSSION: This study is the first randomised controlled trial to evaluate the risks and benefits of strengthening the affected muscles in children with CMT. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry. REGISTRATION NUMBER: ACTRN12613000552785.