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Ann Neurol. 2017 Sep;82(3):353-359. doi: 10.1002/ana.25009.

Natural history of Charcot-Marie-Tooth disease during childhood.

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The University of Sydney, Sydney Children's Hospitals Network (Randwick and Westmead, Sydney, New South Wales, Australia.
Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia.
Carver College of Medicine, Department of Pediatrics, University of Iowa, Iowa City, IA.
IRCCS Foundation, Carlo Besta Neurological Institute, Milan, Italy.
Neuromuscular Program, The Children's Hospital of Philadelphia, Philadelphia, PA.
Division of Neurology, The Children's Hospital of Philadelphia, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
UCL Institute of Child Health & Great Ormond Street Hospital, London, United Kingdom.
MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, United Kingdom.
Neuromuscular Program, Division of Neurology, Nemours Children's Hospital, Orlando, FL.
Department of Neurology, University of Rochester, Rochester, NY.
Carver College of Medicine, Department of Neurology, University of Iowa, Iowa City, IA.



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


Two hundred six (103 female) participants aged 3 to 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.


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% confidence interval [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), 9 participants with CMT1B/MPZ mutation progressed by 2.2 ± 5.1 (11% change), 6 participants with CMT2A/MFN2 mutation progressed by 6.2 ± 7.9 (23% change), and 7 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), whereas CMT2A appeared to progress faster during early childhood than adolescence (mean difference, 10.0; 95% CI, -2.2 to 22.2; p = 0.08).


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. Ann Neurol 2017;82:353-359.

[Indexed for MEDLINE]

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