Kayla M D Cornett1, Manoj P Menezes1,2, Rosemary R Shy3, Isabella Moroni4, Emanuela Pagliano4, Davide Pareyson4, Timothy Estilow5, Sabrina W Yum6, Trupti Bhandari7, Francesco Muntoni7, Matilde Laura8, Mary M Reilly8, Richard S Finkel9, Kate J Eichinger10, David N Herrmann10, Paula Bray1, Mark Halaki2, Michael E Shy11, Joshua Burns1,2. 1. The University of Sydney, Sydney Children's Hospitals Network (Randwick and Westmead, Sydney, New South Wales, Australia. 2. Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia. 3. Carver College of Medicine, Department of Pediatrics, University of Iowa, Iowa City, IA. 4. IRCCS Foundation, Carlo Besta Neurological Institute, Milan, Italy. 5. Neuromuscular Program, The Children's Hospital of Philadelphia, Philadelphia, PA. 6. Division of Neurology, The Children's Hospital of Philadelphia, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. 7. UCL Institute of Child Health & Great Ormond Street Hospital, London, United Kingdom. 8. MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, United Kingdom. 9. Neuromuscular Program, Division of Neurology, Nemours Children's Hospital, Orlando, FL. 10. Department of Neurology, University of Rochester, Rochester, NY. 11. Carver College of Medicine, Department of Neurology, University of Iowa, Iowa City, IA.
Abstract
OBJECTIVE: To determine the rate of disease progression in a longitudinal natural history study of children with Charcot-Marie-Tooth (CMT) disease. METHODS: 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. 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% 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). 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. Ann Neurol 2017;82:353-359.
OBJECTIVE: To determine the rate of disease progression in a longitudinal natural history study of children with Charcot-Marie-Tooth (CMT) disease. METHODS: 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. 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% 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). 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. Ann Neurol 2017;82:353-359.
Authors: Melissa R Mandarakas; Manoj P Menezes; Kristy J Rose; Rosemary Shy; Kate Eichinger; Maria Foscan; Timothy Estilow; Rachel Kennedy; Karen Herbert; Paula Bray; Kathryn Refshauge; Monique M Ryan; Eppie M Yiu; Michelle Farrar; Hugo Sampaio; Isabella Moroni; Emanuela Pagliano; Davide Pareyson; Sabrina W Yum; David N Herrmann; Gyula Acsadi; Michael E Shy; Joshua Burns; Oranee Sanmaneechai Journal: Brain Date: 2018-12-01 Impact factor: 13.501
Authors: Gabrielle A Donlevy; Sarah P Garnett; Kayla M D Cornett; Marnee J McKay; Jennifer N Baldwin; Rosemary R Shy; Sabrina W Yum; Timothy Estilow; Isabella Moroni; Maria Foscan; Emanuela Pagliano; Davide Pareyson; Matilde Laura; Trupti Bhandari; Francesco Muntoni; Mary M Reilly; Richard S Finkel; Janet E Sowden; Katy J Eichinger; David N Herrmann; Michael E Shy; Joshua Burns; Manoj P Menezes Journal: Neurology Date: 2021-09-07 Impact factor: 9.910
Authors: Katy Eichinger; Joshua Burns; Kayla Cornett; Chelsea Bacon; Mary Lohse Shepherd; Joan Mountain; Janet Sowden; Rosemary Shy; Michael E Shy; David N Herrmann Journal: Neurology Date: 2018-09-19 Impact factor: 9.910
Authors: Rachel A Kennedy; Kate Carroll; Kade L Paterson; Monique M Ryan; Joshua Burns; Kristy Rose; Jennifer L McGinley Journal: PLoS One Date: 2019-06-12 Impact factor: 3.240
Authors: Katy Eichinger; Janet E Sowden; Joshua Burns; Michael P McDermott; Jeffrey Krischer; John Thornton; Davide Pareyson; Steven S Scherer; Michael E Shy; Mary M Reilly; David N Herrmann Journal: Front Neurol Date: 2022-06-27 Impact factor: 4.086
Authors: Kayla M D Cornett; Manoj P Menezes; Paula Bray; Rosemary R Shy; Isabella Moroni; Emanuela Pagliano; Davide Pareyson; Tim Estilow; Sabrina W Yum; Trupti Bhandari; Francesco Muntoni; Matilde Laura; Mary M Reilly; Richard S Finkel; Katy J Eichinger; David N Herrmann; Michael E Shy; Joshua Burns Journal: Ann Clin Transl Neurol Date: 2020-08-06 Impact factor: 4.511