OBJECTIVE: To evaluate the sensitivity of Rasch analysis-based, weighted Charcot-Marie-Tooth Neuropathy and Examination Scores (CMTNS-R and CMTES-R) to clinical progression in patients with Charcot-Marie-Tooth disease type 1A (CMT1A).
METHODS: Patients with CMT1A from 18 sites of the Inherited Neuropathies Consortium were evaluated between 2009 and 2018. Weighted CMTNS and CMTES modified category responses were developed with Rasch analysis of the standard scores. Change from baseline for CMTNS-R and CMTES-R was estimated with longitudinal regression models.
RESULTS: Baseline CMTNS-R and CMTES-R scores were available for 517 and 1,177 participants, respectively. Mean ± SD age of participants with available CMTES-R scores was 41 ± 18 (range 4-87) years, and 56% were female. Follow-up CMTES-R assessments at 1, 2, and 3 years were available for 377, 321, and 244 patients. A mixed regression model showed significant change in CMTES-R score at years 2 through 6 compared to baseline (mean change from baseline 0.59 points at 2 years, p = 0.0004, n = 321). Compared to the original CMTES, the CMTES-R revealed a 55% improvement in the standardized response mean (mean change/SD change) at 2 years (0.17 vs 0.11). Change in CMTES-R at 2 years was greatest in mildly to moderately affected patients (1.48-point mean change, 95% confidence interval 0.99-1.97, p < 0.0001, for baseline CMTES-R score 0-9).
CONCLUSION: The CMTES-R demonstrates change over time in patients with CMT1A and is more sensitive than the original CMTES. The CMTES-R was most sensitive to change in patients with mild to moderate baseline disease severity and failed to capture progression in patients with severe CMT1A.
CLINICALTRIALSGOV IDENTIFIER: NCT01193075.
Bibliographical noteFunding Information:
The INC is a part of the NIH RDCRN. The authors thank all the patients who participated in the INC and their families, without whom this study would not be possible. The authors also thank the people working at INC sites who contributed to this study, especially Julian Blake, Betsy Burgos, Daniela Calabrese, Vinay Chaudhry, David Corn-blath, Katy Eichinger, Tim Estilow, Claudia Gandioli, Audra Hamilton, Allan M. Glanzman, Ahmet Hoke, Andrea Kelley, Livija Medne, Manoj Menezes, Joan Mountain, Sinead Murphy, Jillian Olsen, Alex Rossor, Oranee Sanmaneechai, Paola Saveri, Anna Sorey, Mariola Skorupinska, Janet Sowden, and Andrea Swenson. This research was also supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre.
The INC (2U54NS065712-07) is a part of the RDCRN, an initiative of the Office of Rare Diseases Research, National Center for Advancing Translational Sciences. The INC is funded through a collaboration between the National Center for Advancing Translational Sciences and the National Institute of Neurological Disorders and Stroke. The INC also receives support from the Muscular Dystrophy Association and Charcot-Marie-Tooth Association.
V. Fridman, S. Sillau, G. Acsadi, C. Bacon, and K. Dooley report no disclosures relevant to the manuscript. J. Burns reports research and clinical activities funded by the Australian Department of Health (Medical Research Future Fund), US NIH, Charcot-Marie-Tooth Australia, Charcot-Marie-Tooth Association (USA), Diabetes Australia, Elizabeth Lottie May Rosenthal Bone Bequest, Perpetual Limited, and Humpty Dumpty Foundation. Dr Burns serves as a consultant for Acceleron Pharma. J. Day, S. Feely, R. Finkel, T. Grider, and L. Gutmann report no disclosures relevant to the manuscript. D. Herrmann reports grant support through U54 NS065712-09, 1R01DK115687-01A1, Muscular Dystrophy Association, Friedreich’s Ataxia Research Alliance and Voyager Pharmaceuticals, Acceleron Pharma, and Flex Pharma. Dr. Herrmann also reports consulting fees from Regenacy Pharmaceuticals, Acceleron Pharma, Alnylam, Neurogene, Flex Pharma, Narrow River Management, Guidepoint Global, GLG, Slingshot Insights, LAM Therapeutics, Inc, Voyager Therapeutics, ClearView Health Partners, MedPace, DDB Health NY, Cydan, Trinity Partners, Schlesinger, and Human First Therapeutics. C. Kirk, S. Knause, and M. Laurá report no disclosures relevant to the manuscript. R. Lewis reports providing consulting services for CSL Behring, Pharnext, Shire, Pharnext, Biotest, Annexon, Alexion, Akcea, and Alnylam. Pharnext has performed clinical trials in CMT1A. He is medical director of Premier Pharmacy Services, a home infusion company. J. Li, T. Lloyd, I. Moroni, F. Muntoni, E. Pagliano, C. Pisciotta, and G. Piscosquito report no disclosures relevant to the manuscript. S. Ramchandren is currently employed by a contract research organization (PRA Health Sciences) that works with pharmaceutical companies. M. Saporta, R. Sadjadi, R. Shy, and C. Siskind report no disclosures relevant to the manuscript. C. Sumner reports providing consulting services regarding spinal muscular atrophy to Biogen, Roche/ Genetech, Avexis, Cytokinetics, Pfizer, Ionis, and PTC Therapeutics. She serves on advisory committees to Cure SMA, SMA Foundation, Muscular Dystrophy Association, and CMT Research Foundation. D. Walk reports serving as a consultant for Acceleron Pharma. J. Wilcox, S. Yum, and S. Züchner report no disclosures relevant to the manuscript. S. Scherer reports serving as a consultant for Biogen and Disarm. D. Pareyson reports grant support from Telethon-UILDM, AFM-Telethon, the Charcot-Marie-Tooth Association; serves on clinical advisory boards for Inflectis, Alnylam, and Akcea; and has received travel grants from Kedrion Spa and Pfizer. Te Istituto Neurologico Carlo Besta receives donations for research from Pfizer, LAM Therapeutics, Acceleron Pharma Inc. M. Reilly reports grant support from U54 NS0657, the Muscular Dystrophy Association, and the Medical Research Council and consulting for Inflectis, Alnylam, and Akcea. M. Shy reports grant support from U54 NS0657, the Muscular Dystrophy Association, and the Charcot-Marie-Tooth Association. Go to Neurology.org/N for full disclosures.
© American Academy of Neurology.
- Aged, 80 and over
- Charcot-Marie-Tooth Disease/diagnosis
- Child, Preschool
- Disease Progression
- Longitudinal Studies
- Middle Aged
- Models, Theoretical
- Sensitivity and Specificity
- Severity of Illness Index
- Time Factors
- Young Adult
PubMed: MeSH publication types
- Research Support, Non-U.S. Gov't
- Multicenter Study
- Journal Article
- Research Support, N.I.H., Extramural