Findings from the Longitudinal CINRG Becker Natural History Study

Paula R. Clemens; Heather Gordish-Dressman; Gabriela Niizawa; Ksenija Gorni; Michela Guglieri; Anne M. Connolly; Matthew Wicklund; Tulio Bertorini; Jean Mah; Mathula Thangarajh; Edward C. Smith; Nancy L. Kuntz; Craig M. McDonald; Erik Henricson; S. Upadhyayula; Barry Byrne; Georgios Manousakis; Amy Harper; Susan Iannaccone; Utkarsh J. Dang

doi:10.3233/JND-230178

Findings from the Longitudinal CINRG Becker Natural History Study

Paula R. Clemens^*, Heather Gordish-Dressman, Gabriela Niizawa, Ksenija Gorni, Michela Guglieri, Anne M. Connolly, Matthew Wicklund, Tulio Bertorini, Jean Mah, Mathula Thangarajh, Edward C. Smith, Nancy L. Kuntz, Craig M. McDonald, Erik Henricson, S. Upadhyayula, Barry Byrne, Georgios Manousakis, Amy Harper, Susan Iannaccone, Utkarsh J. Dang

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

Background: Becker muscular dystrophy is an X-linked, genetic disorder causing progressive degeneration of skeletal and cardiac muscle, with a widely variable phenotype. Objective: A 3-year, longitudinal, prospective dataset contributed by patients with confirmed Becker muscular dystrophy was analyzed to characterize the natural history of this disorder. A better understanding of the natural history is crucial to rigorous therapeutic trials. Methods: A cohort of 83 patients with Becker muscular dystrophy (5-75 years at baseline) were followed for up to 3 years with annual assessments. Muscle and pulmonary function outcomes were analyzed herein. Age-stratified statistical analysis and modeling were conducted to analyze cross-sectional data, time-to-event data, and longitudinal data to characterize these clinical outcomes. Results: Deletion mutations of dystrophin exons 45-47 or 45-48 were most common. Subgroup analysis showed greater pairwise association between motor outcomes at baseline than association between these outcomes and age. Stronger correlations between outcomes for adults than for those under 18 years were also observed. Using cross-sectional binning analysis, a ceiling effect was seen for North Star Ambulatory Assessment but not for other functional outcomes. Longitudinal analysis showed a decline in percentage predicted forced vital capacity over the life span. There was relative stability or improved median function for motor functional outcomes through childhood and adolescence and decreasing function with age thereafter. Conclusions: There is variable progression of outcomes resulting in significant heterogeneity of the clinical phenotype of Becker muscular dystrophy. Disease progression is largely manifest in adulthood. There are implications for clinical trial design revealed by this longitudinal analysis of a Becker natural history dataset.

Original language	English (US)
Pages (from-to)	201-212
Number of pages	12
Journal	Journal of neuromuscular diseases
Volume	11
Issue number	1
DOIs	https://doi.org/10.3233/JND-230178
State	Published - Jan 2 2024

Funding

Dr. Guglieri was Chief Investigator/Principal Investigator for clinical trials of Edgewise, Pfizer, Italfarmaco, Santhera, Roche, ReveraGen, Dynacure, Dyne. She received research funding from Sarepta and PTC. She is a member of Advisory boards for Pfizer, NS Pharma and Dyne. She has received speaker honoraria from Sarepta, Roche and Italfarmaco. Funding for this study was provided by the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (P50 AR060836-01). Travel funding for participants in this study was provided by the Muscular Dystrophy Association. Dr. Connolly has research funding from Biohaven, Edgewise, FibroGen, MDA, Sarepta Therapeutics, Inc. and Scholar Rock. She has done consulting for Biohaven, Edgewise, Sarepta Therapeutics, Inc. and Scholar Rock. Dr. Clemens served as a consultant for Epirum, Catalyst Medical Education and Med Learning Group. She has received research grants from ReveraGen, NS Pharma, Amicus, Sanofi and Spark.

Keywords

Muscular dystrophies
dystrophin
muscle
natural history
skeletal

ASJC Scopus subject areas

Neurology
Clinical Neurology

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10.3233/JND-230178

Cite this

Clemens, P. R., Gordish-Dressman, H., Niizawa, G., Gorni, K., Guglieri, M., Connolly, A. M., Wicklund, M., Bertorini, T., Mah, J., Thangarajh, M., Smith, E. C., Kuntz, N. L., McDonald, C. M., Henricson, E., Upadhyayula, S., Byrne, B., Manousakis, G., Harper, A., Iannaccone, S., & Dang, U. J. (2024). Findings from the Longitudinal CINRG Becker Natural History Study. Journal of neuromuscular diseases, 11(1), 201-212. https://doi.org/10.3233/JND-230178

@article{58c36af13cc1451b857930087fd342cf,

title = "Findings from the Longitudinal CINRG Becker Natural History Study",

abstract = "Background: Becker muscular dystrophy is an X-linked, genetic disorder causing progressive degeneration of skeletal and cardiac muscle, with a widely variable phenotype. Objective: A 3-year, longitudinal, prospective dataset contributed by patients with confirmed Becker muscular dystrophy was analyzed to characterize the natural history of this disorder. A better understanding of the natural history is crucial to rigorous therapeutic trials. Methods: A cohort of 83 patients with Becker muscular dystrophy (5-75 years at baseline) were followed for up to 3 years with annual assessments. Muscle and pulmonary function outcomes were analyzed herein. Age-stratified statistical analysis and modeling were conducted to analyze cross-sectional data, time-to-event data, and longitudinal data to characterize these clinical outcomes. Results: Deletion mutations of dystrophin exons 45-47 or 45-48 were most common. Subgroup analysis showed greater pairwise association between motor outcomes at baseline than association between these outcomes and age. Stronger correlations between outcomes for adults than for those under 18 years were also observed. Using cross-sectional binning analysis, a ceiling effect was seen for North Star Ambulatory Assessment but not for other functional outcomes. Longitudinal analysis showed a decline in percentage predicted forced vital capacity over the life span. There was relative stability or improved median function for motor functional outcomes through childhood and adolescence and decreasing function with age thereafter. Conclusions: There is variable progression of outcomes resulting in significant heterogeneity of the clinical phenotype of Becker muscular dystrophy. Disease progression is largely manifest in adulthood. There are implications for clinical trial design revealed by this longitudinal analysis of a Becker natural history dataset.",

keywords = "Muscular dystrophies, dystrophin, muscle, natural history, skeletal",

author = "Clemens, {Paula R.} and Heather Gordish-Dressman and Gabriela Niizawa and Ksenija Gorni and Michela Guglieri and Connolly, {Anne M.} and Matthew Wicklund and Tulio Bertorini and Jean Mah and Mathula Thangarajh and Smith, {Edward C.} and Kuntz, {Nancy L.} and McDonald, {Craig M.} and Erik Henricson and S. Upadhyayula and Barry Byrne and Georgios Manousakis and Amy Harper and Susan Iannaccone and Dang, {Utkarsh J.}",

note = "Publisher Copyright: {\textcopyright} 2024 - The authors. Published by IOS Press.",

year = "2024",

month = jan,

day = "2",

doi = "10.3233/JND-230178",

language = "English (US)",

volume = "11",

pages = "201--212",

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Clemens, PR, Gordish-Dressman, H, Niizawa, G, Gorni, K, Guglieri, M, Connolly, AM, Wicklund, M, Bertorini, T, Mah, J, Thangarajh, M, Smith, EC, Kuntz, NL, McDonald, CM, Henricson, E, Upadhyayula, S, Byrne, B, Manousakis, G, Harper, A, Iannaccone, S & Dang, UJ 2024, 'Findings from the Longitudinal CINRG Becker Natural History Study', Journal of neuromuscular diseases, vol. 11, no. 1, pp. 201-212. https://doi.org/10.3233/JND-230178

TY - JOUR

T1 - Findings from the Longitudinal CINRG Becker Natural History Study

AU - Clemens, Paula R.

AU - Gordish-Dressman, Heather

AU - Niizawa, Gabriela

AU - Gorni, Ksenija

AU - Guglieri, Michela

AU - Connolly, Anne M.

AU - Wicklund, Matthew

AU - Bertorini, Tulio

AU - Mah, Jean

AU - Thangarajh, Mathula

AU - Smith, Edward C.

AU - Kuntz, Nancy L.

AU - McDonald, Craig M.

AU - Henricson, Erik

AU - Upadhyayula, S.

AU - Byrne, Barry

AU - Manousakis, Georgios

AU - Harper, Amy

AU - Iannaccone, Susan

AU - Dang, Utkarsh J.

PY - 2024/1/2

Y1 - 2024/1/2

N2 - Background: Becker muscular dystrophy is an X-linked, genetic disorder causing progressive degeneration of skeletal and cardiac muscle, with a widely variable phenotype. Objective: A 3-year, longitudinal, prospective dataset contributed by patients with confirmed Becker muscular dystrophy was analyzed to characterize the natural history of this disorder. A better understanding of the natural history is crucial to rigorous therapeutic trials. Methods: A cohort of 83 patients with Becker muscular dystrophy (5-75 years at baseline) were followed for up to 3 years with annual assessments. Muscle and pulmonary function outcomes were analyzed herein. Age-stratified statistical analysis and modeling were conducted to analyze cross-sectional data, time-to-event data, and longitudinal data to characterize these clinical outcomes. Results: Deletion mutations of dystrophin exons 45-47 or 45-48 were most common. Subgroup analysis showed greater pairwise association between motor outcomes at baseline than association between these outcomes and age. Stronger correlations between outcomes for adults than for those under 18 years were also observed. Using cross-sectional binning analysis, a ceiling effect was seen for North Star Ambulatory Assessment but not for other functional outcomes. Longitudinal analysis showed a decline in percentage predicted forced vital capacity over the life span. There was relative stability or improved median function for motor functional outcomes through childhood and adolescence and decreasing function with age thereafter. Conclusions: There is variable progression of outcomes resulting in significant heterogeneity of the clinical phenotype of Becker muscular dystrophy. Disease progression is largely manifest in adulthood. There are implications for clinical trial design revealed by this longitudinal analysis of a Becker natural history dataset.

AB - Background: Becker muscular dystrophy is an X-linked, genetic disorder causing progressive degeneration of skeletal and cardiac muscle, with a widely variable phenotype. Objective: A 3-year, longitudinal, prospective dataset contributed by patients with confirmed Becker muscular dystrophy was analyzed to characterize the natural history of this disorder. A better understanding of the natural history is crucial to rigorous therapeutic trials. Methods: A cohort of 83 patients with Becker muscular dystrophy (5-75 years at baseline) were followed for up to 3 years with annual assessments. Muscle and pulmonary function outcomes were analyzed herein. Age-stratified statistical analysis and modeling were conducted to analyze cross-sectional data, time-to-event data, and longitudinal data to characterize these clinical outcomes. Results: Deletion mutations of dystrophin exons 45-47 or 45-48 were most common. Subgroup analysis showed greater pairwise association between motor outcomes at baseline than association between these outcomes and age. Stronger correlations between outcomes for adults than for those under 18 years were also observed. Using cross-sectional binning analysis, a ceiling effect was seen for North Star Ambulatory Assessment but not for other functional outcomes. Longitudinal analysis showed a decline in percentage predicted forced vital capacity over the life span. There was relative stability or improved median function for motor functional outcomes through childhood and adolescence and decreasing function with age thereafter. Conclusions: There is variable progression of outcomes resulting in significant heterogeneity of the clinical phenotype of Becker muscular dystrophy. Disease progression is largely manifest in adulthood. There are implications for clinical trial design revealed by this longitudinal analysis of a Becker natural history dataset.

KW - Muscular dystrophies

KW - dystrophin

KW - muscle

KW - natural history

KW - skeletal

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Findings from the Longitudinal CINRG Becker Natural History Study

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