Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024;11(1):201-212.
doi: 10.3233/JND-230178.

Findings from the Longitudinal CINRG Becker Natural History Study

Paula R Clemens  1 , Heather Gordish-Dressman  2 , Gabriela Niizawa  1 , Ksenija Gorni  3 , Michela Guglieri  4 , Anne M Connolly  5 , Matthew Wicklund  6 , Tulio Bertorini  7 , Jean Mah  8 , Mathula Thangarajh  9 , Edward C Smith  10 , Nancy L Kuntz  11 , Craig M McDonald  12 , Erik Henricson  12 , S Upadhyayula  13 , Barry Byrne  14 , Georgios Manousakis  15 , Amy Harper  9 , Susan Iannaccone  16 , Utkarsh J Dang  17
Affiliations

Findings from the Longitudinal CINRG Becker Natural History Study

Paula R Clemens et al. J Neuromuscul Dis. 2024.

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.

PubMed Disclaimer

Conflict of interest statement

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.

Dr. Gordish-Dressman is a part owner of TRiNDS, LLC, a paid consultant for AGADA Biosciences and SOLID GT, and has consulted for ReveraGen and Audentes.

Ms. Niizawa has no disclosures.

Dr. Gorni is Global Senior Medical Director at HOFFMAN-LA ROCHE INC.

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.

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. Wicklund has research funding from Edgewise Therapeutics and Sarepta Therapeutics. He has done consulting for Edgewise Therapeutics. He is on the Advisory Board for Sarepta Therapeutics.

Dr. Bertorini has no disclosures.

Dr. Mah received research grants to her institution from CINRG, Sarepta; PTC Therapeutics; NS Pharma, Inc.; ReveraGen; Italfarmaco; Biogen; Roche; Pfizer; and the Alberta Children’s Hospital Foundation.

Dr. Thangarajh was a speaker for NS Pharma and PTC Therapeutics.

Dr. Smith has no disclosures.

Dr. Kuntz serves as PI on research grants to her institution for Argenx, Astellas, Biogen, Novartis, Roche, Sarepta and Scholar Rock; on Medical Advisory Boards for Argenx, BioMarin, Biogen, Roche, Sarepta; on DSMB for Sarepta; she is a speaker on gene therapy for Sarepta.

Dr. McDonald received personal consulting fees from Astellas/Mitobridge, Avidity Biosciences, Bristol-Myers Squibb, Capricor Therapeutics, Catabasis Pharmaceuticals, Edgewise Therapeutics, Eli Lilly and Company, Epirium Bio, FibroGen, Halo Therapeutics, Italfarmaco, BioMarin Pharmaceutical, Novartis, Pfizer, Prosensa, PTC Therapeutics, Santhera Pharmaceuticals, and Sarepta Therapeutics. He has served on Advisory Boards for Avidity Biosciences, Capricor Therapeutics, Edgewise Therapeutics, PTC Therapeutics, and Sarepta therapeutics.

Dr. Henricson has served as a consultant or advisory board member for, or received research funds from Sarepta, Santhera, Pfizer, Epirium, Capricor, Catabasis, Mallinkrodt, Bristol-Myers-Squibb and PTC Therapeutics.

Dr. Upadhyayula has no disclosures.

Dr. Byrne serves on the North America Pompe Registry Advisory Board, Edgewise Therapeutics Scientific Advisory Board and Global DMD Advisory Board for Pfizer.

Dr. Manousakis has no disclosures.

Dr. Harper is site PI for clinical research studies sponsored by Novartis, NSPharma, Italafarmaco, Reveregan/Santhera, Astellas, Dyne, Fulcrum and MLBio.

Dr Iannaccone serves on advisory boards or as a consultant for Audentes Therapeutics Inc, Biomarin Pharmaceutical Inc, Edgewise Therapeutics Inc, Entrada Therapeutics Inc, Genentech Inc, Octapharma Use Inc, Taysha Gene Therapies Inc, Vertex Pharmaceutics Inc. Dr Iannaccone has research funding from AveXis/Novartis, Biogen, Capricor, Genentech, RegenxBio, Sarepta and Scholar Rock.

Dr. Dang has served as consultant to ReveraGen, and received research grants from Foundation to Eradicate Duchenne and NIH.

Figures

Fig. 1
Fig. 1
Boxplots using one median observation per participant per age interval stratified by age group and mutation status.
Fig. 2
Fig. 2
Spearman correlations of baseline outcome values for participants <18 years (left panel) and ≥18 years of age (right panel).
Fig. 3
Fig. 3
Overall trajectory plots of outcomes for participants in the Becker Natural History Study.
See this image and copyright information in PMC

References

    1. Bushby KM, Gardner-Medwin D The clinical, genetic and dystrophin characteristics of Becker muscular dystrophy. I. Natural history. J Neurol. 1993;240(2):98–104. - PubMed
    1. Bushby KM, Gardner-Medwin D, Nicholson LV, Johnson MA, Haggerty ID, Cleghorn NJ et al.., The clinical, genetic and dystrophin characteristics of Becker muscular dystrophy. II. Correlation of phenotype with genetic and protein abnormalities. J Neurol. 1993;240(2):105–12. - PubMed
    1. McDonald CM, Abresch RT, Carter GT, Fowler WM Jr, Johnson ER, Kilmer DD Profiles of neuromuscular diseases. Becker’s muscular dystrophy. Am J Phys Med Rehabil. 1995;74(5 Suppl):S93–103. - PubMed
    1. van den Bergen JC, Wokke BH, Janson AA, van Duinen SG, Hulsker MA, Ginjaar HB et al.., Dystrophin levels and clinical severity in Becker muscular dystrophy patients. J Neurol Neurosurg Psychiatry. 2014;85(7):747–53. - PubMed
    1. Clemens PR, Niizawa G, Feng J, Florence J, D’Alessandro AS, Morgenroth LP et al.., The CINRG Becker Natural History Study: Baseline characteristics. Muscle Nerve. 2020;62(3):369–76. - PMC - PubMed