Modeling of Dysferlinopathy (LGMDR2) Progression: A Longitudinal Fat Fraction Analysis

Carla Florencia Bolano-Diaz, The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Central Parkway, Newcastle Upon Tyne, United Kingdom.
Harmen Reyngoudt, NMR Laboratory, Neuromuscular Investigation Centre, Institute of Myology, Paris, France.
Ian J. Wilson, Newcastle Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, United Kingdom.
Meredith K. James, The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Central Parkway, Newcastle Upon Tyne, United Kingdom.
Fiona Elizabeth Smith, Newcastle Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, United Kingdom.
Ericky Caldas de Almeida Araujo, NMR Laboratory, Neuromuscular Investigation Centre, Institute of Myology, Paris, France.
Heather Gordish-Dressman, Center for Translational Science, Division of Biostatistics and Study Methodology, Children's National Health System, Washington, DC.
Heather Hilsden, The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Central Parkway, Newcastle Upon Tyne, United Kingdom.
Laura E. Rufibach, The Jain Foundation, Seattle, WA.
Dorothy Wallace, Newcastle Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, United Kingdom.
Louise Ward, Newcastle Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, United Kingdom.
Roberto Stramare, Radiology Unit, Department of Medicine, University of Padova, Italy.
Alessandro Rampado, Radiology Unit, Department of Medicine, University of Padova, Italy.
Mark Smith, Department of Radiology, Nationwide Children's Hospital, Columbus, OH.
Jean-Marc Boisserie, NMR Laboratory, Neuromuscular Investigation Centre, Institute of Myology, Paris, France.
Julien Le Louer, NMR Laboratory, Neuromuscular Investigation Centre, Institute of Myology, Paris, France.
Sheryl Foster, Department of Radiology, Westmead Hospital; Faculty of Health Sciences, The University of Sydney, Australia.
Anthony Peduto, Department of Radiology, Westmead Hospital; Faculty of Health Sciences, The University of Sydney, Australia.
Noriko Sato, Department of Radiology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.
Takeshi Tamaru, Department of Radiology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.
Anne Marie Sawyer, Lucas Centre for Imaging, Stanford University School of Medicine, CA.
John W. Day, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, CA.
Kristi J. Jones, Sydney Children's Hospital Network, Sydney, Austrialia.
Maggie Christine Walter, Friedrich Baur Institute at the Department of Neurology, LMU University Hospital, LMU Munich.
Tanya Stojkovic, Institut de Myologie, AP-HP, Hôpital Pitié-Salpêtrière, Centre de référence des maladies neuromusculaires Nord/Est/Ile de France, Paris, France.
Madoka Mori-Yoshimura, Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry Tokyo, Japan.
Jerry R. Mendell, Nationwide Children's Hospital, Columbus, OH.
Elena Pegoraro, Department of Neuroscience, University of Padova, Italy; and.
Volker Straub, The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Central Parkway, Newcastle Upon Tyne, United Kingdom.
Andrew M. Blamire, Newcastle Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, United Kingdom.
Pierre Carlier, NMR Laboratory, Neuromuscular Investigation Centre, Institute of Myology, Paris, France.
Jordi Diaz-Manera, The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Central Parkway, Newcastle Upon Tyne, United Kingdom.

Document Type

Journal Article

Publication Date

8-1-2025

Journal

Neurology. Genetics

Volume

11

Issue

4

DOI

10.1212/NXG.0000000000200283

Abstract

BACKGROUND AND OBJECTIVES: Limb-girdle muscular dystrophy R2 (LGMDR2) is characterized by progressive muscle weakness usually leading to severe disability. The rate of progression and disease severity is variable among patients, although factors influencing this variability are not completely understood. The Dysferlinopathy Clinical Outcome Study is a natural history study that followed patients with LGMDR2 for 3 consecutive years using functional outcome measures and skeletal muscle MRI.The aim of our study was to develop statistical models able to describe fat fraction (FF) progression of the lower limbs in patients with LGMDR2 using clinical and radiologic variables to better understand which factors influence disease progression and improve the design of future clinical trials. METHODS: We used linear-mixed modeling to analyze changes in FF over time according to patients' age. We calculated the average FF trajectory for each muscle of the lower limbs. We built 2 multivariate models for each segment adding other clinical factors and using likelihood ratio test and residuals' analysis to determine whether they better fitted observed FF values. RESULTS: Muscles that participated in the same joint movement progressed similarly over time. FF was expected to be higher the older patients were and the earlier the age at symptom onset. Women had absolute FF values 8.8% higher than men in the lower leg. No differences in FF trajectory were seen based on ethnic groups (White, Asian, Black, or Hispanic), genetic variants, or residual dysferlin expression. Although multivariate models showed a better global fit to the data, there was no improvement in representing individual patient variability. DISCUSSION: In conclusion, this study provides a better understanding of skeletal muscle fat replacement progression in the lower limb muscles of patients with LGMDR2, highlighting the influence of age at symptom onset, sex, and baseline motor function, which should be considered in the design and analysis of clinical trials. Although complex models improved the overall data fit, they did not improve the accuracy in identifying changes at a patient level, underlying the need for further research and validation and the fact that other variables we have not measured are probably influencing progression.

Department

Pediatrics

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