High-Density Lipoprotein-Associated Cholesterol Abnormalities in a Clinical Outcomes Study of Dysferlin-Deficient Limb-Girdle Muscular Dystrophy Type R2

Zoe White, Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia (UBC), Vancouver, Canada.
Laura Rufibach, Jain Foundation, Seattle, Washington, USA.
Heather Gordish Dressman, Center for Translational Science, Division of Biostatistics and Study Methodology, Children's National Health System, Washington, District of Columbia, USA.
Heather Hilsden, The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Dan Cox, The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Simone Spuler, Charité Muscle Research Unit, Experimental and Clinical Research Center, a Joint Cooperation of the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine, Berlin, Germany.
John W. Day, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
Kristi J. Jones, The Children's Hospital at Westmead, The University of Sydney, Sydney, New South Wales, Australia.
Diana X. Bharucha-Goebel, Department of Neurology, Children's National Health System, Washington, District of Columbia, USA.
Emmanuelle Salort-Campana, Neuromuscular and ALS Reference Center of Marseille, La Timone University Hospital, Marseille, France.
Alan Pestronk, Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
Maggie C. Walter, Friedrich-Baur-Institute, Department of Neurology, Ludwig Maximilian University of Munich, Munich, Germany.
Carmen Paradas, Neuromuscular Unit, Department of Neurology, Hospital U. Virgen del Rocío/Instituto de Biomedicina de Sevilla, Sevilla, Spain.
Tanya Stojkovic, Centre de Référence des Maladies Neuromusculaires, Institut de Myologie, Sorbonne Université, Hôpital Pitié-Salpêtrière, APHP, Paris, France.
Madoka Mori-Yoshimura, Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.
Elena Bravver, Neuroscience Institute, Carolinas Neuromuscular/ALS-MDA Center, Carolinas HealthCare System, Charlotte, North Carolina, USA.
Jordi Diaz-Manera, The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Elena Pegoraro, Department of Neuroscience, University of Padova, Padova, Italy.
Jerry R. Mendell, The Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio, USA.

Document Type

Journal Article

Publication Date

8-1-2025

Journal

Journal of cachexia, sarcopenia and muscle

Volume

16

Issue

4

DOI

10.1002/jcsm.70042

Keywords

cholesterol; dysferlin; dyslipidemia; muscular dystrophy

Abstract

BACKGROUND: Limb-girdle muscular dystrophy (MD) type R2 (LGMDR2, formerly LGMD2B) is an autosomal recessive form of MD caused by variants in the dysferlin gene, DYSF. It leads to slow proximal and distal muscle weakening that generally results in loss of ambulation around early adulthood but without the lethal cardiorespiratory dysfunction observed in the more severe Duchenne MD. How loss of dysferlin causes muscle fibre death is poorly understood, but recent evidence suggests a link between muscle wasting and loss of muscle cholesterol homeostasis with circulating lipoprotein abnormalities in many forms of MD. METHODS: Cross-sectional circulating total cholesterol (CHOL), high-density lipoprotein-associated cholesterol (HDL-C), non-HDL-C, creatine kinase (CK), transaminase levels and bilirubin were collected as part of the Jain Clinical Outcomes Study of Dysferlinopathy, a large multicentre LGMDR2 patient cohort (N = 188), along with ambulatory function values. RESULTS: We report that 43%, 49% and 50% of male patients were found to have abnormal circulating CHOL, HDL-C and non-HDL-C levels, respectively, whereas in female patients 39%, 37% and 30% of values were in the abnormal range. Overall, 68% of the total cohort had at least one abnormal cholesterol value (78% of males and 60% of females) and 89% of male CHOL/HDL-C ratios were in the suboptimal range (above 3.5). Although most patients were ambulant, the severity of circulating lipid abnormalities did not correlate with early loss of ambulation. Transaminase levels were lower in late-stage LGMDR2 samples, whereas bilirubin remained unchanged, suggesting a low muscular mass rather than hepatic origin and the absence of major liver damage. CONCLUSIONS: Data from the largest natural history cohort of LGMDR2 patients support the concept that dyslipidemia is a comorbidity of LGMDR2, and the causal role of cholesterol abnormalities in muscle death should be further investigated.

Department

Epidemiology

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