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

Elena Pegoraro, Pascal Bernatchez, Elena Bravver, Emmanuelle Salort-Campana, Diana X Bharucha-Goebel, Kristi J Jones, Dan Cox, Heather Hilsden, Heather Gordish Dressman, Laura Rufibach, Zoe White, John W Day, Maggie C Walter, Jerry R Mendell, Jordi Diaz-Manera, Volker Straub, Carmen Paradas, Tanya Stojkovic, Simone Spuler, Alan Pestronk, Madoka Mori-Yoshimura

Journal: Journal of cachexia, sarcopenia and muscle 2025;16(4):e70042

PMID: 40814795

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.

© 2025 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.

Address: Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia (UBC), Vancouver, Canada.; UBC Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, Canada.; Jain Foundation, Seattle, Washington, USA.; Center for Translational Science, Division of Biostatistics and Study Methodology, Children's National Health System, Washington, District of Columbia, USA.; Pediatrics, Epidemiology and Biostatistics, George Washington University, Washington, District of Columbia, USA.; The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.; 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.; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.; The Children's Hospital at Westmead, The University of Sydney, Sydney, New South Wales, Australia.; Department of Neurology, Children's National Health System, Washington, District of Columbia, USA.; National Institutes of Health (NINDS), Bethesda, Maryland, USA.; Neuromuscular and ALS Reference Center of Marseille, La Timone University Hospital, Marseille, France.; Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.; Friedrich-Baur-Institute, Department of Neurology, Ludwig Maximilian University of Munich, Munich, Germany.; Neuromuscular Unit, Department of Neurology, Hospital U. Virgen del Rocío/Instituto de Biomedicina de Sevilla, Sevilla, Spain.; Centre de Référence des Maladies Neuromusculaires, Institut de Myologie, Sorbonne Université, Hôpital Pitié-Salpêtrière, APHP, Paris, France.; Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.; Neuroscience Institute, Carolinas Neuromuscular/ALS-MDA Center, Carolinas HealthCare System, Charlotte, North Carolina, USA.; Department of Neuroscience, University of Padova, Padova, Italy.; The Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio, USA.
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