High‐Density Lipoprotein‐Associated Cholesterol Abnormalities in a Clinical Outcomes Study of Dysferlin‐Deficient Limb–Girdle Muscular Dystrophy Type R2
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...
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2025-08-01
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| Series: | Journal of Cachexia, Sarcopenia and Muscle |
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| Online Access: | https://doi.org/10.1002/jcsm.70042 |
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| author | Zoe White Laura Rufibach Heather Gordish Dressman Heather Hilsden Dan Cox Simone Spuler John W. Day Kristi J. Jones Diana X. Bharucha‐Goebel Emmanuelle Salort‐Campana Alan Pestronk Maggie C. Walter Carmen Paradas Tanya Stojkovic Madoka Mori‐Yoshimura Elena Bravver Jordi Diaz‐Manera Elena Pegoraro Jerry R. Mendell the Jain COS Consortium Volker Straub Pascal Bernatchez |
| author_facet | Zoe White Laura Rufibach Heather Gordish Dressman Heather Hilsden Dan Cox Simone Spuler John W. Day Kristi J. Jones Diana X. Bharucha‐Goebel Emmanuelle Salort‐Campana Alan Pestronk Maggie C. Walter Carmen Paradas Tanya Stojkovic Madoka Mori‐Yoshimura Elena Bravver Jordi Diaz‐Manera Elena Pegoraro Jerry R. Mendell the Jain COS Consortium Volker Straub Pascal Bernatchez |
| author_sort | Zoe White |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-dbc8fea5f2c4476182389de75818bb4b |
| institution | Kabale University |
| issn | 2190-5991 2190-6009 |
| language | English |
| publishDate | 2025-08-01 |
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| series | Journal of Cachexia, Sarcopenia and Muscle |
| spelling | doaj-art-dbc8fea5f2c4476182389de75818bb4b2025-08-22T07:30:53ZengWileyJournal of Cachexia, Sarcopenia and Muscle2190-59912190-60092025-08-01164n/an/a10.1002/jcsm.70042High‐Density Lipoprotein‐Associated Cholesterol Abnormalities in a Clinical Outcomes Study of Dysferlin‐Deficient Limb–Girdle Muscular Dystrophy Type R2Zoe White0Laura Rufibach1Heather Gordish Dressman2Heather Hilsden3Dan Cox4Simone Spuler5John W. Day6Kristi J. Jones7Diana X. Bharucha‐Goebel8Emmanuelle Salort‐Campana9Alan Pestronk10Maggie C. Walter11Carmen Paradas12Tanya Stojkovic13Madoka Mori‐Yoshimura14Elena Bravver15Jordi Diaz‐Manera16Elena Pegoraro17Jerry R. Mendell18the Jain COS ConsortiumVolker Straub19Pascal Bernatchez20Department of Anesthesiology, Pharmacology & Therapeutics University of British Columbia (UBC) Vancouver CanadaJain Foundation Seattle Washington USACenter for Translational Science, Division of Biostatistics and Study Methodology Children's National Health System Washington District of Columbia USAThe John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute Newcastle University and Newcastle Hospitals NHS Foundation Trust Newcastle upon Tyne UKThe John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute Newcastle University and Newcastle Hospitals NHS Foundation Trust Newcastle upon Tyne UKCharité 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 GermanyDepartment of Neurology and Neurological Sciences Stanford University School of Medicine Stanford California USAThe Children's Hospital at Westmead The University of Sydney Sydney New South Wales AustraliaDepartment of Neurology Children's National Health System Washington District of Columbia USANeuromuscular and ALS Reference Center of Marseille La Timone University Hospital Marseille FranceDepartment of Neurology Washington University School of Medicine St. Louis Missouri USAFriedrich‐Baur‐Institute, Department of Neurology Ludwig Maximilian University of Munich Munich GermanyNeuromuscular Unit, Department of Neurology Hospital U. Virgen del Rocío/Instituto de Biomedicina de Sevilla Sevilla SpainCentre de Référence des Maladies Neuromusculaires, Institut de Myologie, Sorbonne Université, Hôpital Pitié‐Salpêtrière APHP Paris FranceDepartment of Neurology, National Center Hospital National Center of Neurology and Psychiatry Tokyo JapanNeuroscience Institute, Carolinas Neuromuscular/ALS‐MDA Center Carolinas HealthCare System Charlotte North Carolina USAThe John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute Newcastle University and Newcastle Hospitals NHS Foundation Trust Newcastle upon Tyne UKDepartment of Neuroscience University of Padova Padova ItalyThe Abigail Wexner Research Institute Nationwide Children's Hospital Columbus Ohio USAThe John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute Newcastle University and Newcastle Hospitals NHS Foundation Trust Newcastle upon Tyne UKDepartment of Anesthesiology, Pharmacology & Therapeutics University of British Columbia (UBC) Vancouver CanadaABSTRACT 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.https://doi.org/10.1002/jcsm.70042cholesteroldysferlindyslipidemiamuscular dystrophy |
| spellingShingle | Zoe White Laura Rufibach Heather Gordish Dressman Heather Hilsden Dan Cox Simone Spuler John W. Day Kristi J. Jones Diana X. Bharucha‐Goebel Emmanuelle Salort‐Campana Alan Pestronk Maggie C. Walter Carmen Paradas Tanya Stojkovic Madoka Mori‐Yoshimura Elena Bravver Jordi Diaz‐Manera Elena Pegoraro Jerry R. Mendell the Jain COS Consortium Volker Straub Pascal Bernatchez High‐Density Lipoprotein‐Associated Cholesterol Abnormalities in a Clinical Outcomes Study of Dysferlin‐Deficient Limb–Girdle Muscular Dystrophy Type R2 Journal of Cachexia, Sarcopenia and Muscle cholesterol dysferlin dyslipidemia muscular dystrophy |
| title | High‐Density Lipoprotein‐Associated Cholesterol Abnormalities in a Clinical Outcomes Study of Dysferlin‐Deficient Limb–Girdle Muscular Dystrophy Type R2 |
| title_full | High‐Density Lipoprotein‐Associated Cholesterol Abnormalities in a Clinical Outcomes Study of Dysferlin‐Deficient Limb–Girdle Muscular Dystrophy Type R2 |
| title_fullStr | High‐Density Lipoprotein‐Associated Cholesterol Abnormalities in a Clinical Outcomes Study of Dysferlin‐Deficient Limb–Girdle Muscular Dystrophy Type R2 |
| title_full_unstemmed | High‐Density Lipoprotein‐Associated Cholesterol Abnormalities in a Clinical Outcomes Study of Dysferlin‐Deficient Limb–Girdle Muscular Dystrophy Type R2 |
| title_short | High‐Density Lipoprotein‐Associated Cholesterol Abnormalities in a Clinical Outcomes Study of Dysferlin‐Deficient Limb–Girdle Muscular Dystrophy Type R2 |
| title_sort | high density lipoprotein associated cholesterol abnormalities in a clinical outcomes study of dysferlin deficient limb girdle muscular dystrophy type r2 |
| topic | cholesterol dysferlin dyslipidemia muscular dystrophy |
| url | https://doi.org/10.1002/jcsm.70042 |
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