Quantitative Measurement of Glycosylated ⍺-Dystroglycan as a Biomarker for Disease Severity in Limb-Girdle Muscular Dystrophy Type 2I/R9
Background and Objectives: Limb-girdle muscular dystrophy type 2I (LGMD2I/R9) is caused by biallelic variants in the gene for Fukutin-related protein (FKRP), an enzyme required for proper glycosylation of α-dystroglycan (⍺DG), a critical structural protein of the dystrophin glycoprotein complex. Hypoglycosylation of αDG results in impaired function of αDG, which in turn leads to chronic myocyte injury and muscular dystrophy. The "Biomarker Development in LGMD2I/R9" (MLB-01-001) natural history study explored glycosylated ⍺DG as a muscle biomarker for LGMD2I/R9 to support clinical trial design for the development of potential therapeutics. Methods: MLB-01-001 was a prospective, 12-month observational study of clinically affected participants 10-65 years of age with genetically confirmed LGMD2I/R9 at 11 academic centers in the United States and Denmark. Tibialis anterior (TA) muscle biopsies were obtained at baseline, month 6, month 9, and/or month 12 and measured for glycosylated ⍺DG levels relative to that of an unaffected human control using a validated, quantitative western blot assay. Results: genotypes (4.6% of control, IQR 4.3%, n = 17). Glycosylated αDG levels remained stable over 6-12 months. Discussion: Glycosylated ⍺DG was consistently lower in participants with LGMD2I/R9 than in the unaffected control, reflected disease severity by genotype, and remained stable over 6-12 months, suggesting that it may be an appropriate biomarker for assessing the effect of potential therapies for LGMD2I/R9. Trial Registration Information: ClinicalTrials.gov ID NCT04202627, first posted 17 Dec 2019.
Authors
- Douglas M. Sproule
- Tricia Blankenbiller
- Lindsay N. Alfano (ORCID: https://orcid.org/0000-0002-2263-7569)
- Jessica St. Romain (ORCID: https://orcid.org/0000-0002-8735-3583)
- Katherine D. Mathews (ORCID: https://orcid.org/0000-0003-4160-0435)
- Peter B. Kang (ORCID: https://orcid.org/0000-0002-4270-7325)
- George McLendon
- Hector M. Rodriguez
- Thulashitha Rajasingham
- Carla D. Zingariello (ORCID: https://orcid.org/0000-0001-9884-2190)
- Tahseen Mozaffar (ORCID: https://orcid.org/0000-0002-1230-0188)
- Marjet D. Heitzer
- Linda Lowes (ORCID: https://orcid.org/0000-0003-4206-0557)
- Kenneth Tripp
- Jeffrey M. Statland
- Kameron Bates
- Alyssa X. Wu-Zhang
- John Vissing
- Matthew P. Wicklund
- Nicholas E. Johnson
- Conrad Weihl
- Urvi Desai
- Doris G. Leung
Institutions
- University of Copenhagen (DK)
- Kennedy Krieger Institute (US)
- University of Minnesota (US)
- Nationwide Children's Hospital (US)
- The University of Texas at San Antonio Health Science Center (US)
- Virginia Commonwealth University (US)
- University of California, Irvine (US)
- Washington University in St. Louis (US)
- Carolinas Medical Center (US)
- University of Iowa Hospitals and Clinics (US)
- Copenhagen University Hospital (DK)
- Rigshospitalet (DK)
- University of Florida (US)
- University of Kansas Medical Center (US)
- Clinical Solutions (US)
Publication Details
- Journal
- Neurology Genetics
- Published
- 2026-04-01
- DOI
- https://doi.org/10.1212/nxg.0000000000200370
- Primary Topic
- Muscle Physiology and Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- ALS Association
- Friedreich's Ataxia Research Alliance
- AstraZeneca
- Sanofi
- Muscular Dystrophy Association
- Biogen
- Alexion Pharmaceuticals
- Alnylam Pharmaceuticals
- Cumberland Pharmaceuticals
- Virginia Commonwealth University
- Regeneron Pharmaceuticals
- Vertex Pharmaceuticals
- Friends of FSH Research
- AveXis
- Sarepta Therapeutics
- Amicus Therapeutics
- Harmony Biosciences
- Argenx
- Horizon Therapeutics
- Italfarmaco
- National Institutes of Health
- Centers for Disease Control and Prevention
- Sanofi Genzyme
- Spark Therapeutics
- National Institute of Neurological Disorders and Stroke
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- National Center for Advancing Translational Sciences