John Vissing, Tahseen Mozaffar, Nicholas E. Johnson, Katherine D. Mathews, Matthew P. Wicklund, Conrad Weihl, Doris G. Leung, Jeffrey M. Statland, Peter B. Kang, Carla D. Zingariello, Linda Lowes, Urvi Desai, Kameron Bates, Lindsay N. Alfano, Han Xie, Jessica St. Romain, Tricia Blankenbiller, George McLendon, Thulashitha Rajasingham, Marjet D. Heitzer, Alyssa X. Wu-Zhang, Kenneth Tripp, Hector M. Rodriguez, Douglas M. Sproule
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.