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Quantitative Measurement of Glycosylated ⍺-Dystroglycan as a Biomarker for Disease Severity in Limb-Girdle Muscular
John Vissing1, Tahseen Mozaffar2, Nicholas E Johnson3
1Copenhagen Neuromuscular Center, Rigshospitalet, University of Copenhagen, Denmark.
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:
Of 96 participants enrolled, 71 participants underwent at least 1 TA biopsy (54 homozygous for the c.826C>A variant and 17 with other FKRP genotypes). Participants who were homozygous for the c.826C>A variant tended to be older, to be composed of a higher percentage of females, to have had less time since diagnosis, and to be composed of a greater percentage of ambulatory participants than those who had other FKRP genotypes. Glycosylated ⍺DG levels were consistently lower in LGMD2I/R9 participants than in the control at baseline (median 8.5% of control, interquartile range [IQR] 10.8%) and reflected disease severity by genotype, with c.826C>A homozygotes showing higher median glycosylated ⍺DG levels (10.5% of control, IQR 10.9%, n = 54) than participants with other FKRP 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.
