Background: Limb-girdle muscular dystrophy subtype 2I/R9 (LGMD2I/R9) is a rare muscular disorder caused by loss-of-function mutations in the fukutin-related protein gene, reducing glycosylation of α-dystroglycan (αDG), a key protein for muscle integrity. Patients (pts) experience progressive weakness and loss of muscle function leading to mobility challenges, loss of independence, and reduced quality of life. This systematic literature review (SLR) examined the association between glycosylated αDG and clinical outcomes in pts with LGMD2I/R9, and the clinical, humanistic, and economic burden of LGMD2I/R9.
Methods: The SLR followed PRISMA 2020 guidelines (PROSPERO: CRD42025640843). Searches were conducted in Embase, MEDLINE, and the Cochrane Library (Jan 2004–Dec 2024), and were supplemented by congress abstract searches (2021–2024). Titles and abstracts were screened in duplicate against predefined eligibility criteria, full texts reviewed by multiple reviewers, and data extracted with independent validation. Risk of bias was assessed for included studies.
Results: Of 2039 records screened, 71 studies (62 full-text; 9 abstracts) were included in the SLR. Five studies reported reduced glycosylated αDG levels in pts with LGMD2I/R9, with some evidence correlating lower αDG glycosylation with poorer outcomes and genotype, although data were limited and largely cross-sectional. Muscle function was reported in 28 studies; muscle weakness ranged from 17.6–100.0% across varied assessments and populations, with hypertrophy, atrophy, and contractures also documented. Proportions of ambulatory individuals varied by study; in the largest (n=305), 24.6% were nonambulatory and ambulation varied by genotype. Cardiac involvement (reported in 23 studies) ranged from 13.2–87.5% (23.2% in the largest cohort). Respiratory involvement ranged up to 64.3% (ventilatory support: noninvasive, 15.1–31.6%; invasive, 2.9%). Nine studies showed poorer quality of life vs healthy controls, with fatigue, pain, and poor sleep quality contributing to impaired well-being. Economic evidence was limited (1 study); no studies evaluated caregiver experience. Given the rarity of LGMD2I/R9, studies are often small and heterogeneous, with a potential risk of bias.
Conclusions: SLR findings demonstrated the considerable burden of LGMD2I/R9. Key evidence gaps include economic and caregiver impact and longitudinal data on the association between glycosylated αDG and functional outcomes.