OBJECTIVES: LGMD comprises a group of rare neuromuscular disorders. Patients with sarcoglycanopathies (autosomal recessive subtypes LGMD2C/R5, LGMD2D/R3, LGMD2E/R4, LGMD2F/R6) usually experience progressive muscle weakness that can lead to LOA and complications like respiratory insufficiency or cardiomyopathy. As the clinical course varies between patients even of the same subtype, designing clinical and real-world studies is challenging. Our objective was to summarize contemporary data on LOA among those with sarcoglycanopathies by subtype.

METHODS: A systematic review following PRISMA guidelines was conducted in May 2023. Among those with sarcoglycanopathies, aggregate and individual patient-level data (IPD) from cohort studies and case reports were extracted. Outcomes of interest were mean (standard deviation [SD]) age at disease onset and LOA (as defined by original investigators) by subtype. Potential predictors of earlier LOA were summarized.

RESULTS: From 1,123 abstracts, 16 studies reported IPD on ambulatory status among 185 patients with sarcoglycanopathies; 114 patients (62%) had LOA (n=11 LGMD2C/R5; n=17 LGMD2D/R3; n=70 LGMD2E/R4; n=16 LGMD2F/R6). Among patients with LOA, mean (SD) age at onset of LGMD symptoms was similar across subtypes (from 6.0 [1.6] for LGMD2C/R5 to 6.5 [2.5] years for LGMD2D/R3); age at LOA ranged from 13.6 (6.7) for LGMD2F/R6 to 17.6 (14.5) years in LGMD2C/R5. Three studies described the relationship between level of sarcoglycan protein expression and disease onset or LOA. Across subtypes, sarcoglycanopathy patients with reduced protein expression experienced earlier disease onset and earlier LOA (p<0.05).

CONCLUSIONS: Findings from this comprehensive synthesis suggest that patients with sarcoglycanopathies have disease onset in early childhood and commonly experience LOA. When LOA occurs, it typically occurs in adolescence; LGMD subtype and level of sarcoglycan expression may influence timing of LOA. Limitations included potential publication biases and small subgroup-specific sample sizes. These findings could have implications for designing and interpreting clinical and real-world studies to understand the clinical course of LGMD across subtypes.