A prospective observational study assessing the functional disease progression of LGMDR4, betasarcoglycan-related limb girdle muscular dystrophy.

Background: Limb-girdle muscular dystrophy (LGMD) R4, betasarcoglycanopathy, is a progressive muscle disease that frequently presents in childhood and results in loss of ambulation around 20 years of age. With interventional trials on the horizon it is essential to document functional disease progression using standardized performance outcome assessments (PerfO).

Methods: We present a prospective longitudinal observational study of individuals recruited through both Nationwide Children's Hospital neuromuscular clinics and through outreach events held in an area with a high incidence of Founder variant (c.452C > G). PerfOs included the NorthStar Assessment for limb-girdle dystrophies (NSAD), Performance of Upper Limb (PUL), timed function tests, and spirometry, as appropriate.

Results: Forty-six individuals enrolled (aged 3-55 years) with 22 (55%) ambulant. Most PerfOs quantified change over time. We found heterogeneity of functional abilities at all ages. In our cohort, children's performance improved until around age 7, followed by a plateau until around 10-12 years. The ability to rise from the floor was the first milestone lost and was unable to be completed by anyone who took longer than 7.7 s on the 10-meter. Further, performance on select PerfOs were related to skills of functional independence, informing clinical care and data driven trial design.

Conclusions: There is a great deal of functional heterogeneity. The selected PerfOs measured motor function and disease progression in individuals with LGMDR4, for the benefit of both data driven clinical management and clinical trial design.