Objective: To determine progression in limb girdle muscular dystrophy R9 (LGMD R9) measured by functional clinical outcome assessments (COAs).
Background: LGMD R9, an autosomal recessive form of LGMD due to mutations in the Fukutin-related protein (FKRP) gene, can lead to loss of ambulation, cardiomyopathy, and respiratory compromise. Clinical trials for this disease are being planned, but previously reported outcome measures have shown slow progression, a barrier to trial design.
Methods: We conducted a prospective observational study of clinically affected, genetically defined LGMD R9 participants at 11 international academic centers. COAs measured at baseline, 6, 9 and 12 months included the 100-meter timed walk, North Star Assessment for LGMD (NSAD), 4-stair climb, Timed Up and Go, Performance of Upper Limb 2.0 (PUL), and handheld dynamometry (HHD) in 6 bilateral upper extremity muscles. Participants were classified as ambulators (A) or difficulty with ambulation (DA) based on a baseline 10-meter walk/run cutoff of 12 seconds. We present mean changes with 95% confidence limits (CL).
Results: Twenty-three participants (52% women) completed 12 months of follow up. Mean age was 30.9 years, mean age of onset was 11.9 years, mean duration was 10.2 years, and 65.2% were homozygous for c.826C>A. The NSAD declined an average of 1.3 points (95% CL 0.3, 2.2) or 10%; the decline was larger for men (15.9%) or DA (18.7%). The PUL was stable (mean loss of 1.1 points or 2.5%; 95% CL -0.2, 2.4), with no differences based on gender, genetics, or ambulatory status. HHD was stable over 12 months, with change ranging from -5.3% to 5.1%. Results from other functional testing with considerations for trial design will be presented.
Conclusion: Preliminary results suggest a functional decline as measured by the NSAD and PUL over 12 months in LGMD R9. Variability estimates for future power calculations will be presented.
Funding: ML Bio Solutions