Prospective Natural History Study in 24 Adult Patients With LGMDR12 Over 2 Years’ Follow-up: Quantitative MRI and Clinical Outcome Measures

Abstract

Background and Objectives:

Limb-Girdle Muscular Dystrophy autosomal recessive type 12 (LGMDR12) is a rare hereditary muscular dystrophy for which outcome measures are currently lacking. We evaluated quantitative MRI and clinical outcome measures to track disease progression, in order to determine which tests could be useful in future clinical trials to evaluate potential therapies.

Methods:

We prospectively measured the following outcome measures in all participants at baseline and after 1 and 2 years: six-minute walk distance (6MWD), 10-meter walk test (10MWT), Medical Research Council (MRC) sum scores, Biodex® isometric dynamometry, serum creatine kinase (CK) and 6-point Dixon MRI of the thighs.

Results:

We included 24 genetically confirmed, adult LGMDR12 patients and 24 age- and sex-matched healthy controls. Patients with intermediate stage thigh muscle fat replacement at baseline (proton density fat fraction (PDFF) 20-70%) already showed a significant increase in PDFF in 8/14 evaluated thigh muscles after one year. The standardized response mean (SRM) demonstrated a high responsiveness to change in PDFF for 6 individual muscles over 2 years in this group. However, in patients with early (<20%) or end stage (>70%) muscle fat replacement, PDFF did not increase significantly over two years of follow-up.

Biodex® isometric dynamometry showed a significant decrease of muscle strength in all patients in the right and left hamstrings (-6.2Nm, p<0.002 and -4.6 Nm, p<0.009, respectively) and right quadriceps muscles (-9 Nm, p=0.044) after 1 year of follow-up, whereas the 6MWD, 10MWT, and MRC sum scores were not able to detect a significant decrease in muscle function/strength even after two years. There was a moderately strong correlation between total thigh PDFF and clinical outcome measures at baseline.

Discussion:

Thigh muscle PDFF imaging is a sensitive outcome measure to track progressive muscle fat replacement in selected LGMDR12 patients even after one year of follow-up and correlates with clinical outcome measures. Biodex® isometric dynamometry can reliably capture loss of muscle strength over the course of one year in LGMDR12 patients and should be included as an outcome measure in future clinical trials as well.