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.
Objective To investigate biomarkers of disease progression in cerebrospinal fluid (CSF) and serum in adult patients with spinal muscular atrophy (SMA). Furthermore, we assess the clinical response to nusinersen treatment in adults with SMA over a longer follow‐up period than the previously reported 6–14 months. Methods We included 16 adults with SMA type 3–4 for nusinersen treatment over 22 months in this prospective study. We evaluated chitotriosidase‐1 (CHIT1) and chitinase‐3‐like protein 1 (YKL‐40) as neuroinflammatory biomarkers in CSF, and neurofilament light chain (NfL) and heavy chain (pNfH) as neurodegenerative markers in CSF and serum at baseline, month 6, 14 and 22, together with a wide range of clinical outcome measures. Results Levels of CHIT1 increased significantly (p = 0.048) throughout the 22‐month treatment period and pNfH decreased significantly (p = 0.022) in CSF, but both did not correlate with clinical outcome measures. YKL‐40 correlated strongly with neurofilaments in CSF (rho = 0.76) and decreased significantly (p = 0.037) in patients with improvements in the revised upper limb module (RULM). Finally, patients showed significant improvements in hand grip strength, hand motor function, medical research council (MRC) sum score, and peak expiratory flow (PEF) after 22 months of treatment. Interpretation YKL‐40 in CSF correlated with clinical improvements during nusinersen treatment. In contrast, CHIT1 and pNfH in CSF changed significantly during treatment but did not correlate with clinical outcomes. Finally, we demonstrated a sustained clinical effect of nusinersen treatment in adults after 22 months.
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