The international clinical outcome study in dysferlinopathy

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Objectives The Jain Clinical Outcome Study (COS) is the largest international natural history study in patients with genetically confirmed dysferlinopathy. We recruited 203 participants across 15 sites in 8 countries. The aim of the study was to analyse longitudinal clinical data over the first year of the study, describe the muscle MRI pattern and longitudinal changes in quantitative muscle MRI. Methods An adapted North Star Ambulatory Assessment (aNSAA), MFM-20 and timed tests (rise from floor, 10 metre walk/run, four stair climb and descend, Timed Up and Go (TUG) and 6MWD) were completed at baseline, six months and year 1. A semi-quantitative MRI analysis was performed on T1-weighted axial sequences at baseline in 182 patients using the Mercuri scale modified by Fisher. Hierarchical analysis was performed to define the selective pattern of involvement. Results of the T1-weighted were correlated with appropriate functional tests. Quantitative muscle MRI is made annually based on fat/water separation (Dixon techniques) and muscle water T2 mapping (Multi-Slice Multi-Echo, MSME). Results aNSAA, MFM-20, 10m walk test, and TUG demonstrated consistent deterioration in scores or time taken over each 6 months window, although variation in the change scores was wide. The rise from floor, stair climb and stair descend detected significant change over one year. On muscle MRI scans, gastrocnemius medialis and soleus were most frequently affected. A similar pattern of involvement was identified regardless of clinical phenotype. The increase of fat replacement on MRI correlated positively with disease duration and functional tests. MRI fat fraction showed significant change over a year. However water T2 did not change significantly. Conclusions Functional tests showed changes at 6 months and 1 year. Semi-quantitative MRI can help define the muscle pattern of fat replacement. We detected significant changes in thigh and calf muscles using muscle MRI quantitative Dixon sequences.