Assessment of disease progression in dysferlinopathy: A 1-year cohort study

Abstract

Objective: To assess the ability of functional measures to detect disease progression in dysferlinopathy over 6 months and 1 year.

Methods: One hundred ninety-three patients with dysferlinopathy were recruited to the Jain Foundation's International Clinical Outcome Study for Dysferlinopathy. Baseline, 6-month, and 1-year assessments included adapted North Star Ambulatory Assessment (a-NSAA), Motor Function Measure (MFM-20), timed function tests, 6-minute walk test (6MWT), Brooke scale, Jebsen test, manual muscle testing, and hand-held dynamometry. Patients also completed the ACTIVLIM questionnaire. Change in each measure over 6 months and 1 year was calculated and compared between disease severity (ambulant [mild, moderate, or severe based on a-NSAA score] or nonambulant [unable to complete a 10-meter walk]) and clinical diagnosis.

Results: The functional a-NSAA test was the most sensitive to deterioration for ambulant patients overall. The a-NSAA score was the most sensitive test in the mild and moderate groups, while the 6MWT was most sensitive in the severe group. The 10-meter walk test was the only test showing significant change across all ambulant severity groups. In nonambulant patients, the MFM domain 3, wrist flexion strength, and pinch grip were most sensitive. Progression rates did not differ by clinical diagnosis. Power calculations determined that 46 moderately affected patients are required to determine clinical effectiveness for a hypothetical 1-year clinical trial based on the a-NSAA as a clinical endpoint.

Conclusion: Certain functional outcome measures can detect changes over 6 months and 1 year in dysferlinopathy and potentially be useful in monitoring progression in clinical trials.

Clinicaltrialsgov identifier: NCT01676077.

Figure 1. Flowchart of patient numbers at each visit

Number of patients who completed each assessment (baseline, 6 months, and 12 months) and how many of them were used for each analysis window.

Figure 2. Change in timed tests over 6 months and 1 year

Boxplots showing range, interquartile range (IQR), and median values of time taken to perform timed tests. Paired comparisons of calculated velocity (1/time in seconds) were used to determine significant vs insignificant change in order to include those unable to complete the test. These are displayed as time taken to complete each task (rather than velocity) to aid visual interpretation. Comparisons of baseline and year 1, baseline and 6 months, and 6 months and 1 year are shown. The numbers differ depending on the number of patients completing each test at both visits. Blue shows significant change (p < 0.05) over 1 year; red shows if change is seen over both 6-month periods; and green shows change in only the green 6-month window. Some patients were very slow, and those taking >25 seconds to complete a test are not displayed but are included in median and IQR calculations.