Background
Dysferlinopathy is caused by DYSF gene mutations. Rates of progression are variable, presenting challenges for clinical trials.
Aims
The Jain Foundation Clinical Outcome Study (COS) aims to address these issues by collecting natural history data in a multinational
cohort. Here, we present longitudinal progression of functional outcomes, considering changes over a 3-year period and progression
since symptom onset. Patients underwent physiotherapy assessments to capture current function. Previously identified sensitive
measures of progression [North Star Assessment for Dysferlinopathy (NSAD), ACTIVLIM, 10 Meter Walk Test (10MWT)] were
selected for longitudinal analysis; the 6 Minute Walk Test (6MWT), the most commonly used outcome in muscle disorders, was
included for comparison. Generalized estimating equations (GEE) were used to examine progression over time. Demographic and
clinical characteristics were evaluated to determine functional differences as well as differential progression rates by including
characteristic by time interaction terms. All 3-year models controlled for age.
Results
Significant decline in function was noted for all outcome measures over 3 years (p < 0.0001). Older age, younger age at onset, and
longer disease duration were all associated with greater functional decline (p < 0.0001). Patients who were earlier in their disease
(younger (< 30), shorter disease duration (≤ 10 years)) had steeper progression over 3 years, particularly participants 3-8 years from
symptom onset. Low to moderate timed test scores (velocity < 0.1) at baseline was also associated with greater progression. A
non-linear pattern of progression was noted across disease duration, with decline leveling off 30 years post symptom onset. A non-linear pattern of progression was noted across disease duration, with decline leveling off approximately 30 years post symptom onset. No differences in overall disease trajectories were noted based on patient characteristics, though patients with earlier onset had slightly poorer function.
Significant decline in function was noted for all outcome measures over 3 years (p < 0.0001). Older age, younger age at onset, and longer disease duration were all associated with greater functional decline. Patients who were earlier in their disease (disease duration ≤ 10 years) had steeper progression over 3 years, particularly participants 3-8 years from symptom onset. Low to moderate timed test scores at baseline (velocity < 0.21) was also associated with greater progression.
While overall disease progression is relatively consistent across patients, current disease state may inform inclusion criteria for clinical trials, though inclusion criteria should be weighed against the size of potentially eligible patient populations.
Conclusions
The present investigation provides a broad estimate of functional trajectories across disease duration, and aims to identify a specific patient group that could be targeted to power clinical trials efficiently.
Though this study provides a starting point for a better understanding of disease progression in patients with dysferlinopathy, there are a number of factors that should be explored further, including genetic differences and biochemical measures.
Linearisation of the NSAD will further strengthen its use as an outcome measure in dysferlinopathy and intrepreting change scores.
The relationship between the NSAD and the PUL (Performance of the Upper Limb) requires further evaluation.
Future studies will aim to explore these factors and confirm the present findings in an expanded patient population. Additionally, continued follow-up of the present population will permit a more detailed understanding of long term performance trajectories and functional loss.