The Clinical Outcome Study for dysferlinopathy: An international multicenter study

Abstract

Objective: To describe the baseline clinical and functional characteristics of an international cohort of 193 patients with dysferlinopathy.

Methods: The Clinical Outcome Study for dysferlinopathy (COS) is an international multicenter study of this disease, evaluating patients with genetically confirmed dysferlinopathy over 3 years. We present a cross-sectional analysis of 193 patients derived from their baseline clinical and functional assessments.

Results: There is a high degree of variability in disease onset, pattern of weakness, and rate of progression. No factor, such as mutation class, protein expression, or age at onset, accounted for this variability. Among patients with clinical diagnoses of Miyoshi myopathy or limb-girdle muscular dystrophy, clinical presentation and examination was not strikingly different. Respiratory impairment and cardiac dysfunction were observed in a minority of patients. A substantial delay in diagnosis was previously common but has been steadily reducing, suggesting increasing awareness of dysferlinopathies.

Conclusions: These findings highlight crucial issues to be addressed for both optimizing clinical care and planning therapeutic trials in dysferlinopathy. This ongoing longitudinal study will provide an opportunity to further understand patterns and variability in disease progression and form the basis for trial design.

Figures

Figure 1.. Age of patients at symptom onset and diagnosis

The mean time from onset to diagnosis was 6 years.

Figure 2.. Patient stratification by the reported duration of symptoms and disease severity at the time of assessment

The percentage of patients within each severity category is given. Severity is defined as mild if the adapted North Star Ambulatory Assessment score is 40–51, moderate: 6–39, severe: 5 or less or nonambulatory. Symptomatic patients for whom sufficient data were available to assign severity were included (n = 182). Numbers of patients within each category are as follows: mild n = 34, moderate n = 89, severe n = 59.

Figure 3.. Comparison of median manual muscle test scores in the upper and lower limbs

Data were available for 189 study participants. The 5-point Medical Research Council power grade was converted to an 11-point scale (0, 1, 2, 3−, 3, 3+, 4−, 4, 4+, 5−, and 5). Observed Manual Muscle Testing scores ranged from 0 or 1 to 10 for each movement assessed, with the exception of wrist extension for which the lowest observed score was 2. Overall, the most severely affected muscle groups were hip adduction, extension, knee flexion and extension, and ankle plantar flexion, dorsiflexion, and eversion. The least severely affected muscle groups were wrist flexion and extension. Red indicates the upper limb muscles and blue indicates the lower limb muscles. COS = Clinical Outcome Study.