M. James

The Clinical Outcome Study for dysferlinopathy: An international multicenter study

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.

Teenage exercise is associated with earlier symptom onset in dysferlinopathy: a retrospective cohort study

Dysferlinopathy, an autosomal recessive muscular dystrophy caused by DYSF mutations, demonstrates a variable phenotype and progression rate, with symptom onset ranging from first to eighth decade and some patients requiring wheelchairs for mobility within 10 years, with others remaining minimally affected.1 Dysferlinopathy populations have previously been described as having an unusually high level of presymptomatic sporting ability.2 We hypothesised that this activity could be related to subsequent disease progression and investigated the hypothesis using data from the Jain Foundation’s Clinical Outcomes Study (COS) of 202 patients with dysferlinopathy.1 Data were used from 182 of the 202 patients enrolled in the Jain COS; 10 dropped out and did not give permission to use their data and 10 did not fully complete the exercise questionnaire. The questionnaire used in the screening visits (online supplementary information) between 6 November 2012 and 19 March 2015 asked about the type, level and frequency of all physical activity prior to symptom onset. Self-reported age of first symptoms, first wheelchair use and full-time wheelchair use was taken from screening questionnaires. Exercises were classified based on metabolic equivalents (METs) as moderate (MET 3–6) or vigorous (MET >6) (online supplementary table 1).3 Participants were coded, based on the maximum frequency of activity reported between ages 10 and 18 years, as 0—no physical activity; 1—vigorous activity occasionally/monthly, or moderate activity once weekly; 2— moderate activity multiple times per week or vigorous activity once weekly; and 3—vigorous activity multiple times per week. ### Supplementary file 1 [jnnp-2017-317329-SP1.pdf] ### Statistical analysis Age of symptom onset was compared by analysis of variance (ANOVA) with least squares means for individual group differences. Risk of symptom onset, occasional wheelchair use and full-time wheelchair requirement over time were compared for exercise groups 1, 2 and 3 against group 0 using Cox proportional hazards regression. Proportional hazards assumption was violated …

Muscle MRI in patients with dysferlinopathy: pattern recognition and implications for clinical trials

Background and objective Dysferlinopathies are a group of muscle disorders caused by mutations in the DYSF gene. Previous muscle imaging studies describe a selective pattern of muscle involvement in smaller patient cohorts, but a large imaging study across the entire spectrum of the dysferlinopathies had not been performed and previous imaging findings were not correlated with functional tests. Methods We present cross-sectional T1-weighted muscle MRI data from 182 patients with genetically confirmed dysferlinopathies. We have analysed the pattern of muscles involved in the disease using hierarchical analysis and presented it as heatmaps. Results of the MRI scans have been correlated with relevant functional tests for each region of the body analysed. Results In 181 of the 182 patients scanned, we observed muscle pathology on T1-weighted images, with the gastrocnemius medialis and the soleus being the most commonly affected muscles. A similar pattern of involvement was identified in most patients regardless of their clinical presentation. Increased muscle pathology on MRI correlated positively with disease duration and functional impairment. Conclusions The information generated by this study is of high diagnostic value and important for clinical trial development. We have been able to describe a pattern that can be considered as characteristic of dysferlinopathy. We have defined the natural history of the disease from a radiological point of view. These results enabled the identification of the most relevant regions of interest for quantitative MRI in longitudinal studies, such as clinical trials. Clinical trial registration NCT01676077.

P71 International clinical outcomes study in dysferlinopathy (COS): results of screening questionnaires in UK patients

Mutations in dysferlin cause a variety of phenotypes collectively known as dysferlinopathies, including Limb Girdle Muscular Dystrophy type 2B and Myoshi Myopathy. Although there is currently no treatment for dysferlinopathies there is a need to develop clinically validated outcome measures in dysferlinopathy in preparation for future clinical trials. The International Clinical Outcomes Study for Dysferlinopathy (COS) is a multicentre international study, funded by The Jain Foundation and sponsored by Newcastle upon Tyne NHS Foundation Trust, which aims to develop and validate clinical outcome measures in addition to collecting natural history data. The recruitment target of 150 patients has now been successfully achieved, with a total of 193 patients recruited in 14 centres worldwide, including 38 UK patients. Data will be collected over 3years, including physiotherapy and medical assessments, MRI and questionnaires. In this poster we present data from screening questionnaires, including mutations identified and patient-reported details of disease presentation in all 38 UK patients. In total 49 different mutations were identified. Mean age at symptom onset was 22.3years and mean time to subsequent diagnosis was 6.1years. Polymyositis was initially incorrectly diagnosed in 6/38 patients. Lower limbs were the most common first affected area (23/38), and muscle weakness the most frequent first symptom (20/38). This data confirms that dysferlinopathies primarily present in young adulthood, often initially with lower limb symptoms, and are associated with significant allelic heterogeneity. Completion of this study and subsequent analyses will enhance our understanding of the natural history this variable condition.