Investigating the natural history of dysferlinopathy

Abstract

Dysferlinopathy is an autosomal recessively inherited muscular dystrophy. It is caused by absence, or disruption, of the skeletal muscle protein dysferlin, and is characterised by progressive muscle weakness and wasting. Clinically, dysferlin deficiency has been described as having several different presentations – most commonly a phenotype with predominantly limb girdle weakness (limb girdle muscular dystrophy R2; LGMDR2) or predominantly distal weakness (Miyoshi myopathy Type 1; MM1). Case reports and retrospective case series describe highly variable rates of progression of skeletal muscle weakness and possible cardiac and pulmonary involvement. However, as a rare disease affecting only 0.13 in 100,000 people in northern Europe, individual centres cannot collate enough patients to adequately describe the natural history of the disease. To counter this, the Jain Foundation sponsored an international clinical outcomes study (COS) for dysferlinopathy. This was the largest cohort study in dysferlinopathy to date, enrolling 207 genetically confirmed patients from 8 countries and assessing their genotypes, muscle pathology, motor, respiratory and cardiac function, and exploring serum biomarkers over 3 years. In this thesis, I used the `study data and samples to investigate the natural history of dysferlinopathy, leading to the development of an internationally agreed Standards of Care and improved trial readiness for patients. I characterised the cardiac and respiratory features of patients, directly informing monitoring recommendations within the Standards of Care. I demonstrated no cardiomyopathy and minimal respiratory involvement but a potential atrial conduction abnormality. In terms of trial readiness, I firstly demonstrated that disease progression was slow and highly variable, such that potential clinical trials would require large cohorts or more sensitive measures to demonstrate treatment effect. To increase the potential pool of patients available for clinical trials or eligible for ensuing treatment, I demonstrated that MM1 and LGMDR2 were not genetically or clinically different, and therefore both sets of patients could be assessed together. To assess for more sensitive outcome measures, I analysed a series of potential serum biomarkers of disease progression and demonstrated that myostatin could form a useful monitoring adjunct early in the disease course. To aid in selecting patients with a more uniform and rapid progression, I demonstrated that teenage exercise levels and water T2 MRI, but not myostatin concentration, predict the rate of subsequent disease progression. This work has increased our understanding of the natural history of dysferlinopathy, informing internationally agreed Standards of Care for patients with dysferlinopathy and contributing to trial readiness in this population.