Muscular Dystrophy Specialized Research Center

Project 2 Summary The long-term goal of Project 2 is to define the natural history of the dystroglycanopathies using established and evolving clinical measures, with the overall objective of optimizing clinical care, and informing and enhancing clinical trial design. This will be accomplished in 3 Aims. In Aim 1, we will further our understanding of the natural history of FKRP-related dystroglycanopathy. We follow a unique cohort of >100 people with a variety of FKRP mutations who range in age from early childhood through late adulthood. We will expand and extend evaluation of this cohort using standardized outcome measures. We are particularly interested in people who might be excluded from clinical trials, such as children and those with advanced disease. We will offer remote assessments to those with advanced disease, allowing us to relate motor outcomes to real-world endpoints (e.g. need for respiratory support). In Aim 2, similar methods will be employed to extend knowledge about the natural history of people with mutations in dystroglycanopathy genes other than FKRP, based on our current (56 individuals across 8 genotype groups) and growing cohort. We will test outcome measures across phenotypes and identify cohorts that share similar rates of motor progression who might be studied together in gene non-specific clinical trials. In Aim 3, we will explore two distinct types of potential biomarkers. First, we will investigate electroretinogram (ERG) as a candidate dystroglycanopathy biomarker based on a small pilot study in which we showed altered photoreceptor function in people with FKRP mutations. We will use an FDA approved handheld ERG device that allows rapid data acquisition and can be used with children to examine relationship of ERG findings with motor function. Finally, urine samples collected from study participants evaluated in Aims 1 and 2 will be utilized for proteomic biomarker assay, starting with urinary titin (collaboration with Project 1), to determine if change can be detected in concert with disease progression. Together these aims are highly likely to facilitate clinical trial design across phenotypes in this group of rare diseases that share the common pathophysiology of - dystroglycan hypoglycosylation.