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 extend our current work to define the natural history of FKRP-related dystroglycanopathy. We follow a unique cohort of patients aged early childhood through late adulthood with a range of FKRP mutations. We will expand and extend evaluation of this cohort using standard, validated outcome measures. We will engage those who are no longer able to travel due to disease progression with remote assessments allowing us to relate motor outcomes to real-world endpoints (loss of ambulation, need for respiratory support). We will also add additional evaluation sites for this patient cohort to expand the cohort and confirm that the outcome measures are valid across sites for the FKRP-related patient population.
In Aim 2, we will extend our follow up of a cohort of dystroglycanopathy patients with mutations in genes other than FKRP. Each of these genotypes is quite rare. We will identify cohorts that share similar rates of motor progression who might be studied together in gene non-specific clinical trials. We will collect annual blood and urine samples from patients evaluated in Aims 1 and 2 and a subset of these samples will be used in Aim 3 for proteomic biomarker identification. Previous work identified a set of candidate protein biomarkers for patients with FKRP mutations. We will validate these in a separate set of patient samples and determine if any change in concert with disease progression. Discovery of new very low abundance proteins will produce novel candidates for validation.
