P.174Establishing divergent phenotypes in limb girdle muscular dystrophies

Abstract

The limb girdle muscular dystrophies (LGMD) are a heterogeneous group of rare genetic disorders characterized by progressive muscle weakness. While there are global similarities between the often proximal to distal progression of weakness, the specifics of disease onset, muscle involvement and sparing, as well as rate of change can vary dramatically across groups. Thus, thorough characterization of the natural history of each LGMD subtype is necessary to select appropriate outcomes for clinical trials. Two recessive forms of LGMD, types 2A (calpainopathy) and 2E (β-sarcoglycanopathy) are each highly prevalent in two unique Plain communities in Indiana. Outreach visits were scheduled at approximately 6 month intervals at which time 53 unique individuals with type 2A and 34 individuals with type 2E were seen over an average of 2.3 visits (range 1-5 visits). Age range between the 2 types were similar (2A=23.2±12.9 years, range 3-64; 2E=23.6±12.8, range 5-54). Subjects completed a battery of functional testing including the 100-meter timed test (100m), North Star Ambulatory Assessment for dysferlinopathy (NSAD), ACTIVE, and Performance of Upper Limb 2.0 (PUL). We had a larger percentage of functionally ambulatory patients (i.e. completed the 10 meter walk in <15 seconds) in the 2A cohort (N=38(72%)) than in our 2E group (N=17 or 50%). However, the LGMD2A cohort demonstrated a more severe decline or progression with average time to complete the 100m increasing 20 seconds over 1 year compared to 4 seconds in LGMD2E. Twenty-eight percent of subjects scored within 3 points of the maximum score on the PUL indicating a potential ceiling effect in strong cohorts. Rates of change across all functional outcomes will be presented. Our data support divergent phenotypes in LGMD2A and LGMD2E underscoring the importance of a thorough analysis of outcomes in each diagnosis. Understanding different rates of expected functional decline is key to interpretation of trial results.