P.160 Clinical outcome assessments in limb girdle muscular dystrophy R1/2A

Abstract

LGMDR1, an autosomal recessive LGMD due to mutations in calpain-3 gene (<i>CAPN3</i>), results in progressive muscle weakness. Advances in gene replacement technologies require planning for future clinical trials and better understanding of disease progression measured by COAs. The purpose of our study was to evaluate the relationship between clinical outcome assessments (COAs) and disease severity in a sample of patients with limb girdle muscular dystrophy R1 (LGMDR1). We report baseline data from our prospective observational study of clinically-affected, genetically-defined LGMDR1 participants. A battery of COAs were performed across two-day baseline visits. Test–retest reliability was evaluated using the intraclass-correlation coefficient (ICC). Linear regression was calculated to assess impact of disease duration on COAs based on genetic variant categorization. Thirty-two (75 target) participants have enrolled. The mean age 38.7 years (11-62 years) with mean symptom onset at 22.7 years (4-47 years). Participants were stratified into variant subcategories based on genetic mutations. The North Star Assessment for Limb Girdle-Type Dystrophies (NSAD) and Performance of Upper Limb (PUL) had excellent test-retest reliability (ICC 0.998 (95% confidence limit [CL] 0.994, 0.999) and 0.976 (95% CL 0.945, 0.990) respectively). Combination of COAs allows for continual evaluation across disease progression, while reducing floor/ceiling effects. Preliminary findings of COA performance in relation to disease duration suggest variants resulting in LoF may result in more rapid disease progression. Additional baseline data on the full cohort enrolled will be presented. Available COAs quantify function across the spectrum of abilities with potential to measure anticipated rate of progression based on genetic mutation and age of onset. Further research is needed to understand COA responsiveness to change in function over time in patients with LGMDR1.