Clinical Outcome Assessments in Limb Girdle Muscular Dystrophy R1/2A

Topic:

Pre-Clinical Research

Poster Number: 142

Author(s):

Stephanie Poelker, PT, DPT, Washington University School of Medicine- St. Louis, MO, Lindsay Alfano, DPT, PCS, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Linda Lowes, PhD, Abigail Wexner Research Institute at Nationwide Children's Hospital, Matthew Wicklund, MD, University of Colorado, Katherine Mathews, MD, University of Iowa, Aileen Jones, PT, Virginia Commonwealth University, Amanda Butler, PT, Virginia Commonwealth University, Melissa Hayes, PT, Kansas University Medical Center, Sandhya Sasidharan, PT, Kansas University Medical Center, Natalie Reash, DPT, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Megan Iammarino, DPT, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Hannah Dwight, PT, University of Colorado, Katie Laubscher, PT, University of Iowa, Shelley Mockler, PT, University of Iowa, Jessica St. Romain, Virginia Commonwealth University, Erin DeSpain, MPA, Virginia Commonwealth University, Michelle Seiffert, Washington University School of Medicine, St. Louis, Jeffrey Statland, MD, University of Kansas School of Medicine, Nicholas Johnson, MD, Virginia Commonwealth University, Conrad Weihl, MD, PhD, Washington University School of Medicine, St. Louis

Objective: To evaluate the relationship between clinical outcome assessments (COAs) and disease severity in a cross-sectional sample of patients with limb girdle muscular dystrophy R1 (LGMDR1).

Background: LGMDR1, an autosomal recessive LGMD due to mutations in calpain-3 (CAPN3), 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.

Methods: 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.

Results: Twenty-three (75 target) participants have enrolled, mostly women (60.9%). The mean age 38.7 years (11-62 years) with mean symptom onset at 22.7 years (4-47 years). Seven were homozygous for indels and/or splice mutations consistent with loss of function (LoF), six had homozygous missense variants, and ten were combination LoF/missense. 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.

Discussion: Our understanding of stability and sources of variability in COAs across baseline visits will inform future clinical trial design in LGMDR1. 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.