Motor Function in Limb-Girdle Muscular Dystrophy R1/2A: Validation of Clinical Outcome Assessments for Clinical Care and Trial Readiness.

Background and Objectives: Limb-girdle muscular dystrophy (LGMD) type R1/2A, calpain-3-related, is a rare, autosomal recessive disorder caused by pathogenic variants in the CAPN3 gene. LGMDR1/2A causes progressive weakness of upper and lower limbs, leading to difficulty walking and use of arms for overhead activities. The rate of progression of LGMDR1/2A is unknown because of the limited number of published cohorts and the lack of validated outcome measures. Quantifying the natural history of LGMDR1/2A using standardized outcome measures is critical for understanding the rate of disease progression and improving clinical care and clinical trial readiness. The aim of this cross-sectional study was to evaluate the suitability of the North Star Assessment for limb-girdle type muscular dystrophies (NSAD), 100-meter timed test (100MTT), and Performance of Upper Limb 2.0 (PUL) as outcome measures for quantifying disease presentation and progression in individuals with LGMDR1/2A. Methods: Ninety-two individuals were evaluated by physiotherapy teams at Nationwide Children's Hospital and the John Walton Muscular Dystrophy Research Centre. Psychometric analysis of NSAD and PUL was completed using Rasch measurement methods. Descriptive statistics and correlation coefficients explored the relationship among all outcomes. Results: Psychometric analyses demonstrated that NSAD and PUL were valid and appropriate functional outcome measures for ambulant and nonambulant individuals with LGMDR1/2A. The NSAD and 100MTT velocity were highly correlated (Spearman rho Rs(88) = 0.89) The 100MTT was particularly useful for the strongest and asymptomatic cohort. Discussion: In this largest reported cohort of individuals with LGMDR1/2A, NSAD, PUL, and 100MTT were suitable to quantify functional impact of the disease. International harmonization of outcome measures creates meaningful clinical data to inform clinical management and trial design.