Prospective observational study of FKRP-related limb-girdle muscular dystrophy R9: A GRASP consortium study

Abstract

Objective: Limb-girdle muscular dystrophy R9 (LGMDR9, formerly known as LGMD2I), caused by variants in the fukutin-related protein (FKRP) gene leads to progressive muscle weakness of the shoulder and pelvic limb-girdles and loss of motor function over time. Clinical management and future trial design are improved by determining which standardized clinical outcome assessments (COA) of function are most appropriate to capture disease presentation and progression, informing endpoint selection and enrollment criteria. The purpose of our study was to evaluate the cross-sectional validity and reliability of clinical outcome assessments in patients with FKRP-related LGMDR9 participating in the Genetic Resolution and Assessments Solving Phenotypes in LGMD (GRASP) natural history study.

Methods: Enrolled patients completed a battery of COA on two consecutive days, including the North Star Assessment for limb girdle-type dystrophies (NSAD), the 100-m timed test (100 m), and the Performance of Upper Limb 2.0 (PUL).

Results: A total of 101 patients with FKRP-related LGMDR9 completed COA evaluations. All functional COA were highly and significantly correlated even across constructs, except for the 9-hole peg test. Similarly, all tests demonstrated excellent test-retest reliability across 2-day visits. The NSAD and PUL demonstrate robust psychometrics with good targeting, ordered response thresholds, fit and stability, and limited dependency of items across the scales.

Conclusions: This study has determined the suitability of several functional COA, cross-sectionally, in LGMDR9 to inform future trial design and clinical care.

Figure 1

Performance of key clinical outcome assessments (COA) plotted by years since report of symptom onset (A) 100‐m timed test (100 m) converted to velocity, (B) North Star Assessment for limb girdle‐type dystrophies (NSAD), and (C) Performance of Upper Limb (PUL). Note patients are plotted by variant group (circles = homozygous, squares = compound heterozygous) and linear regression lines (solid = homozygous, dotted = compound heterozygous) indicate differences in age of onset but similar slope of progression over time.

Figure 2

Relationship between key COA (A) NSAD and 100 m. No patients reached top running velocity with a good distribution of abilities over the course of disease progression. Thresholds for typical “running,” “community” ambulation, and “household” ambulation are marked as dotted lines. (B) NSAD and PUL indicate a greater spread of NSAD score over time with PUL increasingly informative as ambulatory ability declines. (C) NSAD and ACTIVLIM demonstrate increasing patient‐reported difficulty with activities correlating to clinician‐measured function. Note the mild floor effect of the ACTIVLIM as patients become nonambulatory. Patients with homozygous variants are marked as black circles (solid line) and patients with compound heterozygous variants are marked as open squares (dashed line).

Figure 3

Bland–Altman plots of performance of functional outcomes across days which includes individual average performance (Day 1 and Day 2) and change across baseline visits for (A) North Star Assessment for limb girdle‐type dystrophies (NSAD), (B) rise from floor (RFF). Note data for RFF were transposed to indicate decreased performance (meaning increasing time) across days are displayed as a negative number for ease of interpretation and comparison to NSAD as an ordinal variable with decreasing score indicative of worsening performance.