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Prospective observational study of FKRP-related limb-girdle muscular dystrophy R9: A GRASP consortium study
Lindsay N Alfano1,2, Meredith K James3, Kristine Grosfjeld Petersen4
1Center for Biobehavioral Health, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
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.
Insights
Clinical outcome assessments for limb-girdle muscular dystrophy R9 (LGMDR9) were evaluated. The North Star Assessment for limb girdle-type dystrophies (NSAD) and Performance of Upper Limb 2.0 (PUL) show strong validity and reliability for trial design.
Area of Science:
- Neurology
- Genetics
- Clinical Trials
Background:
- Limb-girdle muscular dystrophy R9 (LGMDR9), caused by FKRP gene variants, results in progressive muscle weakness and motor function loss.
- Standardized clinical outcome assessments (COA) are crucial for effective disease management and clinical trial design in LGMDR9.
- Identifying appropriate COA helps define endpoint selection and enrollment criteria for therapeutic studies.
Purpose of the Study:
- To evaluate the cross-sectional validity and reliability of functional COA in patients with FKRP-related LGMDR9.
- To inform the selection of the most suitable COA for capturing disease presentation and progression in LGMDR9.
Main Methods:
- 101 patients with FKRP-related LGMDR9 were enrolled in the GRASP natural history study.
- Participants completed a battery of COA, including the North Star Assessment for limb girdle-type dystrophies (NSAD), 100-m timed test, and Performance of Upper Limb 2.0 (PUL), on two consecutive days.
Main Results:
- All tested functional COA demonstrated high and significant correlations, with the exception of the 9-hole peg test.
- Excellent test-retest reliability was observed for all COA across 2-day visits.
- The NSAD and PUL exhibited robust psychometric properties, including good targeting, ordered response thresholds, and stability.
Conclusions:
- The study confirmed the suitability of several functional COA for cross-sectional evaluation in LGMDR9.
- These findings will aid in optimizing future clinical trial design and improving patient care for LGMDR9.
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