Natural History of Limb Girdle Muscular Dystrophy D1 (LGMDD1)

Background and ObjectivesLimb‐girdle muscular dystrophy type D1 (LGMDD1) is caused by dominantly inherited pathogenic variants in DNAJB6, a cochaperone of HSP70. Prior work has described the clinical spectrum of LGMDD1, including genotype-phenotype correlations and cross-sectional functional impairments, but prospective longitudinal data remain limited. The primary objective of this study was to identify outcome assessments that reliably measure disease progression in LGMDD1 and are most suitable for use as end points in future natural history and interventional studies. MethodsAs part of the Genetic Resolution and Assessments Solving Phenotypes in LGMD (GRASP-LGMD) study, participants with genetically confirmed LGMDD1 were enrolled across 11 sites and completed 2 consecutive baseline visits and a 12-month follow-up. Clinical outcome assessments (COAs) included the North Star Assessment for Limb Girdle‑Type Dystrophies (NSAD), several timed mobility tests, Performance of the Upper Limb (PUL), handheld dynamometry (HHD), pulmonary function tests, and multiple patient-reported outcome measures. Test-retest reliability was calculated for COAs. Twelve-month change, responsiveness, and anchor-based minimal clinically important difference (MCID) values were assessed, and distribution-based thresholds were used to contextualize detectability. ResultsFifteen participants enrolled; 13 completed baseline and 12-month visits. Functional COAs and HHD showed high test-retest reliability. Significant 12-month decline was detected in the Disability of the Arm, Shoulder and Hand (DASH), NSAD, the NSAD-10-m walk/run (NSAD-10M), and NSAD-rise from floor (NSAD-RFF). NSAD-10M, DASH, NSAD, NSAD-RFF, hip abduction, and deltoid strength were the most responsive. MCID values were interpreted alongside average annual change and distribution-based detectability. NSAD-10M, NSAD-RFF, NSAD, PUL, DASH, and LGMD-Health Index demonstrated the most feasible and consistent MCID profiles. DiscussionA focused set of outcome assessments—particularly NSAD-10M, NSAD-RFF, NSAD, PUL, and DASH—demonstrated robust measurement characteristics over 12 months across the LGMDD1 severity spectrum and represent promising end points for future LGMDD1 natural history studies and interventional trials. Trial Registration InformationNCT03981289, prospectively registered, observational. First registered: 2019-06-03. Actual study start date: 2019-06-14 clinicaltrials.gov/study/NCT03981289?term=GRASP-LGMD&rank=1&tab=study