Abstract
Functional variability among boys with Duchenne muscular dystrophy (DMD) is well recognised and complicates interpretation of clinical studies. We hypothesised that boys with DMD could be clustered into groups sharing similar trajectories of ambulatory function over time, as measured by the North Star Ambulatory Assessment (NSAA) total score. We also explored associations with other variables such as age, functional abilities, and genotype. Using the NorthStar Clinical Network database, 395 patients with >1 NSAA assessment were identified. We utilised latent class trajectory analysis of longitudinal NSAA scores, which produced evidence for at least four clusters of boys sharing similar trajectories versus age in decreasing order of clinical severity: 25% of the boys were in cluster 1 (NSAA falling to ≤ 5 at age ~10y), 35% were in cluster 2 (NSAA ≤ 5 ~12y), 21% in were cluster 3 (NSAA≤ 5 ~14y), and 19% in cluster 4 (NSAA > 5 up to 15y). Mean ages at diagnosis of DMD were similar across clusters (4.2, 3.9, 4.3, and 4.8y, respectively). However, at the first NSAA assessment, a significant (p<0.05) association was observed between earlier declining clusters and younger age, worse NSAA, slower rise from supine, slower 10 metre walk/run times, and younger age of steroid initiation. In order to assess the probability of observing complete loss of function for individual NSAA items, we examined the proportion of patients who shifted from a score of 1 or 2 at baseline to a score of 0. We also assessed the probability of gain of function using the inverse assessment and stratified the probability of deterioration, improvement–or static behavior–by age ranges and using baseline functional status. Using this tool, our study provides a comprehensive assessment of the NSAA in a large population of patients with DMD and, for the first time, describes discrete clusters of disease progression; this will be invaluable for future DMD clinical trial design and interpretation of findings.
Highlights
Duchenne muscular dystrophy (DMD) is a recessive, X-linked neuromuscular disorder caused by mutations in the dystrophin gene, and is characterised by progressive degeneration of skeletal and cardiac muscles [1, 2]
A better understanding of the varied nature of natural history of North Star Ambulatory Assessment (NSAA) scores in patients with DMD can aid in the assessment of treatment efficacy, in the design of clinical trials including defining better inclusion and exclusion criteria and importantly in the identification of variable disease progression rates [24]. The aims of this present study were to: (1) assess whether patients with DMD could be clustered into groups sharing similar trajectories of ambulatory function over time as measured by the total NSAA score, (2) to describe the pattern in which skills are lost or gained at different ages in patients with DMD, and (3) assess the effect that different genotypes and glucocorticoid therapies have on the longitudinal progression of disease in patients with DMD
An ‘n’ of 395 patients with DMD were included in the study, with ages ranging from 1.8 to 16.7 years at first assessment; average ± standard deviation of age at first assessment was 7.1 ± 2.6 years, average age at diagnosis of DMD was 4.1 ± 2.2 years and average NSAA total score at first assessment was 21.8 ± 7.1 (Table 1)
Summary
Duchenne muscular dystrophy (DMD) is a recessive, X-linked neuromuscular disorder caused by mutations in the dystrophin gene, and is characterised by progressive degeneration of skeletal and cardiac muscles [1, 2]. The primary manifestation of patients with DMD is progressive muscle weakness, which impairs walking, motor function, posture, breathing, and leads to a progressive decline in cardiac function [4]. Ambulatory function may initially improve in younger patients due to growth and development, the progression of muscle pathology leads to inexorable progression of weakness leading to loss of ambulation by the age of 13 years [6, 7]. There is no cure for DMD, and the goal of treatment is to manage symptoms, slow disease progression, and delay disability. Glucocorticoid therapy, which has been shown to improve motor and pulmonary functions, and potentially delay cardiomyopathy, is currently part of the standard of care in patients with DMD [8,9,10,11]
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