Ambulatory function in spinal muscular atrophy: Age-related patterns of progression

Abstract

Individuals with spinal muscular atrophy (SMA) type 3 are able to walk but they have weakness, gait impairments and fatigue. Our primary study objective was to examine longitudinal changes in the six-minute walk test (6MWT) and to evaluate whether age and SMA type 3 subtype are associated with decline in ambulatory function. Data from three prospective natural history studies were used. Seventy-three participants who performed the 6MWT more than once, at least 6 months apart, were included; follow-up ranged from 0.5–9 years. Only data from patients who completed the 6MWT were included. The mean age of the participants was 13.5 years (range 2.6–49.1), with 52 having disease onset before age 3 years (type 3A). At baseline, type 3A participants walked a shorter distance on average (257.1 m) than type 3B participants (390.2 m) (difference = 133.1 m, 95% confidence interval [CI] 71.8–194.3, p < 0.001). Distance walked was weakly associated with age (r = 0.25, p = 0.04). Linear mixed effects models were used to estimate the mean annual rate of change. The overall mean rate of change was -7.8 m/year (95% CI -13.6 –-2.0, p = 0.009) and this did not differ by subtype (type 3A: -8.5 m/year, type 3B: -6.6 m/year, p = 0.78), but it did differ by age group (< 6: 9.8 m/year; 6–10: -7.9 m/year; 11–19: -20.8 m/year; ≥ 20: -9.7 m/year; p = 0.005). Our results showed an overall decline on the 6MWT over time, but different trajectories were observed depending on age. Young ambulant SMA patients gain function but in adolescence, patients lose function. Future clinical trials in ambulant SMA patients should consider in their design the different trajectories of ambulatory function over time, based on age.

Nusinersen improves walking distance and reduces fatigue in later‐onset spinal muscular atrophy

“…A longitudinal natural history study of ambulatory patients with SMA type III showed that 6MWT trajectories were age‐dependent . The mean rate of change in 6MWT distance improved by 9.8 meters/year in patients <6 years of age, but declined by 20.8 meters/year in adolescents and young adults 11–19 years of age, regardless of age at time of diagnosis . In this study, 5 participants were >11 years old at baseline and 3 additional participants became ≥11 years old during the study.…”

“…Older children and adolescents with SMA are more at risk for declining ambulatory function . A longitudinal natural history study of ambulatory patients with SMA type III showed that 6MWT trajectories were age‐dependent .…”

“…Older children and adolescents with SMA are more at risk for declining ambulatory function . A longitudinal natural history study of ambulatory patients with SMA type III showed that 6MWT trajectories were age‐dependent . The mean rate of change in 6MWT distance improved by 9.8 meters/year in patients <6 years of age, but declined by 20.8 meters/year in adolescents and young adults 11–19 years of age, regardless of age at time of diagnosis .…”

“…SMA type II and III are milder forms than type I, with symptom onset at age 7–18 months and >18 months, respectively . Individuals with SMA type III attain the ability to walk unaided at some point; however, muscle weakness causes gait impairment and reduced endurance . Over time, patients may lose the ability to walk independently …”

“…Tools assessing walking ability and fatigue are clinically relevant in individuals with milder forms of SMA . The 6‐minute walk test (6MWT) is a valid and clinically meaningful measure of ambulatory function and has demonstrated sensitivity to fatigue‐related changes in individuals with SMA .…”