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.

Performance fatigability in adults with spinal muscular atrophy treated long‐term with nusinersen

“…In a previous study on untreated adult pwSMA, a mean annual decline in 6MWD of 9.7 m was observed during the natural course of the disease. 49 Thus, our long-term data on 6MWT support results from previous studies in which stabilization, and in some cases even improvement, of 6MWD were observed in adult pwSMA treated with nusinersena finding that would not be expected in a progressive disease. 5,6,[50][51][52][53] The relatively small number of participants, especially the decrease in sample size over time, is a limitation of our study, as evidenced by a marked increase of confidence intervals particularly during the second half of the observation period.…”

“…During long‐term treatment with nusinersen, we observed an overall stable 6MWD. In a previous study on untreated adult pwSMA, a mean annual decline in 6MWD of 9.7 m was observed during the natural course of the disease 49 . Thus, our long‐term data on 6MWT support results from previous studies in which stabilization, and in some cases even improvement, of 6MWD were observed in adult pwSMA treated with nusinersen — a finding that would not be expected in a progressive disease 5,6,50–53 …”

Performance fatigability in adults with spinal muscular atrophy treated long‐term with nusinersen

“…In a previous study on untreated adult pwSMA, a mean annual decline in 6MWD of 9.7 m was observed during the natural course of the disease. 49 Thus, our long-term data on 6MWT support results from previous studies in which stabilization, and in some cases even improvement, of 6MWD were observed in adult pwSMA treated with nusinersena finding that would not be expected in a progressive disease. 5,6,[50][51][52][53] The relatively small number of participants, especially the decrease in sample size over time, is a limitation of our study, as evidenced by a marked increase of confidence intervals particularly during the second half of the observation period.…”

“…During long‐term treatment with nusinersen, we observed an overall stable 6MWD. In a previous study on untreated adult pwSMA, a mean annual decline in 6MWD of 9.7 m was observed during the natural course of the disease 49 . Thus, our long‐term data on 6MWT support results from previous studies in which stabilization, and in some cases even improvement, of 6MWD were observed in adult pwSMA treated with nusinersen — a finding that would not be expected in a progressive disease 5,6,50–53 …”

Prognostic Factors and Treatment‐Effect Modifiers in Spinal Muscular Atrophy

“…Two low‐ROB natural history studies examined the effect of subtype on motor function outcomes in types 2 and 3 SMA and did not find any differences in motor decline across subtypes at month 12, although declines were more pronounced in less severe types of the disease ( Table 4 ). 70 , 71 These findings are consistent with observations in high‐ROB natural history studies, 66 , 72 although one study found significantly better motor function outcomes in patients with type 3a SMA compared with patients with type 3b with regard to stair climbing ( Table S5 ). 26 …”

“…REVIEW types of the disease (Table 4). 70,71 These findings are consistent with observations in high-ROB natural history studies, 66,72 although one study found significantly better motor function outcomes in patients with type 3a SMA compared with patients with type 3b with regard to stair climbing (Table S5). 26 An RCT of olesoxime in types 2 and 3 SMA found no effect of disease severity (defined by Motor Function Measure Domain 1 + Domain 2 total score) on outcomes (Table 4).…”

Six‐minute walk test as outcome measure of fatigability in adults with spinal muscular atrophy treated with nusinersen

“…In addition, about half of the patients showed stable performance on the 6MWT. The improvement we observed may be an effect of the drug considering the natural history of SMA, according to which a worsening of 7.8 m per year is expected 26 . This further supports a potential effect of nusinersen in walker patients.…”

Performance fatigability in adults with spinal muscular atrophy treated long‐term with nusinersen

“…In a previous study on untreated adult pwSMA, a mean annual decline in 6MWD of 9.7 m was observed during the natural course of the disease. 49 Thus, our long-term data on 6MWT support results from previous studies in which stabilization, and in some cases even improvement, of 6MWD were observed in adult pwSMA treated with nusinersena finding that would not be expected in a progressive disease. 5,6,[50][51][52][53] The relatively small number of participants, especially the decrease in sample size over time, is a limitation of our study, as evidenced by a marked increase of confidence intervals particularly during the second half of the observation period.…”

“…During long‐term treatment with nusinersen, we observed an overall stable 6MWD. In a previous study on untreated adult pwSMA, a mean annual decline in 6MWD of 9.7 m was observed during the natural course of the disease 49 . Thus, our long‐term data on 6MWT support results from previous studies in which stabilization, and in some cases even improvement, of 6MWD were observed in adult pwSMA treated with nusinersen — a finding that would not be expected in a progressive disease 5,6,50–53 …”

Prognostic Factors and Treatment‐Effect Modifiers in Spinal Muscular Atrophy

“…Two low‐ROB natural history studies examined the effect of subtype on motor function outcomes in types 2 and 3 SMA and did not find any differences in motor decline across subtypes at month 12, although declines were more pronounced in less severe types of the disease ( Table 4 ). 70 , 71 These findings are consistent with observations in high‐ROB natural history studies, 66 , 72 although one study found significantly better motor function outcomes in patients with type 3a SMA compared with patients with type 3b with regard to stair climbing ( Table S5 ). 26 …”

“…REVIEW types of the disease (Table 4). 70,71 These findings are consistent with observations in high-ROB natural history studies, 66,72 although one study found significantly better motor function outcomes in patients with type 3a SMA compared with patients with type 3b with regard to stair climbing (Table S5). 26 An RCT of olesoxime in types 2 and 3 SMA found no effect of disease severity (defined by Motor Function Measure Domain 1 + Domain 2 total score) on outcomes (Table 4).…”

Six‐minute walk test as outcome measure of fatigability in adults with spinal muscular atrophy treated with nusinersen

“…In addition, about half of the patients showed stable performance on the 6MWT. The improvement we observed may be an effect of the drug considering the natural history of SMA, according to which a worsening of 7.8 m per year is expected 26 . This further supports a potential effect of nusinersen in walker patients.…”

Performance fatigability in adults with spinal muscular atrophy treated long‐term with nusinersen

“…In a previous study on untreated adult pwSMA, a mean annual decline in 6MWD of 9.7 m was observed during the natural course of the disease. 49 Thus, our long-term data on 6MWT support results from previous studies in which stabilization, and in some cases even improvement, of 6MWD were observed in adult pwSMA treated with nusinersena finding that would not be expected in a progressive disease. 5,6,[50][51][52][53] The relatively small number of participants, especially the decrease in sample size over time, is a limitation of our study, as evidenced by a marked increase of confidence intervals particularly during the second half of the observation period.…”

“…During long‐term treatment with nusinersen, we observed an overall stable 6MWD. In a previous study on untreated adult pwSMA, a mean annual decline in 6MWD of 9.7 m was observed during the natural course of the disease 49 . Thus, our long‐term data on 6MWT support results from previous studies in which stabilization, and in some cases even improvement, of 6MWD were observed in adult pwSMA treated with nusinersen — a finding that would not be expected in a progressive disease 5,6,50–53 …”

Prognostic Factors and Treatment‐Effect Modifiers in Spinal Muscular Atrophy

“…Two low‐ROB natural history studies examined the effect of subtype on motor function outcomes in types 2 and 3 SMA and did not find any differences in motor decline across subtypes at month 12, although declines were more pronounced in less severe types of the disease ( Table 4 ). 70 , 71 These findings are consistent with observations in high‐ROB natural history studies, 66 , 72 although one study found significantly better motor function outcomes in patients with type 3a SMA compared with patients with type 3b with regard to stair climbing ( Table S5 ). 26 …”

“…REVIEW types of the disease (Table 4). 70,71 These findings are consistent with observations in high-ROB natural history studies, 66,72 although one study found significantly better motor function outcomes in patients with type 3a SMA compared with patients with type 3b with regard to stair climbing (Table S5). 26 An RCT of olesoxime in types 2 and 3 SMA found no effect of disease severity (defined by Motor Function Measure Domain 1 + Domain 2 total score) on outcomes (Table 4).…”

Six‐minute walk test as outcome measure of fatigability in adults with spinal muscular atrophy treated with nusinersen

“…In addition, about half of the patients showed stable performance on the 6MWT. The improvement we observed may be an effect of the drug considering the natural history of SMA, according to which a worsening of 7.8 m per year is expected 26 . This further supports a potential effect of nusinersen in walker patients.…”