Systematic Literature Review of the Natural History of Spinal Muscular Atrophy: Motor Function, Scoliosis, and Contractures

Abstract

Background and objectives: Spinal muscular atrophy (SMA) is a progressive neuromuscular disorder associated with continuous motor function loss and complications, such as scoliosis and contractures. Understanding the natural history of SMA is key to demonstrating the long-term outcomes of SMA treatments. This study reviews the natural history of motor function, scoliosis, and contractures in patients with SMA.

Methods: Electronic databases were searched from inception to June 27, 2022 (Embase, MEDLINE, and Evidence-Based Medicine Reviews). Observational studies, case-control studies, cross-sectional studies, and case series reporting on motor function (i.e., sitting, standing, and walking ability), scoliosis, and contracture outcomes in patients with types 1-3 SMA were included. Data on study design, baseline characteristics, and treatment outcomes were extracted. Data sets were generated from studies that reported Kaplan-Meier (KM) curves and pooled to generate overall KM curves.

Results: Ninety-three publications were included, of which 68 reported on motor function. Of these, 10 reported KM curves (3 on the probability of sitting in patients with types 2 and 3 SMA and 8 on the probability of walking/ambulation in patients with type 3 SMA). The median time to loss of sitting (95% CI) was 14.5 years (14.1-31.5) for the type 2 SMA sitter population (their maximum ability was independent sitting). The median time to loss of ambulation (95% CI) was 13.4 years (12.5-14.5) for type 3a SMA (disease onset at age younger than 3 years) and 44.2 years (43.0-49.4) for type 3b SMA (disease onset at age 3 years or older). Studies including scoliosis and contracture outcomes mostly reported non-time-to-event data.

Discussion: The results demonstrate that a high degree of motor function loss is inevitable, affecting patients of all ages. In addition, data suggest that untreated patients with types 2 and 3 SMA remain at risk of losing motor milestones during late adulthood, and patients with types 3a and 3b SMA are at risk of loss of ambulation over time. These findings support the importance of stabilization of motor function development even at older ages. Natural history data are key for the evaluation of SMA treatments as they contextualize the assessment of long-term outcomes.

Figure 1. PRISMA Flow Diagram for the Systematic Literature Review (June 2021)

*A PRISMA flow diagram of the original search conducted in May 2021 is provided in eFigure 1 (links.lww.com/WNL/D158). ^†A total of 16 studies included in the review reported only respiratory and bulbar outcomes and are not considered further in this manuscript. HTA = health technology assessment; PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Figure 2. Recreated Kaplan-Meier Curves for the Probability of Losing the Ability to Sit

*The pooled curve across all 7 study arms (i.e., Kaneko et al., 2017 [types 2a and 2b], Russman et al., 1996 type 2, and Wadman et al., 2017 [types 2a, 2b, 3a, and 3b]), which is based on a total of 248 patients, is presented (along with the corresponding 95% CI). The follow-up length was variable across study arms, ranging from 1 year (Kaneko et al., 2017 [type 2a SMA]) to 79 years (Wadman et al., 2017 [type 3b]). The median time to no longer sitting in all pooled study arms was not reached. ^†The pooled curve across all 5 study arms (i.e., Kaneko et al., 2017 [types 2a and 2b], Russman et al., 1996 [type 2], and Wadman et al., 2017 [types 2a and 2b]), which is based on a total of 182 patients, is presented (along with the corresponding 95% CI). The median time to no longer sitting based on pooled study arms was estimated to be 31.5 years (95% CI 31.5–NR). ^‡The pooled curve across all 4 study arms (i.e., Kaneko et al., 2017 type 2a, Kaneko et al., 2017 type 2b, Russman et al., 1996 type 2, and Wadman et al., 2017 type 2a), which is based on a total of 144 patients, is presented (along with the corresponding 95% CI). The median time for the sitter population based on the pooled curve across all 4 study arms was estimated to be 14.5 years (95% CI 14.1–31.5). In the sensitivity analysis (which excluded Kaneko et al., 2017 [types 2a and 2b SMA]), the median time to no longer sitting based on the pooled curve across the 2 study arms is estimated to be 19.5 years (95% CI 13.5–31.5). Compared with the base-case analysis, in the sensitivity analysis, the median increased by 5 years; however, the pooled curves seemed very similar both with and without the data from Kaneko et al., 2017 (types 2a and 2b SMA). ^§The pooled curve across both study arms, which is based on a total of 66 patients, is presented (along with the corresponding 95% CI). The data are immature for both type 3a and type 3b SMA, with no events observed in patients with type 3b SMA, and the median time to no longer sitting in type 3 SMA based on pooled study arms was not reached. NR = not reached; SMA = spinal muscular atrophy.

Figure 3. Recreated Kaplan-Meier Curves for the Probability of Losing Ambulation

*The pooled curve for the 7 individual studies (i.e., Bladen et al., 2014, Chung et al., 2004, Kaneko et al., 2017, Lusakowska et al., 2021, Russman et al., 1996, Wadman et al., 2017, and Zerres et al., 1997) is presented (along with the corresponding 95% CI). The pooled curve across all 22 study arms (i.e., Bladen et al., 2014 [Argentina, Germany and Austria, Hungary, Serbia, Switzerland, the United Kingdom, and Ukraine], Chung et al., 2004 [type 3a and type 3b], Kaneko et al., 2017 [type 3a onset younger than 3 years and type 3b onset 3 years or older], Lusakowska et al., 2021 [type 3a 3 copies, type 3a 4 copies, type 3b 3 copies, and type 3b 4 copies], Russman et al., 1996 [type 3b younger than 2 years, type 3b 2 years or older], Wadman et al., 2017 [type 3a, type 3b onset younger than 12 years, and type 3b onset younger than 12 years], and Zerres et al., 1997 [type 3a and type 3b]), which is based on a total of 1,327 patients, is presented. ^†The pooled curve across all 7 study arms (i.e., Chung et al., 2004 [type 3a] and Kaneko et al., 2017 [type 3a onset younger than 3 years], Lusakowska et al., 2021 [type 3a 3 copies and type 3a 4 copies], Russman et al., 1996 [type 3b onset younger than 2 years], Wadman et al., 2017 [type 3a], and Zerres et al., 1997 [type 3a]), which is based on a total of 413 patients, is presented (along with the corresponding 95% CI). The median time to loss of walking/ambulation based on pooled study arms was estimated to be 13.4 years (95% CI 12.5–14.5). In the sensitivity analysis (which excluded Russman et al., 1996 [type 3b onset younger than 2 years]), the median time to loss of walking/ambulation across pooled study arms is estimated to be 14.0 years (95% CI 12.5–14.9). Compared with the base-case analysis, in the sensitivity analysis, the median increased by 7 months. ^‡The pooled curve across all 8 study arms (i.e., Chung et al., 2004 [type 3b], Kaneko et al., 2017 [type 3b onset 3 years or older], Lusakowska et al., 2021 [type 3b 3 copies and type 3b 4 copies], Russman et al., 1996 [type 3b onset 2 years or older], Wadman et al., 2017 [type 3b onset younger than 12 years and type 3b onset older than 12 years], and Zerres et al., 1997 [type 3b]), which is based on a total of 331 patients, is presented (along with the corresponding 95% CI). The median to loss of walking/ambulation based on pooled study arms was estimated to be 44.2 years (95% CI 43.0–49.4). In the sensitivity analysis (which excluded Russman et al., 1996 type 3b 2 years or older), the median time to loss of walking/ambulation across pooled study arms is estimated to be 46.1 years (95% CI 43.0–58.4). Compared with the base-case analysis, the median increased by 1.9 years. SMA = spinal muscular atrophy.