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Fatiguability and perceived fatigue are common unrelated symptoms in ambulatory individuals with spinal muscular atrophy (SMA). Ratings of perceived exertion (RPE) measures the sense of effort during an activity and has been used as a proxy for fatigue. Relationships between perceived fatigue, fatiguability, and RPE have been described in healthy populations, but the relationship in SMA has not been examined.Eighteen ambulatory individuals with SMA and 16 age-matched controls (age, 13 to 57 years; 26 [76.5%] males) performed the 6-minute walk test (6MWT) and cardiopulmonary exercise tolerance test (CPET) and completed the International Physical Activity Questionnaire---short form (IPAQ). RPE was collected during the CPET and 6MWT. Fatiguability was measured during the 6MWT. Physical activity (PA) volume was calculated using the IPAQ. Wilcoxon rank-sum tests were used to compare groups. Spearman correlation coefficients evaluated associations between variables. SMA subgroups were predetermined using 6MWT distances of over or under 300 meters.There were no significant associations between fatiguability and RPE or PA in SMA (P .05). PA was strongly associated with 6MWT RPE (r = 0.71) in SMA individuals who walked fewer than 300 meters (n = 7). There were no significant associations between any variables in controls (P .05).RPE is not associated with fatiguability in SMA. The possible association of PA and RPE may reflect the increased intensity of the 6MWT in weaker patients. RPE represents a sense of effort during exercise and should not be used as a substitute for fatiguability but may be a measure of patient experience during exercise.

Introduction Ambulatory individuals with spinal muscular atrophy (SMA) experience muscle weakness, gait impairments, and fatigue that affect their walking ability. Improvements have been observed in motor function in children treated with nusinersen, but its impact on fatigue has not been studied. Methods Post hoc analyses were used to examine changes in 6‐minute walk test (6MWT) distance and fatigue in children and adolescents with SMA type II and III who received their first dose of nusinersen in the phase Ib/IIa, open‐label CS2 study and were ambulatory during CS2 or the extension study, CS12. Results Fourteen children performed the 6MWT. Median (25th, 75th percentile) distance walked increased over time by 98.0 (62.0, 135.0) meters at day 1050, whereas median fatigue changed by −3.8% (−19.7%, 1.4%). Discussion These results support previous studies demonstrating clinically meaningful effects of nusinersen on motor function in children and adolescents with later‐onset SMA.

Introduction The aim of the study was to assess 12 month changes in upper limb function in patients affected by spinal muscular atrophy type 2 and 3. Methods Longitudinal 12 month data was collected in 114 patients, 60 type 2 and 54 type 3, using the Revised Upper Limb Module. Results The 12 month changes ranged between -7 and 9 (mean: -0.41; SD: 2.93). The mean changes were not significantly different between the three spinal muscular atrophy groups (-0.45 in type 2, -0.23 in non-ambulant type 3 and -0.34 in ambulant type 3, p = 0.96) and the relationship between 12 month change and age classes was not significantly different among the three types of SMA patients. Discussion Our results confirm that the Module explores a wide range of functional abilities and can be used in ambulant and non-ambulant patients of different ages in conjunction with other functional scales. Muscle Nerve 59:426-430, 2019.

INTRODUCTION: We examined the feasibility of assessing motor milestone performance of infants with spinal muscular atrophy (SMA) using the Hammersmith Infant Neurological Exam - Part 2 (HINE-2) in a Phase 2 study of nusinersen. METHODS: Nineteen SMA infants were assessed using the HINE-2 at baseline (≤ 7 months of age), and periodically up to 39 months of age. We evaluated whether the HINE-2 was feasible, reliable, and sensitive to change. RESULTS: Motor milestone assessments in SMA infants were feasible using the HINE-2. Baseline test-retest reliability was excellent (R= 0.987; p

Background: Gait impairment is common in spinal muscular atrophy (SMA) and is described using clinical assessments and instrumented walkways. Continuous over-ground walking has not been studied. Methods: Nine SMA participants completed the six-minute walk test (6MWT) and 10-meter walk/run wearing instrumented footwear (SoleSound). Data were simultaneously collected using a reference system (GAITRiteTM). The root mean square error (RMSE) indicated criterion validity. The decrease in walking speed represented fatigue. Foot loading patterns were evaluated using force sensors. Results: The RMSE for stride time, length, and velocity ranged from 1.3–1.7%. Fatigue was 11.6±9.1%, which corresponded to an average deceleration of 0.37±0.28mm/s2. Participants spent most of stance without heel contact. Forefoot contact occurred early in the gait cycle. Conclusions: These results suggest that footwear-based devices are an alternative to specialized equipment for gait assessment. Better understanding of gait disturbances should inform ongoing treatment efforts and provide a more sensitive outcome measure. This article is protected by copyright. All rights reserved.

Introduction In this study we evaluated the suitability of a caregiver-reported functional measure, the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT), for children and young adults with spinal muscular atrophy (SMA). Methods PEDI-CAT Mobility and Daily Activities domain item banks were administered to 58 caregivers of children and young adults with SMA. Rasch analysis was used to evaluate test properties across SMA types. Results Unidimensional content for each domain was confirmed. The PEDI-CAT was most informative for type III SMA, with ability levels distributed close to 0.0 logits in both domains. It was less informative for types I and II SMA, especially for mobility skills. Item and person abilities were not distributed evenly across all types. Conclusions The PEDI-CAT may be used to measure functional performance in SMA, but additional items are needed to identify small changes in function and best represent the abilities of all types of SMA. Muscle Nerve 54: 1097-1107, 2016.

Introduction The Six-Minute Walk Test (6MWT) was adopted as a clinical outcome measure for ambulatory spinal muscular atrophy (SMA). However, a systematic review of measurement properties reported significant variation among chronic pediatric conditions. Our purpose was to assess the reliability/validity of the 6MWT in SMA. Methods Thirty participants performed assessments, including the 6MWT, strength, and function. Reproducibility was evaluated by intraclass correlation coefficients. Criterion/convergent validity were determined using Pearson correlation coefficients. Results Test-retest reliability was excellent. The 6MWT was associated positively with peak oxygen uptake, Hammersmith Functional Motor Scale Expanded (HFMSE), lower extremity manual muscle testing, knee flexion hand-held dynamometry, and inversely with 10-m walk/run. The 6MWT discriminates between disease severity, unlike the HFMSE. Conclusions This study documents measurement properties of reproducibility, positive criterion validity, and convergent validity with established clinical assessments and reaffirms the value of the 6MWT as a pivotal outcome measure in SMA clinical trials. Muscle Nerve 54: 836-842, 2016.

Introduction: With clinical trials underway, our objective was to construct a composite score of global function that could discriminate among people with spinal muscular atrophy (SMA). Methods: Data were collected from 126 participants with SMA types 2 and 3. Scores from the Hammersmith Functional Motor Scale—Expanded and Upper Limb Module were expressed as a percentage of the maximum score and 6-minute walk test as percent of predicted normal distance. A principal component analysis was performed on the correlation matrix for the 3 percentage scores. Results: The first principal component yielded a composite score with approximately equal weighting of the 3 components and accounted for 82% of the total variability. The SMA functional composite score, an unweighted average of the 3 individual percentage scores, correlated almost perfectly with the first principal component. Conclusions: This combination of measures broadens the spectrum of ability that can be quantified in type 2 and 3 SMA patients. Muscle Nerve 52: 942–947, 2015

Introduction The timed “up & go” (TUG) test is a quick measure of balance and mobility. TUG scores correlate with clinical, functional, and strength assessment and decline linearly over time. Reliability and validity have not been tested in spinal muscular atrophy (SMA). Methods: Fifteen ambulatory SMA participants performed TUG testing and strength, functional, and clinical assessments. Intraclass correlation coefficients quantified test–retest reliability. Convergent validity was determined using Pearson correlation coefficients. Results: Test–retest reliability was excellent for all participants. TUG was associated significantly with total leg and knee flexor strength, as well as the Hammersmith Functional Motor Scale Expanded, the 10-meter walk/run, and 6-minute walk tests. TUG findings were not associated with knee extensor strength, pulmonary function, or fatigue. Conclusions: In SMA, the TUG test is easily administered, reliable, and correlates with established outcome measures. TUG testing is a potentially useful outcome measure for clinical trials and a measure of disability in ambulatory patients with SMA. Muscle Nerve 50:273–277, 2014

Introduction: Spinal muscular atrophy (SMA) causes muscle weakness and fatigue. Better understanding of the relationship between weakness and fatigue may help identify potential targets for rehabilitation. Methods: Gait and surface electromyography (EMG) from 4 muscle groups were measured during the Six-Minute Walk Test (6MWT) in 10 ambulatory participants, aged 9–49 years. Average root mean square amplitude (RMS) of muscle activity was calculated. Strength was assessed using manual and quantitative methods. Results: RMS, stride length, and velocity decreased during the 6MWT. Knee flexor and hip abductor strength was associated with fatigue-related changes; overall strength correlated with disease duration; and leg strength was associated with 6MWT distance. Conclusions: Clinical measures are valid in assessing fatigue and function in SMA, and these assessments can be enhanced by use of gait analysis and EMG. Disease duration and strength measures may represent further stratification refinements when enrolling patients in clinical trials. Muscle Nerve 50: 34–39, 2014

Department of Rehabilitation and Regenerative Medicine, Columbia University Medical Center, New York, New York, USAAccepted 24 August 2012ABSTRACT: Introduction: Falls can cause injury and may com-promise function in spinal muscular atrophy (SMA) patients. Weak-ness and gait variability are associated with falls in otherneurological disorders, and fatigue is well documented in SMA.The relationship of weakness, fatigue, and gait variability to fallshas never been investigated. Methods: Seven ambulatory patientswith SMA completed a falls history questionnaire, 6MWT, gait anal-ysis, and strength testing. Pearson correlation coefficients wereused to examine associations between thesevariables. Results: All7 subjects reported falls in the previous year. Stride-length variabili-ty was significantly associated with falls, unlike strength, fatigue, orother gait variables. Conclusions: Stride-length variability was thekey variable associated with falls. Preventive strategies to avoidfalls should be incorporated into patient management plans. Gaitanalysis provides actionable information not revealed by standardassessments and should be included in clinical trials designed toaddress the prevention of falls in the SMA population.

Introduction: Impaired mobility and fatigue are common in ambulatory spinal muscular atrophy (SMA) patients. The 6-minute walk test (6MWT) is a reliable measure of fatigue in SMA patients. To further evaluate fatigue, we used quantitative gait analysis during the 6MWT. Methods: Nine subjects with SMA and 9 age- and gender-matched, healthy controls were evaluated. Gait parameters of speed and dynamic balance were correlated with 6MWT distance. Performance during the first and last 25 meters of the 6MWT was compared. Results: Speed-related gait parameters and support base correlated with 6MWT distance. Walking performance was worse for SMA patients. The deterioration in stride length during the 6MWT was greater in SMA patients than in controls. Conclusions: Gait analysis detects fatigue, and the decrement in stride length may reflect selective muscle involvement in SMA. Further understanding of the mechanisms underlying fatigue may suggest additional targets for future therapeutic interventions. Muscle Nerve, 2010