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Literature Review

Systematic Review of Motor Function Scales and Patient-Reported Outcomes in Spinal Muscular Atrophy

Wu, Jennifer W. PhD; Pepler, Laura PhD; Maturi, Bridget MSc; Afonso, Alexandria C. F. PhD; Sarmiento, Janice PhD; Haldenby, Renee MSc

Author Information
American Journal of Physical Medicine & Rehabilitation: June 2022 - Volume 101 - Issue 6 - p 590-608
doi: 10.1097/PHM.0000000000001869

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive disease caused by homozygous deletion or loss-of-function mutation in the survival motor neuron 1 (SMN1) gene.1,2 The reduction of SMN protein results in motor neuron death, leading to progressive weakness and skeletal muscle atrophy.2 The paralogous SMN2 gene primarily produces a truncated, nonfunctional protein because of alternative splicing; however, limited expression of functional SMN2 (10%–20%) may provide partial rescue for insufficient SMN protein levels. Gene copy number of SMN2 varies by patient and is a major determinant of disease severity, resulting in a wide range of clinical features.3,4

Spinal muscular atrophy subtypes 0–4 are classified according to age of onset and degree of motor milestone achievement (Table 1).7 Although speed and extent of motor function decline may vary depending on subtype, age at symptom onset ranges from before birth to adulthood, with muscle weakness often progressing more rapidly in patients with infantile (SMA1) versus adult-onset SMA (SMA4).2 Monitoring a patient’s clinical status is necessary, as the extent and type of supportive care required changes with disease progression.8

TABLE 1 - Description of SMA subtypes5,6
SMA Type Age at Onset6 Age at Diagnosis6 Defining Clinical Features at Presentation6 Maximal Motor Function Achieved6 Median Survival5
0 Fetal Birth ▪ Lack of movement in limbs, face, trunk, and inability to suck
▪ Muscle atrophy
▪ Areflexia
▪ Congenital contractures
▪ Mechanical ventilation support required at birth
None Weeks
1-A Fetal First 2 wks of life ▪ Hypotonia: severe, generalized
▪ Weakness of limbs and neck
▪ Areflexia, ± tongue fasciculation
▪ Poor feeding—requiring support
▪ Labored breathing—mechanical ventilation may be required from the neonatal period onward
None <1 yr
1-B Infancy By age of 3 mos ▪ Hypotonia: severe, generalized
▪ Weakness of limbs and neck
▪ Areflexia, tongue fasciculation
▪ Bell-shaped thorax, paradoxical breathing pattern
Cannot roll or sit independently <1 yr
1-C Infancy 3–6 mos ▪ Hypotonia: severe, generalized
▪ Weakness: proximal > distal, lower > upper limbs
▪ May gain neck support
▪ Areflexia, tongue fasciculation
▪ ± Bell-shaped thorax, paradoxical breathing pattern
Cannot roll or sit independently <2 yrs
2 Infancy 6–18 mos ▪ Hypotonia: mild-moderate
▪ Weakness: proximal > distal, lower > upper limbs > trunk
▪ ± Areflexia
▪ Finger polymyoclonus tremor
Sits, may stand, unable to walk independently >25 yrs
3-A Early childhood 18–36 mos ▪ Plateau in motor development
▪ Reflexes reduced or absent
▪ Finger polymyoclonus tremor
▪ Majority lose ambulation before or during puberty
Walks, never runs or jumps well Survive to adulthood
3-B Later childhood 3–21 yrs2 ▪ Milder decline in gross motor function compared with 3A Walks, runs, jumps, and can participate in sports Survive to adulthood
4 Adult >21 yrs2 ▪ Difficulty with gross motor function Normal until early adult yrs Survive to adulthood

A variety of motor function scales have been developed to monitor natural disease course and measure treatment efficacy in patients with SMA. Mild improvement or stabilization of functional scores over time can be meaningful depending on the disease stage and current status of the patient. Assessment instruments must be suitable for the patient population being examined and adequately sensitive to detect changes.

An evolving treatment landscape is changing the developmental trajectory of SMA.2 Innovative and approved therapies for SMN gene replacement (onasemnogene abeparvovec; Food and Drug Administration approved 2019), SMN2 gene splicing (nusinersen, risdiplam; Food and Drug Administration approved 2016 and 2020, respectively), or muscle proliferation and contraction have demonstrated significant improvements in both motor function and survival for patients with SMA.2,9 Current instruments used to monitor the natural history of SMA were developed before these therapies were available. Motor function instruments alone may not fully reflect the impact of therapy-related improvements in functional status over time,10 particularly at the upper and lower limits of disease severity in adult patients.11–13 Patient-reported outcomes (PROs) may offer additional insights because of their ability to reflect how the disease impacts quality of life (QoL) and may help provide additional perspective on long-term outcomes, regardless of disease status.13–15

Motor function scales and PROs are an essential part of assessing patients with SMA, and appropriate selection is necessary to account for the diverse clinical phenotypes. The aim of this systematic literature review was to examine and describe the utility of commonly used instruments in the evaluation of patients with SMA. To aid with instrument selection, we identify advantages and limitations and discuss validity in assessing motor function, QoL, and clinical benefit.

METHODS

This systematic review followed guidelines in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (S1 Appendix, Supplemental Digital Content 1, https://links.lww.com/PHM/B395).16

Search Strategy and Selection Criteria

PubMed (MEDLINE) database searches were conducted on July 14–15, 2020, to identify studies using motor function scales or PROs in patients with SMA. A predetermined list of terms that included known interventions and motor function scales/PROs was searched (S2 Appendix, Supplemental Digital Content 2, https://links.lww.com/PHM/B396). To account for natural history studies, a search of “‘spinal muscular atrophy’ OR ‘survival of motor neuron 1 protein’” designated as MeSH terms was conducted. Search results were limited to text available in English. No other restrictions were imposed (e.g., publication dates, publication status, or full-text availability). Because of the rapidly evolving field of SMA research, secondary literature searches were performed on September 1, 2020, and June 1, 2021. The entire body of literature that was reviewed included articles published up until June 1, 2021, with no start date restriction. Using titles and abstracts, results were refined by removing duplicates and subsequently excluding: (1) review articles, meta-analyses, systematic reviews, case series, congress reports, editorials/commentaries, guidelines/consensus papers, news reports, and nonscientific articles; (2) studies conducted using cell lines and/or animal models; (3) articles that did not investigate SMA; and (4) SMA articles that did not report use of motor function scales or PROs. Investigators also reviewed and handpicked additional articles for consideration from an extensive congress report17 and a comprehensive review article.18

Data Extraction

Full text of remaining articles was reviewed to determine eligibility for inclusion, and the following data were summarized in evidence tables by four investigators: type of study (e.g., randomized controlled trial or observational); intervention (if applicable); patient characteristics (e.g., total number of patients, number of patients <18 yrs and adult patients, age of symptom onset, age at enrolment, sex, SMA diagnostic criteria and type [Table 1]); type of motor function scales or PROs; data on motor function or QoL assessments (e.g., baseline scores, change in scores); potential sources of bias; and any validity assessments of motor function scales, if applicable.

Validity assessments included reliability studies measuring interrater or intrarater consistency (S3 Appendix, Supplemental Digital Content 3, https://links.lww.com/PHM/B397). Information on minimal clinically important difference (MCID) was recorded, if available (Table 2).

TABLE 2 - Minimal clinically important differences defined for motor function scales and PROs
Instrument MCID
CHOP-INTEND Based on data from the ENDEAR trial with patients aged 30–262 days, a 3.4- to 4-point improvement was considered meaningful.19
GMFM In patients with cerebral palsy (mean age = 10.8 [SD = 3.8] yrs), an improvement of 0.1%–3.0% is meaningful.20
Hammersmith scales
°HFMS MCID not available
°MHFMS MCID not available
°HFMSE Patient and caregivers consider a 1-point increase meaningful.21
A change of >3 points in a 6-mo period is clinically meaningful to patients with SMA aged 8–46 yrs.22
Estimated MCID values according to distribution-based approach (presented as SEM, 1/2 SD, and 1/3 SD of the patient’s baseline scores) in patients aged 18–71 yrs were 4.3, 10.6, and 7.0. MCID values for ambulatory and nonambulatory patients were very similar, ranging from 1.5- to 4-points.23
°HINE MCID not available
°HINE-2 Based on data from the ENDEAR trial with patients aged 30–262 days, a 0.4- to 0.7-point improvement was considered meaningful.19
Motor function measures
°MFM32 MCID not available
°MFM20 MCID not available
Upper limb modules
°ULM Over a 12-mo period, changes above ± 1 or, even more, above ± 2 should be considered of clinical relevance as determined in a population of patients with SMA aged 3.5–29.0 yrs.24
°RULM Estimated MCID values according to distribution-based approach (presented as SEM, 1/2 SD, and 1/3 SD of the patient’s baseline scores) in patients aged 18–71 yrs were 2.9, 6.4, and 4.3, respectively. MCID range for ambulatory patients was approximately 0.5- to 1-point and ranged from 2- to 4-points for nonambulatory patients.23
A change of 2- to 3-points may be considered meaningful.25
Timed tests
°Time to climb MCID not available
°Time to rise MCID not available
°Time to walk 10 m MCID not available
°6MWT Estimated MCID values according to distribution-based approach (presented as SEM, 1/2 SD, and 1/3 SD of the patient’s baseline scores) in patients aged 18–71 yrs were 55.5, 71.1, and 47.8 m, respectively.23
PROs
°smafrs MCID not available
°PedsQL–generic core In a general population of individuals aged 2–18 yrs, 4.4 points for self-report and 4.5 points for proxy report were considered meaningful; however, MCID has not been defined for SMA population.26
°PedsQL neuromuscular module MCID not available
SEM, standard error of measurement.

Identification of a floor or ceiling effect, defined as a truncated score distribution concentrated on the lower or higher limits of the scale, respectively, was also recorded.27 Factors considered during the critical appraisal of each article were: SMA diagnostic criteria (e.g., genetic confirmation of deletion/mutation of SMN1) for patient inclusion, availability of controls, methodology, sample size, population representation, confounding factors, limitations, data validity, risk of bias, and statistical analyses performed. Literature was also assessed for use of established motor function scales or PROs, and feasibility of accurate data extraction. Risk of bias was considered in randomized control trials using the criteria outlined in the Revised Cochrane risk of Bias tool for Randomization (RoB2.0), a standardized framework provided by the Cochrane Methods Network to assess risk of bias in randomized trials.28 Single-arm trials and observational studies were also evaluated with careful consideration for the inherent biases in study design. Small sample size was not considered a risk of bias because of the rarity of SMA. Study deficiencies, missing data, or risk of bias was included in the evidence tables. Studies with missing data related to motor function scales, PROs, or diagnostic criteria, or those with high-risk of bias as outlined in RoB2.0, were excluded.

Evidence tables were reviewed in duplicate. Discrepancies regarding inclusion or exclusion of articles were resolved through discussion. Motor function scales or PROs that appeared in 5 or more articles were included and those appearing in 10 or more articles are discussed in depth hereinafter.

RESULTS

After applying the inclusion/exclusion criteria, 122 articles remained with 24 studies focused on validating motor function scales or PROs (Tables 3, 4; Figs. 1A, B; S2A-B Appendices, Supplemental Digital Content 2, https://links.lww.com/PHM/B396) were identified.

TABLE 3 - Summary of 98 articles included in the review that used motor function scales and PROs found in ≥5 SMA studies
Instrument SMA Type Ambulatory Status Age Range a Study Type Study Observation Period Notes
Motor function scales
 CHOP-INTEND Type 129–54
Type 229,32,34,37,43,51
Type 329,51
Infants30–33,35,36,39–50,52,53
Children29–31,34,37–40,43,48,49,51,53,54
Adolescents37,39,50
Adults37
Observational37,38,42–45,49,53
Interventions:
Nusinersen29–36,39,40,48,50–52,54
AVXS-10141,46,47
4–27 mos29–36,39–42,45–48,50,52,54,55 • CHOP-INTEND scores correlate well with TIMPSI scores in patients with SMA (r = 0.866, P < 0.0001) and healthy individuals (r = 0.839, P = 0.005)44
• Patients with ≤2 copies of SMN2 have lower baseline CHOP-INTEND scores40
• CHOP-INTEND is inversely associated with age at disease onset48
 GMFM Type 212,56–59
Type 312,56–59
Ambulatory57,59
nonambulatory57,59
Children12,56–59
Adolescents12,56,57,59
Adults12,56,57,59
Observational12,57,59
Interventions:
Hydroxyurea56
Whole-body vibration58
12–36 mos12,56–59 • GMFM and MMT scores show positive correlation with one another over a 12-mo period59
 HFMS Type 160
Type 212,57,58,60–68
Type 312,57,58,60–63
Ambulatory65
Nonambulatory61,63,65
Children12,57,58,60–68
Adolescents12,57,60–63,65
Adults12,57,60,61,63,65
Observational12,57,60,65
Interventions:
Oral phenylbutyrate64,66
Valproic acid62
Olesoxime61
Whole-body vibration58
Salbutamol68
5 wks–36 mos12,57,58,61–64,66,68 • Conflicting reports on the correlation between HFMS and SMN2 copy number65,67
• Floor effect seen in participants who cannot sit or lift their forearms65
• Ceiling effect has been noted in SMA type 3 patients60
 HFMSE Type 111,29,37,38,55,60,69,70
Type 211,12,24,29,37,38,55,57,60,69–91
Type 311,24,29,38,55,60,69–77,79,81,82,84–87,90–96
Type 411,55,70,91
Ambulatory76,78,82,87,90,91,96
Nonambulatory24,74,76,78,82,87,90,91,96
Sitters88,89
Nonsitters88,89
Infants
Children11,12,24,29,37,38,55,57,60,71,72,74–76,78,80–89,93,94,96,97
Adolescents11,12,37,55,57,60,69,71,72,75,76,78,79,81–84,86–89,91,93,94,96
Adults11,24,37,55,60,69,70,72,73,77–79,81,82,84,86–96
Observational12,24,37,38,55,57,60,69,70,72,76,78–83,86–88,94,96
Interventions:
Somatropin74
Nusinersen11,29,71,73,75,77,84,85,90,92,93,95,97
AVXS-101
Reldesemtiv91
2–38 mos11,12,24,29,55,57,71,74,75,77,79,82,84–86,88–93,95–97 • Significantly correlated with age of onset (P < 0.0001), in SMA types 2 and 3.69
• PCS is significantly correlated with HFMSE (P = 0.020)70
• There is no association between HFMSE and total SDSC score80
• HFMSE scores are lower in older patients, irrespective of SMA subtype (P < 0.05)60
• Floor effect of HFMSE in SMA types1c and 2.55,60
• Floor effect in adult and elderly patients with type 3a SMA55
• HFMSE is strongly correlated with ADM MUNIX (r = 0.63)83
• HFMSE shows a modest negative correlation with fat fraction and fractional anisotropy in patients with SMA (P < 0.001 for both)87
• HFMSE correlated with muscle strength (% MRC) except in patients with very low HFMSE55
 HINE-2 Type 130–34,36,39,40,53,98,99
Type 232,34,99
Sitters30,99
Nonsitters30,99
Infants30–36,39,40,53,98,100
Children30–32,39,40,53,99,100
Adolescents32,39
Observational33,53
Intervention:
Nusinersen30–32,34–36,39,40,99,100
6–48 mos30,31,34–36,39,40,98–100 • High baseline score before treatment with nusinersen was associated with higher probability of gaining ability to sit30
 MFM b Type 131,32,55,99,101
Type 232,55,63,99,101–103
Type 355,63,101–103
Type 455
Ambulatory101,102
Nonambulatory63,101,102
Sitters99
Nonsitters99
Infants31,32
Children31,32,55,63,99,101–103
Adolescents32,55,63,101–103
Adults55,63,101–103
Observational55,63,101–103
Interventions:
Nusinersen31,32,99
6–45 mos31,32,55,63,99,101,103 • In SMA types 2 and 3, there is a moderate inverse relationship between age and MFM total score101
• Scores are significantly lower in SMA type 2 patients than SMA type 3 patients103
• Annual MFM decline rates did not differ significantly between SMA types55
• No floor effect noted in any SMA types55
• MFM correlated strongly with muscle strength (% MRC)55
 MHFMS Type 1104
Type 256,76,104–107
Type 356,76,104–107
Ambulatory76,107
Nonambulatory76,106,107
Children35,56,76,104–107
Adolescents56,76,105,107
Adults56,107
Observational76,104,105
Interventions:
Valproic acid107
Valproic acid + l-carnitine106
Hydroxyurea56
12–18 mos56,106,107 • Increases in MHFMS scores in ambulatory SMA type 3 subjects are limited by ceiling effects107
• CMAP is moderately correlated with MHFMS (r = 0.61–0.63, P < 0.001)76
• FVC is significantly correlated with MHFMS104
 RULM Type 111,37
Type 211,25,37,73,77,90,91
Type 311,25,73,77,90–92,95
Type 411,77,91
Ambulatory25,90,91
Nonambulatory25,90,91
Children11,25,37,97
Adolescents11,25,37,91
Adults11,25,37,73,77,90–92,95
Observational25,37
Interventions:
Nusinersen11,25,73,77,90,92,95,97
Reldesemtiv91
2 mos91
Approximately 10–18 mos11,25,77,90,92,95,97
• Upper limb function should be assessed in ambulant patients, although a ceiling effect may be seen in approximately 1/3 of ambulant patients25
• In natural history of SMA, improvement is mainly seen in children <5 yrs over a 12-mo period25
• A change of ≥2 points can be seen in some patients within 12 mos25
 ULM Type 224,38,71,72
Type 324,38,71,72
Nonambulatory24,71 Children24,71,72
Adolescents24,71,72
Adults24,72
Observational24,38,72
Interventions:
Nusinersen71
12 to approximately 34 mos24,71
Timed tests
 6MWT Type 111,29
Type 211,29,33,71,72,90,91,102,108
Type 311,29,33,71,72,81,90,91,93–95,102,108–114
Type 411,91
Ambulatory90,91,95,111 Children71,72,81,93,94,102,108,109,113,114
Adolescents33,71,72,81,91,93,94,102,109,113,114
Adults33,72,81,90,91,93–95,102,109,112–114
Observational72,81,94,102,112–114
Interventions:
Exercise109
Salbutamol111
Nusinersen11,29,33,71,90,93,95,108
Valproic acid110
Reldesemtiv91
2 mos91
6–14 mos90
3–9 yrs11,29,33,71,81,95,108,109,111,113,114
• In natural history of SMA types 3a and 3b patients, there is no significant association between 1-yr changes and baseline values of 6MWT distance or age113
 Time to climb Type 2102,115,116
Type 3102,115–117
Ambulatory102,115–118 Children102,116–118
Adolescents102,116,117
Adults102,115,116
Observational102,116
Interventions:
Gabapentin115
Valproic acid + l-carnitine117
Whole-body vibration training118
3–12 mos115,117,118 • Important to consider that the number of stairs used across studies is not consistent when comparing results102,115–118
 Time to rise Type 274,102,115,116
Type 374,102,115–117
Ambulatory74,116–118 Children74,102,116–118
Adolescents74,102,116,117
Adults74,102,115,116
Observational102,116,118
Interventions:
Valproic acid + l-carnitine117
Gabapentin115
Whole-body vibration training118
Somatropin74
3–12 mos71,74,115,117,118
 Time to walk 10 m Type 274,102
Type 374,92,102,109
Ambulatory74,118 Children74,102,109,118
Adolescents74,102,109
Adults74,92,102,109
Observational109
Interventions:
Whole-body vibration training118
Somatropin74
Exercise109
Nusinersen92
3–14 mos74,92,109,118
PROs
 PedsQL c Type 151,119
Type 251,61,72,75,119
Type 351,61,72,75,92,109,117,119
Ambulatory117
Nonambulatory61
Children51,61,72,75,109,117,119
Adolescents51,61,72,75,92,109,117,119
Adults51,61
Observational72
Interventions:
Valproic acid + l-carnitine117
Nusinersen75,92
Exercise109
Olesoxime61
1–24 mos51,61,75,92,109,117
 SMAFRS Type 2120,121
Type 392,110,120–122
Type 4122
Ambulatory122
Nonambulatory122
Adolescents120
Adults92,110,120–122
Observational120,122
Interventions:
Valproic acid110
Nusinersen92
Gabapentin121
12–14 mos92,121 • SMAFRS total score is significantly correlated with MUNIX total score,122 MVIC,92 and the 6MWT92
• SMAFRS scores did not reflect patient-reported improvements in function92
a Infants: <1 yr; children: 1–12 yrs; adolescent: 13–18 yrs; adult: >18 yrs.
b Includes MFM20 and MFM32.
c Includes PedsQL neuromuscular module and generic core.
ADM, abductor digiti minimi; CMAP, compound muscle action potential; MMT, Manual Muscle Test; MRC, Medical Research Council; MUNIX, motor unit number index; MVIC, maximal voluntary isometric contracture; PCS, physical component score of the short form–36 health survey; SDSC, sleep disturbance scale for children; TIMPSI, test of infant motor performance screening items.

TABLE 4 - Summary of 24 validation studiesa of 11 motor function scales and 1 PRO
Instrument SMA Type n Ambulatory Status Age b Reliability Assessment Validity Assessment Notes
CHOP-INTEND SMA type 1123,124 Scale development: 26123
Validation: 27124
Not specified Scale development123: 11.5 (1.4–37.9) mos
Validation124: 48.2 (3.8–260) mos
Intrarater123: ICC = 0.96
Interrater for NMD123: ICC = 0.98
Interrater for typically developing children123:
ICC = 0.93
Score was correlated with124:
• Age (r = −0.51, P = 0.007)
• Respiratory support (r = −0.74, P < 0.0001)
SMN2 copy number (2 gene copies, r = −0.60; 3 gene copies, r = −0.83)
Rasch analysis showed targeting to the patient population125
Noted a potential ceiling effect for typically developing infants123
GMFM Not specified126–128 Interrater reliability126: 10
Intrarater reliability127: 34
Validation128: 40
Ambulatory and nonambulatory126–128 Interrater126: 7.4 (2–14) yrs
Intrarater127: 2–17 yrs
Validation128: 5–17 yrs
Intrarater126: ICC = 0.96–0.98 for the 5 domains
Interrater reliability for dimensions A and B127:
κ = 0.72
Correlated with all QMT measures (0.63–0.86, P < 0.0001)128
GMFM able to discriminate between ambulatory status with no overlap in scores in walkers vs. nonwalkers (median = 237 [range = 197–261] vs. 64 [range = 4–177], respectively, P < 0.0001)128
Noted that many patients with SMA were too weak to perform tasks in dimensions C (crawling and kneeling), D (standing), and E (walking, running, jumping)126
Hammersmith scales
 HFMS SMA type 2129,130
SMA type 3129,130
Scale development129: SMA type 2: 39
SMA type 3: 19
Scale reliability130:
SMA type 2: 85
SMA type 3: 5
Scale development:
Ambulatory and nonambulatory129
Scale reliability:
Nonambulatory130
Scale development129:
7.42 (2.5–19) yrs
Scale reliability130: 6.95 (2.2–12.8) yrs
Interrater reliability130: average correlation coefficient = 0.95
Intrarater reliability130:
R 2 = 0.9788–0.9928
Assessment of healthy children verified suitability in young children ≥29 mos129
Scale was sufficiently sensitive to detect changes caused by adverse events (e.g., fractures)130
 HFMSE SMA type 2131
SMA type 3131
Scale development131: SMA type 2: 21 SMA type 3: 17 Ambulatory and nonambulatory131 SMA type 2131: median = 5.7 (2.3–32.5) yrs
SMA type 3131: median = 9.1 (3.9–45.1) yrs
Intrarater131:
Overall ICC = 0.99
SMA type 3 ICC = 0.99
Score was correlated with:
• GMFM (P = 0.98)131
• GMFM-75 (P = 0.97)131
• Clinical presentation (P = 0.90)131
• FVC (r = 0.87)132
• Functional rating (r = 0.92)
Score can differentiate patients according to:
SMN2 copy number (P = 0.0007)132
• Ambulatory status (P < 0.0001)132
• SMA type (P < 0.0001)132
• Bilevel positive airway pressure use, <8 vs. ≥8 hrs/d (P < 0.0001)132
Rasch analysis showed targeting to the patient population125
Items on the scale are relevant to activities of daily living according to patients and caregivers21
Was able to differentiate the motor function of SMA type 3 patients at the ceiling of the original HFMS131
Patients and caregivers question ability to detect small changes in motor function22
 MHFMS SMA type 2133
SMA type 3133,134
Development of scale133:
SMA type 2: 37
SMA type 3: 13
Reliability of scale in younger children:
SMA type 2134: 22
Nonambulatory133,134 Development of scale133:
9.5 mos–12 yrs
Reliability in younger children134:
20 (9–30) mos
Intrarater reliability133: ICC = 0.986
Interrater reliability133,134: ICC = 0.953–0.96
Scale is reliable for younger and older children with SMA type 2 or 3.133,134
Scale is reliable and stable if given within 6 mos133,134
Able to discriminate between SMA types (nonambulatory), with SMA type 2 mean scores of 13.3 vs. 35.9 for SMA type 3.133 No floor/ceiling effects noted for nonambulatory SMA types 2 and 3133
Ceiling effect observed for ambulatory patients with SMA type 3107
Ceiling effect for typically developing children reached by ≥1 yr of age134
 RHS a SMA type 2135
SMA type 3a135
SMA type 3b135
SMA type 2135: 89
SMA type 3a135: 40
SMA type 3b135: 9
Ambulatory and nonambulatory135 Median age (IQR)135:
SMA type 2: 6.3 (4.2, 10.1)
SMA type 3a: 9.3 (7.1, 12.7)
SMA type 3b: 20 (16.3, 23.9)
RHS can differentiate patients according to135:
• SMA type (P < 0.001)
• Ambulatory status (P < 0.001)
• SMA type and current ambulatory status combined (P < 0.001)
• Highest current level of functional ability as classified by the WHO motor milestones (P < 0.001)
• Whether patient had spinal surgery or not (P = 0.001)
MFM
 MFM20 Not specified (developed for patients with NMD)136 Patients with SMA136: 22 Ambulatory and nonambulatory136 NMD group overall136: 4.8 (2.0–6.8) yrs All intrarater and interrater reliability for the total score136: ICC = 0.99
Intrarater and interrater reliability for the total score136: ICC range = 0.91–0.99
Total score correlated with VAS (r = −0.86), Vignos grade (r = −0.89) and Brooke grade (r = −0.85)136
Total score and subscores discriminated between the different NMD groups (P < 0.01)136
 MFM32 NMD validation studies:
Not specified,137 SMA type 2,138 SMA type 3138
SMA validation study:
SMA type 2138
SMA type 3138
NMD validation studies:
Unspecified SMA type137: 35
SMA type 2138: 12
SMA type 3138: 5
SMA validation study138:
SMA type 2: 63
SMA type 3: 18
NMD validation studies:
Not specified137,138
SMA validation study:
nonambulatory138
NMD validation studies:
24.5 (6–62) yrs137; 4.87 (2–5) yrs138
SMA validation study:
11.76 (2–25) yrs138
NMD validation studies:
Intrarater and interrater agreement ranged from ICC = 0.96–0.99 for the total score and the 3 dimensional subscores137
For the 2- to 5-yr old NMD group, the test-retest reliability had an ICC of 0.94, with an internal consistency of 0.96 (Cronbach's α)138
SMA validation study:
The test-retest reliability in the 2- to 25-yr-old group was 0.97, with an internal consistency of 0.95 (Cronbach's α)138
NMD validation studies:
Total score correlated VAS (r = 0.88), Vignos grade (r = 0.91), Brooke grade (r = 0.85), and FIM (r = 0.91)137
For those aged 2–5 yrs, MFM32 strongly correlated with CGI-S (Spearman's ρ = −0.84, P < 0.0001) and moderately strongly correlated with Vignos grade (Spearman's ρ = −0.79, P < 0.0001)138
Known groups validity analyses followed expected patterns according to CGI-S and Vignos grade severity (P < 0.001)138
Able to discriminate between the different NMD groups (P < 0.0001)137
SMA validation study138:
MFM32 modestly correlated with CGI-S (Spearman's ρ = −0.49, P < 0.001)
Known groups validity analyses followed expected patterns according to CGI-S severity (P < 0.001)
The MFM D3 (upper limb) was unable to differentiate between the motor function ability of stronger patients (Brooke level 2/3)139
ULMs
 RULM Suitability study140:
SMA type 2
SMA type 3
Rasch analysis140:
Not specified
Suitability study140:
SMA type 2: 34
SMA type 3: 19
Rasch analysis140:
134 patients with SMA
Ambulatory and nonambulatory140 Suitability study140:
9.5 (2.3–23.4) yrs
Rasch analysis140:
Median = 9 (2–52) yrs
Person separation index = 0.954140
Interrater reliability140:
ICC > 0.9
Each item of the scale could be associated with meaningful activities of daily living by patients140 Has a reduced ceiling effect compared with ULM140
 ULM Not specified141 Patients with SMA141: 45 Nonambulatory141 30 mos–27 yrs141 Interrater reliability = 0.97141 ULM significantly correlated with HFMS141: r = 0.75 (P < 0.0001) Suitable for children as young as 30 mos141
Patients and caregivers question ability to detect small changes in motor function22
Timed tests
 6MWT SMA types 3a and 3b142 SMA type 3a142: 11
SMA type 3b: 7
Ambulatory142 4–48 yrs142 Distance is correlated with HFMSE score (r = 0.83, P < 0.0001), 10-m walk/run time (r = −0.87, P < 0.0001), and knee flexor strength (r = 0.62, P = 0.01)142 Shown ability to detect fatigue-related changes142
PROs
 PedsQL–generic core Not specified143 Patients with SMA: 176143 Ambulatory and nonambulatory143 Mean = 8.53 yrs (SD = 4.75)143 Test-retest reliability of the parent-proxy report143:
ICC = 0.34–0.79
Test-retest reliability of the child self report143:
ICC = 0.72–0.84
Internal consistency143: >0.70
Discriminant validity depending on child’s health status143
All effect sizes observe were large (except for the emotional functioning child self-report)143
Available as a child self-report for children 5–18 yrs, and parent-proxy report143
Can be reliably administered via telephone interview144
 PedsQL–neuromuscular module Not specified143 Patients with SMA: 176143 Ambulatory and nonambulatory143 Mean = 8.53 yrs (SD = 4.75)143 Test-retest reliability of the parent-proxy report143:
ICC = 0.80–0.90
Test-retest reliability of the child self report143:
ICC = 0.58–0.84
Internal consistency143: >0.70
Discriminant validity depending on child’s mobility status143 Available as a child self-report for children 5–18 yrs, and parent-proxy report143
Can be reliably administered via telephone interview144
a The RHS has been validated in SMA; however, it was not used in >5 articles and was therefore not included in the review.
b Age reported as mean (Range), unless otherwise specified.
ADM, abductor digiti minimi; QMT, quantitative muscle testing; RHS, Revised Hammersmith Scale; SEM, standard error of measurement; VAS, visual analog scale.

F1
FIGURE 1:
A and B, PubMed search results. A, Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram summarizing the search results from the initial literature search on July 14–15, 2020, and updated searches on September 1, 2020, and June 1, 2021. B, Detailed flow diagram of studies included/excluded for the review. *Irrelevant to the literature review included cell or animal model studies and those that did not include patients with SMA. Investigators reviewed and handpicked additional articles for consideration from an extensive congress report17 and a comprehensive review article.18 †No clear diagnostic criteria (n = 12), no established motor function scale (n = 68), reporting bias (n = 24), review article (n = 2), missing relevant data (n = 17), SMA patients not included (n = 1), and previously reported data (n = 2). ‡One validation study for the Revised Hammersmith Scale was included in the summary table despite the scale not being used in 5 or more studies.

Motor Function Scales

Tables 3 and 4 summarize the motor function scales and PROs. The utility and limitations of the most frequently used motor function scales (≥10 studies) are described hereinafter.

Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders

The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) is a 16-item scale that captures movement of different muscle groups through active or reflexive movement, and spontaneous or goal-directed tasks, and was developed to assess infants with SMA type 1 with limited motor ability.123 Total scores range from 0 to 64, with higher scores indicating better motor function.

Reliability assessments showed high intrarater (intraclass correlation coefficient [ICC] = 0.96) and interrater reliability (ICC = 0.98) when used in infants with neuromuscular diseases (NMDs; Table 4).123 The scale has also been validated in patients with SMA type 1. The CHOP-INTEND scores significantly correlated with age (r = −0.51, P = 0.007), SMN2 copy number (2 gene copies, r = −0.60; 3 gene copies, r = −0.83), and requirement for respiratory support (r = −0.74, P < 0.0001).124

The CHOP-INTEND was used to assess functional status in SMA type 1 and 2 patients with median ages ranging from 5 to 200 mos in a natural history study.43 In SMA type 1 patients, the mean change over time in the CHOP-INTEND score was −1.27 points/yr (95% confidence interval [CI] = −2.33 to −0.21, P = 0.02).

The CHOP-INTEND was used to assess treatment effect of low- versus higher-dose AVXS-101 in patients with SMA type 1 aged 0.9–7.9 mos.47 There was a rapid increase in the CHOP-INTEND score in the higher-dose cohort (9.8 points at 1 mo, 15.4 points at 3 mos, P < 0.001 for both) versus the decline observed in the natural history control arm and other natural history studies.43,47 At the 20-mo study cutoff, mean score increases were 7.7 and 24.6 points in the lower- and higher-dose arms, respectively. The CHOP-INTEND was used to assess treatment response in a randomized, sham-controlled phase III trial of nusinersen in infantile-onset SMA.36 The percentages of treated patients with a CHOP-INTEND response, defined as an increase of 4 points or greater from baseline, were 71% and 3% in the nusinersen and control groups, respectively (P < 0.001).

Hammersmith Infant Neurological Examination

The Hammersmith Infant Neurological Examination (HINE) is a 37-item instrument that evaluates neurologic function in infants aged 2–24 mos, composed of three modules examining three aspects: neurologic characteristics, development, and behavior.145 The development module (HINE-2) is often used independently to assess development using eight motor milestone categories (head control, sitting, voluntary grasp, rolling, crawling, ability to kick, standing, and walking). The HINE-2 scores range from 0 to 26, with higher scores indicating better motor function.145 No SMA-specific validity studies have been published to date.

Patients with SMA type 1 aged 1–93 mos treated with nusinersen as infants were monitored with HINE-2 and CHOP-INTEND at baseline and 6 mos after treatment initiation.40 At 6 mos, patients experienced a more pronounced mean change score in the CHOP-INTEND (9.0 [SD = 8.0]) compared with HINE-2 (2.3 [SD = 3.3]),40 suggesting that more drastic improvements are required to increase HINE-2 scores compared with CHOP-INTEND, because CHOP-INTEND captures motor function, whereas HINE-2 captures motor development milestones.

The disparity between HINE-2 and CHOP-INTEND score improvement is maintained for longer than 6 mos, as observed in the 12-mo real-world data from the nusinersen trial that included patients aged 2–191 mos.39 At 12 mos, the mean change from baseline in HINE-2 was 1.34 (SD = 2.90) versus 5.48 (SD = 7.62) for CHOP-INTEND.39 Similarly, in an observational cohort study of French patients with SMA receiving nusinersen, the mean change in HINE-2 was less than that observed in CHOP-INTEND at 12 mos (10.5 vs. 15.2).32

Hammersmith Functional Motor Scale

The Hammersmith Functional Motor Scale (HFMS) was designed for use in children with SMA types 2 and 3, particularly those with limited mobility.129 The scale consists of 20 scored activities graded on a 3-point scale (0–2).129 Total scores range from 0 to 40, with higher scores indicating better motor function.

Evaluation of typically developing children and patients with SMA type 2 or 3 determined that the HFMS was suitable for use in children 29 mos or older.129 The scale demonstrated high interrater and intrarater reliability in nonambulant, juvenile patients with SMA types 2 and 3 (Table 4) and showed sufficient sensitivity to detect effects of adverse events (e.g., fractures) on motor function.130

There was a statistically significant, but moderate, correlation between HFMS and age (correlation coefficient = −0.435, P < 0.01) in patients with SMA type 2 aged 2–70 yrs (mean = 23 yrs), although a floor effect was noted in several patients who could not sit unassisted or lift their forearms.65 In those 20 yrs or younger, most scored between 1 and 5 (n = 12 of 22, 54.5%), 9 (40.9%) scored between 6 and 20, and 1 (4.5%) scored 25. In those 21 yrs or older, most scored 0 (n = 15 of 23, 65.2%), 7 (30.4%) scored between 1 and 5, and 1 (4.3%) scored 30.65

Hammersmith Functional Motor Scale–Expanded

To address the ceiling effect of the HFMS in stronger, nonambulant patients, a 13-item expansion module was appended that evaluates advanced motor skills often observed in ambulatory patients with SMA.131 The HFMS-Expanded (HFMSE) comprises 33 items graded on a 3-point scale (0–2).131 The maximum possible score is 66, with higher total scores indicating better motor function ability.

A survey of parents with children living with SMA indicated that the HFMSE items were relevant to activities of daily living and that a gain in ability in one item is clinically significant.21 An increase of greater than 2 points in the total HFMSE score is unlikely to occur in the natural history of SMA,21 therefore providing a benchmark for the impact of medical intervention.

The HFMSE showed high intrarater reliability and capacity to differentiate functional ability of patients with SMA type 3 who would generally be captured at the ceiling of the HFMS (Table 4).131 The HFMSE score correlated with other established measures of motor function, including the Gross Motor Function Measure (GMFM, ρ = 0.98) and GMFM-75 (ρ = 0.97), and with clinical presentation assessments by healthcare providers (ρ = 0.90).131,132 The total HFMSE score significantly correlated with ambulatory status (P < 0.0001), SMA type (P < 0.0001), SMN2 copy number (P = 0.0007), and respiratory function (P < 0.0001).132

The HFMS and HFMSE were used in a cross-sectional cohort study of patients with SMA types 1c, 2, 3, and 4 ranging in age from 1.4 to 68.8 yrs.60 Across all SMA subtypes, older patients had a lower HFMSE score (P < 0.05). A ceiling effect was observed with the HFMS in SMA type 3, whereas a floor effect was reported with the HFMSE in SMA types Ic and 2.60 Another study noted a significant floor effect for HFMSE in patients with SMA type Ic, in adolescents and adults with SMA types 2a and 2b, and in adult patients with SMA type 3a.55 In patients with SMA type Ic, the average decline in motor function was 0.03 points/yr versus 0.06 points/yr for patients with SMA type 3b, due to the fact that patients with SMA type Ic reached a score of 0 at an early age.55

The HFMS, HFMSE, and GMFM were used to evaluate motor function over 48 mos in a prospective observational cohort study of children and young adults with SMA types 2 and 3.12 The HFMSE and GMFM were able to detect significant decreases in motor function over time using mixed-effect models (HFMSE = −1.71 over 3 yrs, P = 0.01; GMFM = −4.39 over 2 yrs, P = 0.03). The HFMS was unable to detect any changes in this population.12

In an open-label phase I trial, the HFMSE was used to monitor change in motor function over 14 mos in patients with SMA types 2 and 3 aged 2–14 yrs receiving various doses of nusinersen.75 There was no significant change in HFMSE score in patients receiving 1, 3, or 6 mg of nusinersen; however, the HFMSE was able to detect a significant improvement in patients receiving 9 mg of nusinersen by day 85 (mean increase = 3.1 points, P = 0.016) and at 9–14 mos (mean increase = 5.8 points, P = 0.008).75 Improvement was distributed across disease severity and age range, indicating that the HFMSE was able to detect differences in motor function in a wide patient population. In the nusinersen phase III trial, HFMSE was used to assess motor function over 15 mos in children with SMA aged 2–9 yrs and was able to detect a difference between the 2 groups as early as 6 mos after treatment initiation.97 At month 15, there was a least-squares mean increase from baseline in the nusinersen group, but a decrease in the control group (least-squares mean difference in change = 5.9 points; 95% CI = 3.7 to 8.1, P < 0.001).97 The difference in response was maintained at the final analysis (least-squares mean difference in change = 4.9 points; 95% CI = 3.1 to 6.7).97

Gross Motor Function Measure

The GMFM is an 88-item scale assessing gross motor activities across five dimensions: (1) lying and rolling; (2) sitting; (3) crawling and kneeling; (4) standing; and (5) walking, running, and jumping.126 Scoring is based on a 3-point ordinal scale, with higher scores indicating better gross motor function.146

Assessment of 34 children with SMA showed high intrarater reliability for the five GMFM domains (Table 4).127 The GMFM demonstrated good interrater reliability for dimensions A and B. Reliability of dimensions C, D, and E could not be assessed because patients were often unable to complete these modules.126

The validity of the GMFM was examined in 40 children with SMA (Table 4). The GMFM scores correlated with Quantitative Muscle Testing measures (ρ range = 0.63–0.86, P < 0.0001).128 The GMFM discriminated by ambulatory status, with walkers and nonwalkers achieving nonoverlapping scores (median = 237 [range = 197–261] vs. 64 [range 4–177], respectively, P < 0.0001).128

The mean rate of change in GMFM score (0.75, 95% CI = −1.07 to 2.57) was not found to correlate with age and SMA subtype in a 12-mo observational cohort study of SMA types 2 and 3 patients.57 In this study, ambulatory status was significantly associated with rate of the GMFM score change (P = 0.01). The mean change in GMFM score was 3.96 (95% CI = 1.20 to 6.72) in ambulatory patients versus −0.70 (95% CI = −2.86 to 1.46) in nonambulatory patients.57 However, a similar study found that ambulatory status did not impact change in GMFM score over 1 yr.59

Motor Function Measure 32

The Motor Function Measure 32 (MFM32) was designed to assess motor abilities in three functional dimensions in individuals with NMDs: standing position and transfers (D1 subscore), axial and proximal motor function (D2 subscore), and distal motor function (D3 subscore).137 Each item is scored from 0 to 3, with higher scores indicating greater motor ability. Total score may be expressed as a percentage of the maximum score of 96.147

The validity of the MFM32 has been examined in two studies that assessed younger (2–5 yrs) and older (6–62 yrs) patients with NMDs, including SMA, and in patients specifically with SMA type 2 or 3 (2–25 yrs; Table 4).137,138 Reliability assessments revealed high intrarater and interrater agreement in the older cohort of patients with NMDs for the three subscores (Table 4).137 The MFM32 also exhibited similar reliability in the younger age group and in patients with SMA.138

Validation studies in the older NMD cohort showed that MFM32 significantly correlated with Vignos grade (r = 0.91), visual analog scale (r = 0.88), Brooke grade (r = 0.85), Functional Independence Measure (r = 0.91), and physician-rated Clinical Global Impression.137 The MFM32 was able to discriminate between diagnosis groups. In the younger NMD cohort, the MFM32 correlated with the Clinical Global Impression of Severity (CGI-S, Spearman's ρ = −0.84, P < 0.0001), and the Vignos grade (Spearman's ρ = −0.79, P < 0.0001). Known groups validity analysis also followed expected patterns according to the CGI-S and Vignos grade severity (P < 0.001).138 Validity analyses in SMA yielded similar results, with the scale modestly correlating with the CGI-S (Spearman's ρ = −0.49, P < 0.001), and known groups analysis following expected patterns according to CGI-S score (P < 0.001).138 The MFM32 D3 (upper limb module [ULM]) was found to have a ceiling effect in stronger patients with SMA (Brooke level 2 or 3).139

The ability of the MFM32 to detect changes in SMA types 1, 2, and 3 was examined in a retrospective study of patients ranging from 5.7 to 59 yrs.101 The MFM32 was unable to detect changes in patients with less than 6 mos of follow-up. A slow deterioration of functional ability (mean = −0.9 [SD = 1.45] points/yr for SMA type 2, −0.6 [SD = 4.0] points/yr for SMA type 3) was detected in those with 6 mos of follow-up or greater. The MFM32 subscores showed responsiveness for SMA subtypes, with the D2 score showing substantial decrease in SMA type 2, and the D1 score markedly decreasing around age of deambulation in SMA type 3.101 Another study of patients aged 10.7–31.1 yrs with SMA types 2 and 3 found that the MFM32 scores were significantly lower in patients with type 2 compared with type 3 (median = 31.8 vs. 49.0, P < 0.05).103

A natural history study examined longitudinal changes in MFM32 among patients with SMA types Ic, 2a-b, 3a-b, and 4 with a median age of 26.8 yrs.55 Annual rates of the MFM32 score decline did not differ significantly between SMA types and averaged 0.5% for type Ic, 0.7% for type 2a, 0.5% for type 2b, 0.75% for type 3a, 1.0% for type 3b, and 0.4% for type 4. No floor effect was observed with MFM32 in patients with more advanced SMA.55

Revised Upper Limb Module

The Revised Upper Limb Module (RULM) is a 20-item scale designed to address the ceiling effect of the ULM and capture a wider range of functional abilities across ambulatory and nonambulatory patients with SMA.140 The first item on the scale serves as a functional class identifier and does not contribute to the total score. The remaining 19 items are graded on a 3-point scale, with a maximum score of 37. Higher scores indicate better upper limb function and a change of greater than 2 points suggests meaningful change.25 No MCID value has been clearly established for the RULM.

Rasch analyses on a data set, including 134 ambulatory and nonambulatory patients with SMA, assessed the validity of the RULM (Table 4).140 Psychometric tests supported RULM’s reliability, with a high Person Separation Index of 0.954. Interrater reliability assessments determined ICCs of greater than 0.9 can be achieved with proper training and instruction.140 Analyses demonstrated a reduced ceiling effect with the RULM compared with the ULM, making it more suitable for patients with improved upper limb function.140 Patients were also able to associate the scale items with meaningful activities of daily living.140

The RULM and HFMSE are commonly used as complimentary scales in studies because of the absence of fine motor skill items in the HFMSE. In one study, the RULM was used alongside the HFMSE and 6-Minute Walk Test (6MWT) to assess treatment effects of nusinersen in adult patients with 5q SMA type 3.95 Patients had a mean age of 35.11 yrs (SD = 11.7 yrs), and mean disease duration of 14.5 yrs (SD = 10.99 yrs). At baseline, the RULM scores ranged from 11 to 37 points (mean = 33, SD = 7.46). Disease duration had a negative impact on motor function, which was more apparent in the HFMSE score than the RULM score (R2 of score and disease duration of −0.643 and 0.332, respectively).95 At 300 days after treatment initiation, there was a significant improvement in RULM scores (P = 0.048) and 6MWT (P = 0.010), but no significant difference in HFMSE scores.95

In the phase III trial of nusinersen, RULM was used to assess motor function in patients with SMA (symptom onset after 6 mos) without severe contractures, scoliosis, respiratory insufficiency, or requirement for gastric tubes.97 Patients in the nusinersen group ranged from 2 to 9 yrs (median = 4 yrs) versus 2 to 7 yrs (median = 3 yrs) in the control group, with disease duration of 39.3 and 30.2 mos, respectively. At baseline, there was no difference in RULM score (mean = 19.4 [SD = 6.2] for nusinersen vs. 18.4 [SD = 5.7] for control), and both groups experienced a least-squares mean increase in RULM at month 15, although the increase was greater for the nusinersen group (4.2 vs. 0.5).97 In young patients, some improvement may be attributed to normal development-associated gain in motor function ability.116,148

Timed Function Tests

Six-Minute Walk Test

The 6MWT is a validated measure of exercise capacity and motor function that has been widely used in several NMDs. The test measures the maximum distance a person can walk in 6 mins over a 25-meter linear course. No MCID for the 6MWT has been identified for patients with SMA.

The ability of the 6MWT to evaluate fatigue-related changes in SMA has been assessed (Table 4). In the study, the total distance walked and mean gait velocity of 18 ambulatory patients with SMA type 3 were measured over time.142 The mean gait velocity was slower for each subsequent minute, with the average first-minute distance being significantly greater than the sixth-minute distance (57.5 vs. 48 m, P = 0.0003).126 Distance walked strongly correlated with the patients’ HFMSE scores (r = 0.83, P < 0.0001).142

A prospective natural history study was conducted over 9 yrs in patients with SMA types 3a and 3b ranging from 2.6 to 49.1 yrs of age at baseline.50 On average, patients with SMA type 3b walked 133 m further than patients with type 3a (P < 0.001); however, the mean rate of change in distance walked over the course of the study did not differ by SMA subtype or sex. The impact of age on motor function loss was demonstrated by the significantly different rate of change in the 6MWT distance in the 11- to 19-yr age group at −20.8 m/yr (P < 0.0001).

In a German observational cohort study of patients aged 16–65 yrs with SMA who received nusinersen treatment, the mean difference from baseline observed at 6, 10, and 14 mos were 22.1 m (95% CI = 8.7 to 35.6), 31.1 m (95% CI = 15.2 to 47.1), and 46.0 m (95% CI = 25.4 to 66.6), respectively.11

Patient-Reported Outcomes

Pediatric QoL Inventory

The Pediatric QoL Inventory (PedsQL) was designed to assess health-related QoL in children. It consists of generic core scales and disease-specific modules, such as the neuromuscular module, which is typically used to evaluate health-related QoL in children aged 2–18 yrs with NMDs, including SMA.143 The neuromuscular module consists of 25 items that encompass three scales examining the child’s NMD, ability to communicate to healthcare professionals and others about the disease, and family resources.143 The report can be completed by children aged 5–18 yrs (child self-report) or by the parent (parent-proxy report), although ICCs between child and parent reports have been reported to range from poor to moderate.143

Validation studies in 176 children with SMA and their parents showed that the test-retest reliability of the PedsQL ranges from good to excellent, for the parent-proxy report (neuromuscular module = 0.80 to 0.90, generic core scales = 0.34 to 0.79), and the child self-report (neuromuscular module = 0.58 to 0.84, generic core scales = 0.72 to 0.84; Table 4).143 Telephone administration of the PedsQL generic and neuromuscular modules demonstrated high reliability with in-person administration (ICC = 0.923).144

The PedsQL is able to discriminate changes in health-related QoL between healthy children and those with SMA and has been shown to correlate with motor function.143 Neuromuscular module scores increased from nonsitters, to sitters, to walkers143 and have been weakly associated with perceived fatigue as measured by the PedsQL Multidimensional Fatigue Scale (r = 0.313),72 suggesting that PedsQL can detect changes in health-related QoL due to the child’s mobility status.

The PedsQL generic core scales and neuromuscular module were used in the phase I study of nusinersen in patients with SMA.75 In the group that received a single intrathecal injection of 9 mg of nusinersen, a slight, but not statistically significant, improvement in the generic core scales and neuromuscular module was observed at day 85 (mean percent change of 9.8% and 17.1% reported by the patient, respectively). For the neuromuscular module, the patient-reported change was greater than the parent-reported change (17.7% vs. 4.6%), although the difference was not statistically significant.

DISCUSSION

This systematic literature review identifies strengths and weaknesses in 13 motor function scales and 2 PROs commonly used in clinical and observational studies involving patients with SMA. Specific advantages highlighted in our review of the literature include reliability and sensitivity of existing scales and ability to differentiate functional capabilities. Limitations that continue to persist include floor and ceiling effects due to use in varied SMA patient populations, particularly in light of the trend toward earlier treatment trajectories. Further work is needed to determine the MCID of scales in SMA to better understand meaningful change at the individual and between-groups level.23

As each instrument has its strengths and limitations, it is imperative the patient population (e.g., age, mobility), goals of treatment (e.g., Food and Drug Administration–approved therapies, including onasemnogene abeparvovec, nusinersen, and risdiplam), and outcomes or end points of interest be considered when selecting the appropriate motor function scales and PROs for clinical studies.

Motor function scales that were not originally developed for or validated in SMA are often used in this patient population. As such, several studies have noted ceiling or floor effects in the HFMS, HFMSE, Modified HFMS (MHFMS), and GMFM depending on the SMA type and functional ability of patients.55,60,65,107,126 The HFMSE, which was initially developed for patients with SMA types 2 and 3, showed a floor effect for patients with SMA type Ic,60 whereas the MHFMS, which was developed for nonambulatory patients with SMA types 2 and 3, demonstrated a ceiling effect in ambulatory patients with SMA type 3.107 Floor and ceiling effects limit utility and sensitivity of instruments in detecting clinical benefit due to treatment or declines in motor function due to disease progression. Therefore, baseline motor function is an important consideration when selecting instruments. Similarly, some scales may experience a ceiling effect with patients who previously were within the normal range of scores. In the recent study by Wijngaarde et al.,55 a floor effect was observed for the HFMSE in adult and elderly patients with SMA types 2a, 2b, and 3a, which would not make it a useful tool for monitoring further disease progression in these patient groups. Further validation of scales within the current therapeutic landscape may be prudent, as was done with the MFM32.138

Recent advancements in therapies for SMA, including approval of onasemnogene abeparvovec, nusinersen, and risdiplam, have helped alter the natural history of disease, and there is mounting evidence supporting earlier use of these treatment options.36,46,149 These factors also warrant careful consideration in selecting appropriate instruments, as using scales in patient populations nearing the lower and upper limits of sensitivity may lead to incorrect assessments.

Patient age should also be considered when selecting a suitable instrument for motor function and QoL assessments. The scale used should have appropriate complexity for the age group being assessed, allow healthcare providers to assess age-appropriate developmental milestones, and, in the case of PROs, be developed based on insight from patients and caregivers, and evaluated in the target population. In evaluating and interpreting PRO scales, recognition should be given to the fact that they may need to be completed by a parent proxy as patients may be too young to respond. In addition, patient age may relate to disease duration and the degree of decline in functional ability, which may limit the utility of certain scales in specific age groups.

Instruments should be selected based on study end points (milestones, motor function, or QoL), treatment goals and expectations given the patients’ age, and baseline functional status, as certain scales have shown better sensitivity to change. The HFMSE and GMFM have shown greater sensitivity than the HFMS to detect changes over time.12 Small gains or losses in functional activity may have implications on the ability to perform activities of daily living, which may be meaningful to patients and their caregivers.21 It would be prudent to measure the effect of interventions using complementary scales to more readily detect changes in motor function ability in clinical trials, as the HFMSE alone misses changes in upper limb function that can be detected using the RULM.95

Regardless of scale used, certain factors, including patient age and methodology, should be considered when comparing results across studies. Considering the natural history of SMA and its progressive course, absence of functional change over an extended time period would be meaningful for patients with SMA. Depending on severity and age of symptom onset, some patients may experience improvement in functional ability at young ages before disease progression and motor function decline. Effect of interventions may be difficult to discriminate without a placebo control and well-balanced treatment arms. Finally, methodology for administering instruments is not standardized and varies across studies. For example, the number of steps used in time-to-climb assessments in studies examined here varied from 3 to 6.102,115–118

To date, this is the first systematic review to qualitatively evaluate the types of motor function scales and PROs administered in patients with SMA in both clinical and observational studies; despite this, there are limitations to this study. Certain scales were excluded from this review because of the limited number of studies available, resulting in only 13 motor function scales and 2 PROs being included. Hence, this does not represent a complete list of scales and PROs used for patients with SMA, and newer instruments developed specifically for SMA, such as the Revised Hammersmith Scale, SMA Independence Scale, and SMA Health Index were not included. Of note, not all instruments included in this review have been specifically validated in the SMA patient population (HINE, time to rise, time to climb, SMA Functional Rating Scale [SMAFRS]), and discretion should be used. Furthermore, only a single-search database was used to identify literature, and data presented at conferences were not included.

As newer therapies continue to emerge and patients initiate treatment earlier, due diligence is encouraged when selecting motor function scales and PROs for use in clinical trials and observational studies to identify meaningful therapy-related changes for patients and their families.

ACKNOWLEDGMENTS

The authors thank Synapse Medical Communications, Inc., Oakville, Ontario, Canada, for providing Medical writing assistance.

REFERENCES

1. Crawford TO, Paushkin SV, Kobayashi DT, et al.: Evaluation of SMN protein, transcript, and copy number in the biomarkers for spinal muscular atrophy (BforSMA) clinical study. PLoS One 2012;7:e33572
2. Nance JR: Spinal muscular atrophy. Continuum (Minneap Minn) 2020;26:1348–68
3. Butchbach ME: Copy number variations in the survival motor neuron genes: implications for spinal muscular atrophy and other neurodegenerative diseases. Front Mol Biosci 2016;3:7
4. Cho S, Dreyfuss G: A degron created by SMN2 exon 7 skipping is a principal contributor to spinal muscular atrophy severity. Genes Dev 2010;24:438–42
5. Arnold WD, Kassar D, Kissel JT: Spinal muscular atrophy: diagnosis and management in a new therapeutic era. Muscle Nerve 2015;51:157–67
6. Finkel R, Bertini E, Muntoni F, et al.; ENMC SMA Workshop Study Group: 209th ENMC International Workshop: outcome measures and clinical trial readiness in spinal muscular atrophy 7–9 November 2014, Heemskerk, the Netherlands. Neuromuscul Disord 2015;25:593–602
7. Messina S, Sframeli M: New treatments in spinal muscular atrophy: positive results and new challenges. J Clin Med 2020;9:2222
8. Pera MC, Coratti G, Berti B, et al.: Diagnostic journey in spinal muscular atrophy: is it still an odyssey?PLoS One 2020;15:e0230677
9. Ramdas S, Servais L: New treatments in spinal muscular atrophy: an overview of currently available data. Expert Opin Pharmacother 2020;21:307–15
10. Pierzchlewicz K, Kępa I, Podogrodzki J, et al.: Spinal muscular atrophy: the use of functional motor scales in the era of disease-modifying treatment. Child Neurol Open 2021;8:2329048x211008725
11. Hagenacker T, Wurster CD, Günther R, et al.: Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study. Lancet Neurol 2020;19:317–25
12. Kaufmann P, McDermott MP, Darras BT, et al.: Prospective cohort study of spinal muscular atrophy types 2 and 3. Neurology 2012;79:1889–97
13. Osmanovic A, Ranxha G, Kumpe M, et al.: Treatment satisfaction in 5q-spinal muscular atrophy under nusinersen therapy. Ther Adv Neurol Disord 2021;14:1756286421998902
14. Monnery D, Webb E, Richardson L, et al.: Targeted palliative care day therapy interventions using modified MYMOP2 tool can improve outcomes for patients with non-malignant diseases. Int J Palliat Nurs 2018;24:92–5
15. Glanz BI, Musallam A, Rintell DJ, et al.: Treatment satisfaction in multiple sclerosis. Int J MS Care 2014;16:68–75
16. Moher D, Shamseer L, Clarke M, et al.: Preferred Reporting items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 statement. Syst Rev 2015;4:1
17. Bertini E, Burghes A, Bushby K, et al.: 134th ENMC International Workshop: outcome measures and treatment of spinal muscular atrophy, 11–13 February 2005, Naarden, the Netherlands. Neuromuscul Disord 2005;15:802–16
18. Messina S, Frongia AL, Antonaci L, et al.: A critical review of patient and parent caregiver oriented tools to assess health-related quality of life, activity of daily living and caregiver burden in spinal muscular atrophy. Neuromuscul Disord 2019;29:940–50
19. Stull DWV, Houghton K, Williams N, Teynor M: Minimal clinically important differences in motor function in patients with infantile-onset spinal muscular atrophy: results from the phase 3 ENDEAR trial. Abstract presented at: 2019 AMCP Annual Meeting; March 25, 2019; San Diego, CA; Session 55
20. Storm FA, Petrarca M, Beretta E, et al.: Minimum clinically important difference of gross motor function and gait endurance in children with motor impairment: a comparison of distribution-based approaches. Biomed Res Int 2020;2020:2794036
21. Pera MC, Coratti G, Forcina N, et al.: Content validity and clinical meaningfulness of the HFMSE in spinal muscular atrophy. BMC Neurol 2017;17:39
22. McGraw S, Qian Y, Henne J, et al.: A qualitative study of perceptions of meaningful change in spinal muscular atrophy. BMC Neurol 2017;17:68
23. Stolte B, Bois JM, Bolz S, et al.: Minimal clinically important differences in functional motor scores in adults with spinal muscular atrophy. Eur J Neurol 2020;27:2586–94
24. Sivo S, Mazzone E, Antonaci L, et al.: Upper limb module in non-ambulant patients with spinal muscular atrophy: 12 month changes. Neuromuscul Disord 2015;25:212–5
25. Pera MC, Coratti G, Mazzone ES, et al.: Revised Upper Limb Module for spinal muscular atrophy: 12 month changes. Muscle Nerve 2019;59:426–30
26. Varni JW, Burwinkle TM, Seid M, et al.: The PedsQL 4.0 as a pediatric population health measure: feasibility, reliability, and validity. Ambul Pediatr 2003;3:329–41
27. Stucki G, Liang MH, Stucki S, et al.: Application of statistical graphics to facilitate selection of health status measures for clinical practice and evaluative research. Clin Rheumatol 1999;18:101–5
28. Sterne JAC, Savović J, Page MJ, et al.: RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019;366:l4898
29. Szabo L, Gergely A, Jakus R, et al.: Efficacy of nusinersen in type 1, 2 and 3 spinal muscular atrophy: real world data from Hungarian patients. Eur J Paediatr Neurol 2020;27:37–42
30. Aragon-Gawinska K, Daron A, Ulinici A, et al.: Sitting in patients with spinal muscular atrophy type 1 treated with nusinersen. Dev Med Child Neurol 2020;62:310–4
31. Aragon-Gawinska K, Seferian AM, Daron A, et al.: Nusinersen in patients older than 7 months with spinal muscular atrophy type 1: a cohort study. Neurology 2018;91:e1312–8
32. Audic F, de la Banda MGG, Bernoux D, et al.: Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study. Orphanet J Rare Dis 2020;15:148
33. Montes J, Dunaway Young S, Mazzone ES, et al.: Nusinersen improves walking distance and reduces fatigue in later-onset spinal muscular atrophy. Muscle Nerve 2019;60:409–14
34. De Vivo DC, Bertini E, Swoboda KJ, et al.: Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: interim efficacy and safety results from the phase 2 NURTURE study. Neuromuscul Disord 2019;29:842–56
35. Finkel RS, Chiriboga CA, Vajsar J, et al.: Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet 2016;388:3017–26
36. Finkel RS, Mercuri E, Darras BT, et al.: Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med 2017;377:1723–32
37. Iwayama H, Wakao N, Kurahashi H, et al.: Administration of nusinersen via paramedian approach for spinal muscular atrophy. Brain Dev 2021;43:121–6
38. LoMauro A, Aliverti A, Mastella C, et al.: Spontaneous breathing pattern as respiratory functional outcome in children with spinal muscular atrophy (SMA). PLoS One 2016;11:e0165818
39. Pane M, Coratti G, Sansone VA, et al.: Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data. Ann Neurol 2019;86:443–51
40. Pechmann A, Langer T, Schorling D, et al.: Evaluation of children with SMA type 1 under treatment with nusinersen within the expanded access program in germany. J Neuromuscul Dis 2018;5:135–43
41. Al-Zaidy SA, Kolb SJ, Lowes L, et al.: AVXS-101 (onasemnogene abeparvovec) for SMA1: comparative study with a prospective natural history cohort. J Neuromuscul Dis 2019;6:307–17
42. De Sanctis R, Pane M, Coratti G, et al.: Clinical phenotypes and trajectories of disease progression in type 1 spinal muscular atrophy. Neuromuscul Disord 2018;28:24–8
43. Finkel RS, McDermott MP, Kaufmann P, et al.: Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology 2014;83:810–7
44. Kolb SJ, Coffey CS, Yankey JW, et al.: Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study. Ann Clin Transl Neurol 2016;3:132–45
45. Kolb SJ, Coffey CS, Yankey JW, et al.: Natural history of infantile-onset spinal muscular atrophy. Ann Neurol 2017;82:883–91
46. Lowes LP, Alfano LN, Arnold WD, et al.: Impact of age and motor function in a phase 1/2A study of infants with SMA type 1 receiving single-dose gene replacement therapy. Pediatr Neurol 2019;98:39–45
47. Mendell JR, Al-Zaidy S, Shell R, et al.: Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med 2017;377:1713–22
48. Olsson B, Alberg L, Cullen NC, et al.: NFL is a marker of treatment response in children with SMA treated with nusinersen. J Neurol 2019;266:2129–36
49. Pane M, Palermo C, Messina S, et al.: Nusinersen in type 1 SMA infants, children and young adults: preliminary results on motor function. Neuromuscul Disord 2018;28:582–5
50. Montes J, McDermott MP, Mirek E, et al.: Ambulatory function in spinal muscular atrophy: age-related patterns of progression. PLoS One 2018;13:e0199657
51. Strauss KA, Carson VJ, Brigatti KW, et al.: Preliminary safety and tolerability of a novel subcutaneous intrathecal catheter system for repeated outpatient dosing of nusinersen to children and adults with spinal muscular atrophy. J Pediatr Orthop 2018;38:e610–7
52. van der Heul AMB, Cuppen I, Wadman RI, et al.: Feeding and swallowing problems in infants with spinal muscular atrophy type 1: an observational study. J Neuromuscul Dis 2020;7:323–30
53. Pane M, Palermo C, Messina S, et al.: An observational study of functional abilities in infants, children, and adults with type 1 SMA. Neurology 2018;91:e696–703
54. Modrzejewska S, Kotulska K, Kopyta I, et al.: Nusinersen treatment of spinal muscular atrophy type 1—results of expanded access programme in Poland. Neurol Neurochir Pol 2021;55:289–94
55. Wijngaarde CA, Stam M, Otto LAM, et al.: Muscle strength and motor function in adolescents and adults with spinal muscular atrophy. Neurology 2020;95:e1988–98
56. Chen TH, Chang JG, Yang YH, et al.: Randomized, double-blind, placebo-controlled trial of hydroxyurea in spinal muscular atrophy. Neurology 2010;75:2190–7
57. Kaufmann P, McDermott MP, Darras BT, et al.: Observational study of spinal muscular atrophy type 2 and 3: functional outcomes over 1 year. Arch Neurol 2011;68:779–86
58. Stark C, Duran I, Cirak S, et al.: Vibration-assisted home training program for children with spinal muscular atrophy. Child Neurol Open 2018;5:2329048X18780477
59. Wang HY, Yang YH, Jong YJ: Correlations between change scores of measures for muscle strength and motor function in individuals with spinal muscular atrophy types 2 and 3. Am J Phys Med Rehabil 2013;92:335–42
60. Wadman RI, Wijngaarde CA, Stam M, et al.: Muscle strength and motor function throughout life in a cross-sectional cohort of 180 patients with spinal muscular atrophy types 1c-4. Eur J Neurol 2018;25:512–8
61. Bertini E, Dessaud E, Mercuri E, et al.: Safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 spinal muscular atrophy: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol 2017;16:513–22
62. Darbar IA, Plaggert PG, Resende MB, et al.: Evaluation of muscle strength and motor abilities in children with type II and III spinal muscle atrophy treated with valproic acid. BMC Neurol 2011;11:36
63. Mazzone E, De Sanctis R, Fanelli L, et al.: Hammersmith Functional Motor Scale and Motor Function Measure-20 in non ambulant SMA patients. Neuromuscul Disord 2014;24:347–52
64. Mercuri E, Bertini E, Messina S, et al.: Pilot trial of phenylbutyrate in spinal muscular atrophy. Neuromuscul Disord 2004;14:130–5
65. Werlauff U, Steffensen BF, Bertelsen S, et al.: Physical characteristics and applicability of standard assessment methods in a total population of spinal muscular atrophy type II patients. Neuromuscul Disord 2010;20:34–43
66. Mercuri E, Bertini E, Messina S, et al.: Randomized, double-blind, placebo-controlled trial of phenylbutyrate in spinal muscular atrophy. Neurology 2007;68:51–5
67. Tiziano FD, Bertini E, Messina S, et al.: The Hammersmith Functional Score correlates with the SMN2 copy number: a multicentric study. Neuromuscul Disord 2007;17:400–3
68. Pane M, Staccioli S, Messina S, et al.: Daily salbutamol in young patients with SMA type II. Neuromuscul Disord 2008;18:536–40
69. Farrar MA, Vucic S, Johnston HM, et al.: Pathophysiological insights derived by natural history and motor function of spinal muscular atrophy. J Pediatr 2013;162:155–9
70. Kruitwagen-Van Reenen ET, Wadman RI, Visser-Meily JM, et al.: Correlates of health related quality of life in adult patients with spinal muscular atrophy. Muscle Nerve 2016;54:850–5
71. Darras BT, Chiriboga CA, Iannaccone ST, et al.: Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies. Neurology 2019;92:e2492–506
72. Dunaway Young S, Montes J, Kramer SS, et al.: Perceived fatigue in spinal muscular atrophy: a pilot study. J Neuromuscul Dis 2019;6:109–17
73. Stolte B, Totzeck A, Kizina K, et al.: Feasibility and safety of intrathecal treatment with nusinersen in adult patients with spinal muscular atrophy. Ther Adv Neurol Disord 2018;11:1756286418803246
74. Kirschner J, Schorling D, Hauschke D, et al.: Somatropin treatment of spinal muscular atrophy: a placebo-controlled, double-blind crossover pilot study. Neuromuscul Disord 2014;24:134–42
75. Chiriboga CA, Swoboda KJ, Darras BT, et al.: Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. Neurology 2016;86:890–7
76. Lewelt A, Krosschell KJ, Scott C, et al.: Compound muscle action potential and motor function in children with spinal muscular atrophy. Muscle Nerve 2010;42:703–8
77. Osmanovic A, Ranxha G, Kumpe M, et al.: Treatment expectations and patient-reported outcomes of nusinersen therapy in adult spinal muscular atrophy. J Neurol 2020;267:2398–407
78. Sproule DM, Montes J, Dunaway S, et al.: Adiposity is increased among high-functioning, non-ambulatory patients with spinal muscular atrophy. Neuromuscul Disord 2010;20:448–52
79. Mazzone E, Montes J, Main M, et al.: Old measures and new scores in spinal muscular atrophy patients. Muscle Nerve 2015;52:435–7
80. Pera MC, Romeo DM, Graziano A, et al.: Sleep disorders in spinal muscular atrophy. Sleep Med 2017;30:160–3
81. Salazar R, Montes J, Dunaway Young S, et al.: Quantitative evaluation of lower extremity joint contractures in spinal muscular atrophy: implications for motor function. Pediatr Phys Ther 2018;30:209–15
82. Sproule DM, Montgomery MJ, Punyanitya M, et al.: Thigh muscle volume measured by magnetic resonance imaging is stable over a 6-month interval in spinal muscular atrophy. J Child Neurol 2011;26:1252–9
83. Verma S, Forte J, Ritchey M, et al.: Motor unit number index in children with later-onset spinal muscular atrophy. Muscle Nerve 2020;62:633–7
84. Wurster CD, Gunther R, Steinacker P, et al.: Neurochemical markers in CSF of adolescent and adult SMA patients undergoing nusinersen treatment. Ther Adv Neurol Disord 2019;12:1756286419846058
85. Bonanno S, Marcuzzo S, Malacarne C, et al.: Circulating MyomiRs as potential biomarkers to monitor response to nusinersen in pediatric SMA patients. Biomedicines 2020;8:21
86. Dunaway Young S, Montes J, Salazar R, et al.: Scoliosis surgery significantly impacts motor abilities in higher-functioning individuals with spinal muscular atrophy1. J Neuromuscul Dis 2020;7:183–92
87. Otto LAM, van der Pol WL, Schlaffke L, et al.: Quantitative MRI of skeletal muscle in a cross-sectional cohort of patients with spinal muscular atrophy types 2 and 3. NMR Biomed 2020;33:e4357
88. Coratti G, Lucibello S, Pera MC, et al.: Gain and loss of abilities in type II SMA: a 12-month natural history study. Neuromuscul Disord 2020;30:765–71
89. Coratti G, Pera MC, Lucibello S, et al.: Age and baseline values predict 12 and 24-month functional changes in type 2 SMA. Neuromuscul Disord 2020;30:756–64
90. Maggi L, Bello L, Bonanno S, et al.: Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3. J Neurol Neurosurg Psychiatry 2020;91:1166–74
91. Rudnicki SA, Andrews JA, Duong T, et al.: Reldesemtiv in patients with spinal muscular atrophy: a phase 2 hypothesis-generating study. Neurotherapeutics 2021;18:1127–36
92. Yeo CJJ, Simeone SD, Townsend EL, et al.: Prospective cohort study of nusinersen treatment in adults with spinal muscular atrophy. J Neuromuscul Dis 2020;7:257–68
93. Faravelli I, Meneri M, Saccomanno D, et al.: Nusinersen treatment and cerebrospinal fluid neurofilaments: an explorative study on spinal muscular atrophy type 3 patients. J Cell Mol Med 2020;24:3034–9
94. Montes J, Dunaway S, Garber CE, et al.: Leg muscle function and fatigue during walking in spinal muscular atrophy type 3. Muscle Nerve 2014;50:34–9
95. Walter MC, Wenninger S, Thiele S, et al.: Safety and treatment effects of nusinersen in longstanding adult 5q-SMA type 3—a prospective observational study. J Neuromuscul Dis 2019;6:453–65
96. Coratti G, Messina S, Lucibello S, et al.: Clinical variability in spinal muscular atrophy type III. Ann Neurol 2020;88:1109–17
97. Mercuri E, Darras BT, Chiriboga CA, et al.: Nusinersen versus sham control in later-onset spinal muscular atrophy. N Engl J Med 2018;378:625–35
98. De Sanctis R, Coratti G, Pasternak A, et al.: Developmental milestones in type I spinal muscular atrophy. Neuromuscul Disord 2016;26:754–9
99. Gómez-García de la Banda M, Amaddeo A, Khirani S, et al.: Assessment of respiratory muscles and motor function in children with SMA treated by nusinersen. Pediatr Pulmonol 2021;56:299–306
100. Acsadi G, Crawford TO, Müller-Felber W, et al.: Safety and efficacy of nusinersen in spinal muscular atrophy: the EMBRACE study. Muscle Nerve 2021;63:668–77
101. Vuillerot C, Payan C, Iwaz J, et al.; MFM Spinal Muscular Atrophy Study Group: Responsiveness of the motor function measure in patients with spinal muscular atrophy. Arch Phys Med Rehabil 2013;94:1555–61
102. Chabanon A, Seferian AM, Daron A, et al.: Prospective and longitudinal natural history study of patients with type 2 and 3 spinal muscular atrophy: baseline data NatHis-SMA study. PLoS One 2018;13:e0201004
103. Seferian AM, Moraux A, Canal A, et al.: Upper limb evaluation and one-year follow up of non-ambulant patients with spinal muscular atrophy: an observational multicenter trial. PLoS One 2015;10:e0121799
104. Finkel RS, Crawford TO, Swoboda KJ, et al.: Candidate proteins, metabolites and transcripts in the biomarkers for spinal muscular atrophy (BforSMA) clinical study. PLoS One 2012;7:e35462
105. de Oliveira CM, Araujo AP: Self-reported quality of life has no correlation with functional status in children and adolescents with spinal muscular atrophy. Eur J Paediatr Neurol 2011;15:36–9
106. Swoboda KJ, Scott CB, Crawford TO, et al.: SMA CARNI-VAL trial part I: double-blind, randomized, placebo-controlled trial of l-carnitine and valproic acid in spinal muscular atrophy. PLoS One 2010;5:e12140
107. Swoboda KJ, Scott CB, Reyna SP, et al.: Phase II open label study of valproic acid in spinal muscular atrophy. PLoS One 2009;4:e5268
108. Kizina K, Stolte B, Totzeck A, et al.: Fatigue in adults with spinal muscular atrophy under treatment with nusinersen. Sci Rep 2020;10:11069
109. Montes J, Garber CE, Kramer SS, et al.: Single-blind, randomized, controlled clinical trial of exercise in ambulatory spinal muscular atrophy: why are the results negative?J Neuromuscul Dis 2015;2:463–70
110. Elsheikh B, King W, Peng J, et al.: Outcome measures in a cohort of ambulatory adults with spinal muscular atrophy. Muscle Nerve 2020;61:187–91
111. Tiziano FD, Lomastro R, Abiusi E, et al.: Longitudinal evaluation of SMN levels as biomarker for spinal muscular atrophy: results of a phase IIb double-blind study of salbutamol. J Med Genet 2019;56:293–300
112. Tiziano FD, Lomastro R, Di Pietro L, et al.: Clinical and molecular cross-sectional study of a cohort of adult type III spinal muscular atrophy patients: clues from a biomarker study. Eur J Hum Genet 2013;21:630–6
113. Mazzone E, Bianco F, Main M, et al.: Six minute walk test in type III spinal muscular atrophy: a 12 month longitudinal study. Neuromuscul Disord 2013;23:624–8
114. Montes J, Blumenschine M, Dunaway S, et al.: Weakness and fatigue in diverse neuromuscular diseases. J Child Neurol 2013;28:1277–83
115. Merlini L, Solari A, Vita G, et al.: Role of gabapentin in spinal muscular atrophy: results of a multicenter, randomized Italian study. J Child Neurol 2003;18:537–41
116. Merlini L, Bertini E, Minetti C, et al.: Motor function-muscle strength relationship in spinal muscular atrophy. Muscle Nerve 2004;29:548–52
117. Kissel JT, Scott CB, Reyna SP, et al.: SMA CARNIVAL TRIAL PART II: a prospective, single-armed trial of l-carnitine and valproic acid in ambulatory children with spinal muscular atrophy. PLoS One 2011;6:e21296
118. Vry J, Schubert IJ, Semler O, et al.: Whole-body vibration training in children with Duchenne muscular dystrophy and spinal muscular atrophy. Eur J Paediatr Neurol 2014;18:140–9
119. Kocova H, Dvorackova O, Vondracek P, et al.: Health-related quality of life in children and adolescents with spinal muscular atrophy in the Czech Republic. Pediatr Neurol 2014;50:591–4
120. Farrar MA, Vucic S, Lin CS, et al.: Dysfunction of axonal membrane conductances in adolescents and young adults with spinal muscular atrophy. Brain 2011;134(pt 11):3185–97
121. Miller RG, Moore DH, Dronsky V, et al.: A placebo-controlled trial of gabapentin in spinal muscular atrophy. J Neurol Sci 2001;191(1–2):127–31
122. Querin G, Lenglet T, Debs R, et al.: The motor unit number index (MUNIX) profile of patients with adult spinal muscular atrophy. Clin Neurophysiol 2018;129:2333–40
123. Glanzman AM, Mazzone E, Main M, et al.: The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND): test development and reliability. Neuromuscul Disord 2010;20:155–61
124. Glanzman AM, McDermott MP, Montes J, et al.: Validation of the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND). Pediatr Phys Ther 2011;23:322–6
125. Cano SJ, Mayhew A, Glanzman AM, et al.: Rasch analysis of clinical outcome measures in spinal muscular atrophy. Muscle Nerve 2014;49:422–30
126. Iannaccone ST; American Spinal Muscular Atrophy Randomized Trials (AmSMART) Group: Outcome measures for pediatric spinal muscular atrophy. Arch Neurol 2002;59:1445–50
127. Iannaccone ST, Hynan LS; American Spinal Muscular Atrophy Randomized Trials (AmSMART) Group: Reliability of 4 outcome measures in pediatric spinal muscular atrophy. Arch Neurol 2003;60:1130–6
128. Nelson L, Owens H, Hynan LS, et al.; AmSMART Group: The Gross Motor Function Measure is a valid and sensitive outcome measure for spinal muscular atrophy. Neuromuscul Disord 2006;16:374–80
129. Main M, Kairon H, Mercuri E, et al.: The Hammersmith Functional Motor Scale for children with spinal muscular atrophy: a scale to test ability and monitor progress in children with limited ambulation. Eur J Paediatr Neurol 2003;7:155–9
130. Mercuri E, Messina S, Battini R, et al.: Reliability of the Hammersmith Functional Motor Scale for spinal muscular atrophy in a multicentric study. Neuromuscul Disord 2006;16:93–8
131. O’Hagen JM, Glanzman AM, McDermott MP, et al.: An expanded version of the Hammersmith Functional Motor Scale for SMA II and III patients. Neuromuscul Disord 2007;17(9–10):693–7
132. Glanzman AM, O’Hagen JM, McDermott MP, et al.: Validation of the Expanded Hammersmith Functional Motor Scale in spinal muscular atrophy type II and III. J Child Neurol 2011;26:1499–507
133. Krosschell KJ, Maczulski JA, Crawford TO, et al.: A modified Hammersmith Functional Motor Scale for use in multi-center research on spinal muscular atrophy. Neuromuscul Disord 2006;16:417–26
134. Krosschell KJ, Scott CB, Maczulski JA, et al.: Reliability of the modified Hammersmith Functional Motor Scale in young children with spinal muscular atrophy. Muscle Nerve 2011;44:246–51
135. Ramsey D, Scoto M, Mayhew A, et al.: Revised Hammersmith Scale for spinal muscular atrophy: a SMA specific clinical outcome assessment tool. PLoS One 2017;12:e0172346
136. de Lattre C, Payan C, Vuillerot C, et al.: Motor function measure: validation of a short form for young children with neuromuscular diseases. Arch Phys Med Rehabil 2013;94:2218–26
137. Berard C, Payan C, Hodgkinson I, et al.; MFM Collaborative Study Group: A motor function measure for neuromuscular diseases. Construction and validation study. Neuromuscul Disord 2005;15:463–70
138. Trundell D, Le Scouiller S, Gorni K, et al.; SMA MFM Study Group: Validity and reliability of the 32-item Motor Function Measure in 2- to 5-year-olds with neuromuscular disorders and 2- to 25-year-olds with spinal muscular atrophy. Neurol Ther 2020;9:575–84
139. Werlauff U, Fynbo Steffensen B: The applicability of four clinical methods to evaluate arm and hand function in all stages of spinal muscular atrophy type II. Disabil Rehabil 2014;36:2120–6
140. Mazzone ES, Mayhew A, Montes J, et al.: Revised Upper Limb Module for spinal muscular atrophy: development of a new module. Muscle Nerve 2017;55:869–74
141. Mazzone E, Bianco F, Martinelli D, et al.: Assessing upper limb function in nonambulant SMA patients: development of a new module. Neuromuscul Disord 2011;21:406–12
142. Montes J, McDermott MP, Martens WB, et al.: Six-Minute Walk Test demonstrates motor fatigue in spinal muscular atrophy. Neurology 2010;74:833–8
143. Iannaccone ST, Hynan LS, Morton A, et al.: The PedsQL in pediatric patients with spinal muscular atrophy: feasibility, reliability, and validity of the Pediatric Quality of Life Inventory generic core scales and neuromuscular module. Neuromuscul Disord 2009;19:805–12
144. Dunaway S, Montes J, Montgomery M, et al.: Reliability of telephone administration of the PedsQL Generic Quality of Life Inventory and Neuromuscular Module in spinal muscular atrophy (SMA). Neuromuscul Disord 2010;20:162–5
145. Haataja L, Mercuri E, Regev R, et al.: Optimality score for the neurologic examination of the infant at 12 and 18 months of age. J Pediatr 1999;135(2 pt 1):153–61
146. Dianne JRPL, Lisa MA, et al.: Gross Motor Function Measure (GMFM-66 & GMFM-88) User’s Manual. Cambridge, England, Cambridge University Press, 2002
147. Berard C, Vuillerot C, Girardot F, et al.; Group Ms: User Manual MFM-32 & MFM-20, 3rd ed. France, Motor Function Measure (C), 2016
148. Mercuri E, Finkel R, Montes J, et al.: Patterns of disease progression in type 2 and 3 SMA: implications for clinical trials. Neuromuscul Disord 2016;26:126–31
149. Baranello G, Darras BT, Day JW, et al.: Risdiplam in type 1 spinal muscular atrophy. New Engl J Med 2021;384:915–23
Keywords:

Spinal Muscular Atrophy; Motor Function; Patient-Reported Outcomes; Systematic Review

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