Available online at www.sciencedirect.

com

Neuromuscular Disorders 31 (2021) 1028–1037

www.elsevier.com/locate/nmd

Review
Clinical outcome assessments in Duchenne muscular dystrophy and spinal
muscular atrophy: past, present and future
Leslie L. Nelson a,∗, Susan T. Iannaccone b
a Department of Physical Therapy, University of Texas Southwestern Medical Center, 6011 Harry Hines Blvd, Dallas, TX, United States
b Department of Pediatrics and Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, United States
Received 30 June 2021; received in revised form 12 July 2021; accepted 16 July 2021

Abstract
Scores and scales used in pediatric motor development for neuromuscular disorders have evolved greatly since the beginning of their
development. In this review we provide a brief history of scales used in pediatric patients with neuromuscular disorders and an update regarding
the advancement of the scales commonly used in patients with spinal muscular atrophy and Duchenne muscular dystrophy. We focus on the
collaborative effort that has led to the development of outcomes and speak to the possible future of Clinical Outcome Assessments.
© 2021 Elsevier B.V. All rights reserved.

Keywords: clinical outcome assessment; spinal muscular atrophy; Duchenne muscular dystrophy; motor performance; motor development; functional outcome.

1. Introduction Identification of genetic mutations, advances in diagnosis,

and improved understanding of underlying disease
Reliable and valid clinical endpoints used to assess motor mechanisms prompted the need for clinical experts to
development and motor function are essential for monitoring establish disease specific natural history studies that
longitudinal change and efficacy of intervention in patients would inform the study design for interventional studies.
with neuromuscular disorders (NMD). Evaluation of pediatric International networks collaborated to collect clinical data in
patients with NMD can be complicated due to factors rare diseases, including spinal muscular atrophy (SMA) and
including effort dependent scales, significant weakness, small Duchenne muscular dystrophy (DMD). These networks would
progressive changes that may occur over time as well as work to integrate clinical research, education, and patient care
the presence and impact of contractures. It is necessary that to construct databases with the goal of achieving the best
clinical endpoints that measure motor function in patients possible health outcomes and to prepare for clinical trials
with NMD encompass the significant heterogeneity of patient [1,2]. As the genetic and clinical nuances of NMD were better
populations and must be able to capture changes in the very understood, the need for improved outcome measures became
weak and very strong. Consideration should be given to increasingly important. Functional outcome measures needed
the endpoint’s ability to accurately measure change across to be valid, reliable, and clinically meaningful. To better
the lifespan, including the potential impact developmental understand longitudinal change, COAs would become the
maturation may have in the very young. Clinical outcome framework on which interventional studies would be based.
assessments (COAs) used to assess motor function are
clinical endpoints that are typically disease specific functional 2. Background
outcome measures established from collaborative natural
history trials. These COAs are essential to assess longitudinal Expert clinicians recognized early on the importance of
change and efficacy of potential interventions. valid functional outcome measures to track longitudinal

∗ Corresponding author.
E-mail addresses: [email protected] (L.L. Nelson), [email protected] (S.T. Iannaccone).

https://doi.org/10.1016/j.nmd.2021.07.015
0960-8966/© 2021 Elsevier B.V. All rights reserved.
L.L. Nelson and S.T. Iannaccone Neuromuscular Disorders 31 (2021) 1028–1037

change in patients with NMD. Early intervention studies modify and develop new scales that are suitable for patients
identified the need for COAs to be sensitive to capture with DMD, SMA and additional neuromuscular patients such
change in these rare progressive disorders. Relevance to a as those with dysferlinopathies [14,16,23].
potentially large phenotypic spectrum had to be considered As multicenter international clinical trials continued to
to effectively measure the heterogeneity of the patient emerge, establishing reliability became a significant necessity
population as outcomes could easily be limited by ceiling for the successful assessment of efficacy of intervention.
and floor effects. To collect valid data and reduce potential Standardized functional motor outcome measures are
outliers, investigators recognized the importance of the trained somewhat limited by dependence on the subjective opinion
clinical evaluator (CE) with understanding and experience of the evaluator and therefore require significant time and
in evaluation of motor development [3]. Physiotherapists expense to ensure training that will result in reliable data
have critical training in musculoskeletal anatomy and collection. Inter and intra-rater as well as test-retest reliability
physiology, as well as biomechanics. They develop critical has been established for several COAs used in assessing
observational and palpation skills, which are required for patients with NMD [14-15,24-32] (Tables 1,2). There is a
certain assessments of strength and function. Since many potential learning curve for the subject and the evaluator
individuals with NMD develop compensatory movements, and growth and development of motor milestones may
physiotherapists have the experience and training to analyze impact change in scores. Reliability requires consistent
movement and ensure that the quality of movement is aligned administration and performance of COAs. Therefore, to
with the test objective. Therefore, physiotherapists at NMD ensure assessments are reliable within site CEs and among
specialty centers filled this CE requirement well and became large multisite clinical trial sites, training protocols were
part of the driving force of the evolution of functional put in place [28-29]. In 2014, a group of international
outcomes. physiotherapists and representatives from patient advocacy
Guidance from regulatory agencies including the U.S. Food groups for patients with DMD gathered to deliberate the
and Drug Administration (FDA) and European Medicines importance of clinical evaluator training and reliability
Agency (EMA) has also contributed to the advancement documentation for randomized controlled trials (RCTs). This
of functional outcomes used in NMD. While efficacy group of physiotherapists had been leaders in establishing
endpoints are not specifically defined by these agencies, the standards and recommendations for outcomes used in multi-
recommendation that scales measure change of function over site clinical trials for drug approvals through the FDA
a wide range of severity of disease and have the ability and EMA. Details and guidelines formulated from this
to detect improvement from baseline, as well as decline, meeting are currently under development for publication.
to capture the spectrum of possible drug effects has been In 2018, Krosschell and others reported on the experience
documented. The importance of patient and caregiver insight of training and establishing reliability in a multicenter
into treatment goals and the outcomes that may meaningful trial investigating the natural history of patients with SMA
in regards to treatment effects has also been highlighted. type I [25]. Moreover, a detailed training methodology
International collaboration of input from regulatory and the resulting excellent reliability of CEs in a large
agencies, input from family advocacy groups, clinical views multicenter international study highlighted the need for
of expert investigators, CE experience with outcomes and implementation of a rigorous training protocol, especially
statistical knowledge and understanding has led to the when training CEs with varying levels of experience [28].
development of several suitable functional outcomes for Additionally, patient advocacy groups, with the guidance of
both SMA and DMD. Determining efficacy of drugs expert physiotherapists, published documents for guidance
and interventions requires accurate and reliable assessment for CEs in both the clinical and research outcomes. The
of patient function for appropriate interpretation of the Cure SMA Industry Collaboration funded and supported
data. Valid and reliable outcomes additionally need to preparation of the “Best Practices for Physical Therapists and
be statistically robust and clinically meaningful. Validity Clinical Evaluators in SMA” document to help ensure that
of several scales has been established utilizing traditional recommendations would effectively help to support CEs at
statistical analysis to determine their psychometric properties clinical trial sites interested in conducting clinical trials in
[4-20] (Tables 1, 2). A modern approach to examining SMA.
outcome measures, the Rasch Measurement Model (RMM), In addition to validity and reliability, trial design for rare
has been used to help assess and advance the scientific neuromuscular disorders should incorporate meaningful rating
merit of outcomes commonly used in NMD, including SMA scales to assess outcomes. As previously noted, regulatory
and DMD [11,21]. Scales using ordinal data may use this agencies have suggested that observed functional changes
method of analysis to establish how well the scale works should be relevant to the patient and their caregivers. In
and to identify possible gaps or redundant items within the 2017, Pera and others reported on the clinical relevance of the
scale. Using Rasch analysis may additionally allow for the HFMSE and found support for its use to detect meaningful
conversion of ordinal data to a more linear measurement. functional change in patients with SMA [33]. Ongoing
Linearization of a scale may allow for the interpretation of international collaboration has facilitated the establishment
a change score being more consistent across the range of of valid and reliable outcomes, improved our understanding
a scale [22]. Furthermore, Rasch analysis has been used to of the psychometric properties of the scales being used and

1029
L.L. Nelson and S.T. Iannaccone Neuromuscular Disorders 31 (2021) 1028–1037

Table 1
Functional motor outcomes used in SMA. Note: This list is not exhaustive.

Outcome Measure Valid Age Reliability in SMA Validity in SMA Natural History Clinical Trials
CHOP INTEND <2 years Glanzman, 2010 [26] Glanzman, 2011 [9] Finkel, 2014 [70] Finkel, 2016 [75]
Krosschell, 2018 [25] Finkel, 2013 [6] Kolb, 2017 [8] Finkel, 2017 [76]
Mercuri, 2020 [71] Mendell, 2017 [77]
Krosschell, 2018 [68]
De Vivo, 2019 [78]
Al-Zaidy, 2019 [79]
HINE-2 2–24 months Bishop, 2018 [7] Bishop, 2018 [7] DeSanctis, 2016 [36] Finkel, 2016 [75]
Finkel, 2017 [76]
Bishop, 2018 [7]
De Vivo, 2019 [78]

HFMSE 24 months and up Mercuri, 2006 [69] Glanzman, 2011 [5] Kaufmann, 2011 [73] Chiriboga, 2016 [81]
O’Hagen, 2007 [27] Mazzone, 2014 [10] Kaufmann, 2012 [2] Mercuri, 2018 [80]
Glanzman, 2018 [28] Pera, 2017 [33] Mazzone, 2014 [10] Darras, 2019 [41]
Mercuri, 2016 [72]
RHS Ramsey, 2017 [16]
RULM 30 months and up Mazzone, 2011 [38] Pera, 2019 [40] Pera, 2019 [40]
Mazzone, 2017 [39]
MFM 2 and up Bérard, 2005 [46] deLattre, 2013 [17] Vuillerot, 2013 [47] Bertini, 2017 [82]
MFM-20 Trundell, 2020 [48] Mazzone, 2014 [10] Mazzone, 2014 [10]
Trundell, 2020 [49] Trundell, 2020 [48]
Trundell, 2020 [49]
6MWT 2 and up Young, 2016 [18] Montes, 2010 [42] Mazzone, 2013 [74] Montes, 2019 [83]
Montes, 2014 [20] Montes, 2018 [19]
Young, 2016 [18]
Pera, 2017 [43]
Montes, 2018 [19]
Montes, 2021 [84]
Endurance 9HPT 8 and up Bartels, 2020 [45] Bartels, 2019 [44]
and Box and Blocks Bartels, 2020 [45]

Table 2
Functional Motor Outcomes Used in DMD. Note: This list is not exhaustive.

Outcome Measure Valid Age Reliability in DMD Validity in DMD Natural History Clinical Trials
NSAA 3.5 and up Mazzone, 2009 [29] Mazzone, 2010 [60] Mazzone, 2011 [87] Ricotti, 2013 [91]
Mayhew, 2011 [11] Mazzone, 2013 [85]
Mayhew, 2013 [12] McDonald, 2013 [1]
Miller, 2020 [64]
PUL 7 and up Mayhew, 2013 [14] Mayhew, 2013 [14] Ricotti, 2019 [88] Pane, 2015 [93]
Pane, 2014 [30] Victor, 2017 [57]
Mayhew, 2020 [65] Taylor, 2019 [92]

6MWT 5 years and up McDonald, 2010 [31] McDonald, 2013 [15] McDonald, 2010 [62] Mendell, 2013 [53]
McDonald, 2013 [15] Mazzone, 2013 [85] Mendell, 2016 [54]
Henricson, 2013 [61] McDonald, 2017 [58]
Mazzone, 2013 [74] Victor, 2017 [57]
McDonald, 2013 [86] Shieh, 2018 [59]
McDonald, 2013 [1] Goemans, 2018 [55]
Pane, 2014 [13] Alfano, 2019 [56]
Mercuri, 2016 [89]
Arora, 2018 [90]
100m 4 years and up Alfano, 2017 [32] Miller, 2020 [64]

1030
L.L. Nelson and S.T. Iannaccone Neuromuscular Disorders 31 (2021) 1028–1037

has given us an overall better understanding of the functional is no established motor assessment sensitive to capture
outcomes used in patients with NMD. changes in this older chronic population. This has led
to the development of the Adult Test of Neuromuscular
3. Evolution of motor function scales in NMD Disorders (ATEND). Scale development considered weaker
individuals with significant contractures and the fact that
The foundation for quantitative assessment of motor ability motor assessments are challenging due to limitations in
in patients with NMD was addressed by Professor Victor the ability to safely transfer or to lie prone. The ATEND
Dubowitz in 1982, based upon the concept of schemes for was developed based on expert experience with the CHOP
graded functional ability and timed function tests initiated ATEND, which was a modified scale constructed from the
by Dr. Paul Vignos in 1963 [34]. Dr. Dubowitz and his CHOP INTEND to measure motor function in non-sitters with
team documented their attempt at establishing an objective SMA while in their wheelchair. Work is on-going to further
quantitative assessment of skeletal muscle function in 61 develop and refine the scale properties with future plans for
patients with DMD. This study was the first to demonstrate modern psychometric analysis including Rasch analysis [35].
that natural history of DMD could be recorded with accurate To determine developmental progress of an infant,
and systematic monitoring. Data would lead to an improved assessment of motor milestones is important. The
capacity to observe the effects of management for boys Hammersmith Infant Neurological Examination (HINE)
with DMD. As time progressed, better understanding of has been used to evaluate developmental milestones in
NMD natural history, pathogenesis, and treatment pathways infantile onset SMA [7,36]. It can be used for assessing
led to the advancement and emergence of new therapeutic infants between 2 and 24 months of age and was originally
modalities, especially in the areas of SMA and DMD. Newly developed to assess global neurological function in typically
diagnosed children and those starting to implement new developing infants. The HINE was constructed on principles
standards of care needed to be assessed using standardized widely accepted in clinical care set forth by Professor Victor
assessment protocols. Subsequent advancement of reliable, Dubowitz and his wife, Dr. Lilly Dubowitz. The HINE-
sensitive, and meaningful outcome measures followed. We 2 is a separate section that examines gross motor items
discuss some examples of adaptations and modifications of to document developmental progress along a continuum
scales and scores used in DMD and SMA. eventually leading to full achievement of a developmental
milestone [36]. Items including head control, sitting, grasp,
3.1. Spinal muscular atrophy kicking, rolling, crawling, standing and walking can be
scored along the continuum. RCTs in infantile onset SMA
Functional motor exams for infantile onset SMA and have shown efficacy when assessing attainment of new
for those unable to sit used historically had been designed milestones using the HINE-2 [7] (Table 1).
to track development in preterm infants. This included the The phenotypic spectrum of later onset SMA is continuous
Alberta Infant Motor Scale (AIMS) and the Test of Infant and types II and III may overlie due to age of disease
Motor Performance (TIMP). Recognizing the need for a more severity and onset and the fact that those that are ambulatory
sensitive assessment to quantify movement for the weakest may lose the ability to walk independently as they age. The
patients with infantile onset SMA and other infantile onset wide age range of people affected and the heterogeneity of
NMD, the Children’s Hospital of Philadelphia Infant Test for the type II and III population make assessment challenging.
Neuromuscular Disorders (CHOP INTEND) was developed Over time, assessment of sitters and walkers with SMA has
[26]. Validation of the scale found that it correlated well evolved. The Hammersmith Functional Motor Scale (HFMS)
with SMN2 copy number and requirement for respiratory was the first outcome measure designed to capture physical
support and reflects measures of disease severity and the abilities of patients with SMA type II and non-ambulatory
motor skills of infants and children across the spectrum of type III [4]. The tool was widely adopted by the SMA
SMA type I [9]. The CHOP INTEND has been used in several community for both research and clinical assessment, but
industry sponsored trials as a primary or secondary endpoint there were issues with measurement properties. The Modified
in determining efficacy of intervention in infantile onset SMA Hammersmith Functional Motor Scale, developed in 2008,
for children under the age of two (Table 1). was developed to mitigate the effects of fatigue and frequent
While the CHOP INTEND was developed to be utilized positional changes that were required with the HFMS. It
with infants, it is not limited to this age range and showed excellent intra-rater reliability in the non-ambulant
CEs may employ it as an assessment for older patients patients but lower reliability in the ambulatory cohort because
that are unable to sit. There are limitations of this scale of significant ceiling effects of the scale [24,37]. An expanded
with older patients due to positional requirements and version of the HFMS, the Expanded Hammersmith Functional
interpretation of items assessing reflexes such as the Galant Motor Scale (HFMSE), was later developed to ameliorate
and Landau spinal reflexes that may require some adaptation the ceiling effects that were found using the original and
to the administration of the scale. With improved patient modified scale [27]. Items from the Gross Motor Function
management with standards of care and the implementation Measure (GMFM) were added as an expansion of the
of DMTs, the need for assessments in older non-sitters HFMS to better examine stronger ambulatory patients. The
has become increasingly important, as currently, there HFMSE is currently commonly used in practice and in

1031
L.L. Nelson and S.T. Iannaccone Neuromuscular Disorders 31 (2021) 1028–1037

RCTs and captures clinically relevant changes due to disease and ambulatory patients. To address the ceiling effect and
progression. A wealth of natural history data are available expand the scale for a broader SMA population, a revision
that have provided valuable insight into trajectories of change process using Rasch analysis was conducted. Thus, the RULM
in patients along the SMA continuum (Table 1). After 10 was created to increase the robustness of the scale and to
years of experience based on lessons learned from clinical capture clinically relevant changes in patients with SMA [39].
use and therapeutic trials using the HFMSE, the International Complaints of fatigability are common in patients with
Spinal Muscular Atrophy Consortium (iSMAC) collaboration SMA and are now an increasingly important area of research.
between SMA REACH UK, the Italian SMA Network The Six Minute Walk Test (6MWT) is an objective evaluation
and the Pediatric Neuromuscular Clinical Research Network of functional exercise capacity, which measures the distance
(PNCR) for SMA (USA) led an effort to revise the original a person can walk in 6 min. It is a global measure of
2009 manual to provide clarification and improvement of multiple body systems including cardiopulmonary, vascular,
item description and scoring details. The intent of the and neuromuscular systems. The 6MWT for ambulatory
updated 2019 HFMSE training manual was to facilitate patients with SMA has been found to be informative in
consistency of administration and scoring of the HFMSE regards to measuring fatigue [42-43]. It has proven to be
for both ambulant and non-ambulant patients with SMA. a measure that may quantify functional endurance and is
While proven a useful and meaningful scale, some limitations sensitive to change. Signs of fatigue can be expressed as
regarding the psychometric properties of the HFMSE have change in gait velocity at minute six compared to minute
been raised [21]. For example, based on Rasch analysis, one and is an important measure in patients with SMA
item misfit of the outcome measure may indicate that items [42]. For non-ambulant patients, the Endurance Shuttle Box
on the scale are measuring different constructs. Multiple and Block Test and the Nine Hole Peg Test for fatigability
constructs within a scale may confound the results and make testing of proximal and distal arm function were developed
interpretation difficult. Therefore, while the HFMSE has been [44-45]. Content validity was established through input from
well established, Rasch analysis has informed an international both experts and patients. Pilot testing showed that this set
group of specialists on how to address these psychometric of endurance tests are well understood and feasible in non-
issues with the development of a new scale. The Revised ambulatory patients with SMA. Further research is needed to
Hammersmith Scale (RHS) has undergone initial pilot testing establish an understanding of the tests’ ability to show change
to establish validity and reliability of the scale [16]. Clinical over time.
expertise and information from statistical analysis led to The Motor Function Measure (MFM) was developed for
a potentially more robust scale with expanded utility and people with neuromuscular disorders, including SMA, to
strength to assess the varied spectrum of weak non-ambulant assess motor function in 3 domains; standing position and
to strong ambulant patients with SMA. Using items from the transfers, axial and proximal motor function, and distal motor
HFMSE and including timed function tests, provides a more function [46]. It was designed to cover a wide spectrum of
sensitive measure of the later onset SMA phenotype and may items to capture different functional abilities (ambulant/non-
have the capacity to capture improvement in even stronger ambulant) and patterns of weakness in patients with various
patients that may benefit from successful DMTs. NMD [47]. While it was not originally designed as a disease
A criticism of the HFMSE was that the scale lacked specific measure, recent efforts have been conducted to
the capability to capture the entire spectrum of disease, establish more disease specific reliability and validity and to
especially those at the lower end of the gross motor determine responsiveness in those with SMA [47-49] It has
function scales. Furthermore, there was a need to identify been used in natural history studies and in studies validating
outcomes that were useful in younger children, as scales often new scales [50-51]. A shortened version has been validated
were validated above age 6 years and included items for for children as young as two years with neuromuscular
which performance was age-dependent. Therefore, to meet diseases [17]. In a correlation study with the HFMS, it was
this need the Upper Limb Measure (ULM) was developed shown to have good sensitivity for determining change in
and subsequently improved upon with the Revised Upper axial and distal items in weaker patients with SMA. For
Limb Module (RULM) [38-39]. The original ULM was stronger non-ambulant patients, it may lack items that assess
developed as an international effort by clinicians, researchers, activities that might be achieved in the more proximal domain
physiotherapists, and patient advocacy groups in an attempt to such as crawling or propping on arms in prone [10]. These
address the need for assessment of upper extremity function results were in line with Rasch analysis that also found some
in non-ambulant patients with SMA. The scale used items gaps along the range of activities [21].
from a variety of developmental scales and some developed
specifically for neuromuscular disorders with the intent of 3.2. Duchenne muscular dystrophy
having the capability to evaluate a wide age range from 30
months to adulthood. The ULM was validated in a multicenter The North Star Ambulatory Assessment (NSAA) is a
setting and has been used in SMA natural history studies and validated functional scale for ambulant boys with DMD
clinical trials [40-41]. Analysis of data from initial studies (Table 2). At the time of its development, scales used
indicated that a ceiling effect was present when assessing to assess motor function in DMD had limited practicality,
cohorts that included both weak and strong non-ambulatory lacked sensitivity to track change, and had limited data

1032
L.L. Nelson and S.T. Iannaccone Neuromuscular Disorders 31 (2021) 1028–1037

supporting reliability of the scales being used. The NSAA maximal performance. Further research is needed to examine
has been proven as suitable for multicenter studies and the potential utilization of the 100 m in RCTs.
is widely used internationally, in clinical settings and as The Performance of Upper Limb (PUL) scale was designed
an outcome measure in clinical trials. Both traditional and specifically to measure upper limb motor performance across
modern psychometric (Rasch) analysis has confirmed this the spectrum of severity of DMD [14,65]. The items are
to be a robust scale [12]. An updated linearized version targeted toward weaker ambulant boys when upper limb
of the scale has been established following an in-depth weakness becomes more apparent as well as non-ambulant
Rasch analysis, to improve the interpretation and capturing of patients with increasing levels of weakness. The proximal
clinically meaningful changes across the scope of the scale to distal progression of muscle weakness typically observed
[22]. The NSAA incorporates skills that may be gained in in DMD is tested using the PUL through three domains:
boys with DMD treated with steroids or DMTs or that may proximal, mid, and distal. Items have been identified as
be lost with the progression of the disease process. The loss relevant and relating to activities of daily living by both
of ambulation occurs in a recognizable pattern due to the patients and clinicians [65]. The development of the PUL
primary underlying pathology of muscle deterioration and began with a systematic review and a preliminary study
related complications such as contractures. Activities included exploring the suitability of the existing measures. Data
on the scale were those necessary to remain functionally collected from the pilot version in a multicenter study was
ambulant and considered as important disease milestones such examined via Rasch analysis and modifications were made to
as rising from the floor and walking ability as measured with develop a version known as the PUL 1.2. This version was
timed function tests. A revised scale more suitable for young shown to be reliable and related to the 6-Minute Walk Test
boys aged three to five was developed in 2016 [52]. Items in ambulant patients [30]. Rasch analysis highlighted some
from the original NSAA were ordered according to the age limitations of the PUL 1.2 including redundancy of items
at which they could be reliably performed. This allows for the and the presence of a ceiling effect. Subsequent collection
observation of acquisition of new skills and abilities in boys of longitudinal data in a larger cohort and additional Rasch
as they mature developmentally. Further studies are needed analysis led to a second modification of the scale, with the
to determine if the revised scale maintains the psychometric revised version known as the PUL 2.0. The changes from
properties of the original NSAA. versions 1.2 to 2.0 were agreed on the basis of both Rasch
In addition to the timed tests included on the NSAA, timed analysis and feedback by clinical experts. The 2.0 version
tests such as the 6MWT and 100 m run have been used has been shown to detect significant change over a 2-year
as functional outcomes in boys with DMD. Generally, trials period in the total score as well as within the three dimensions
investigating DMD potential therapies have almost solely in a large cohort of boys with DMD [65]. This study also
relied on the 6MWT to demonstrate functional improvement confirmed that the PUL 2.0 has the same construct as the
[53-59]. The 6MWT, originally developed for use in adults PUL 1.2, has retained sensitivity and has improved item fit
with cardiopulmonary disease, was modified for use in DMD and scale utility as compared to the PUL 1.2.
to fill the need for an outcome with continuous data that
could monitor ambulatory function over time [31]. Several 4. Future of motor function scales in NMD
studies have since been published to support its validity and
reliability in this population. Mazzone and others found that As DMTs continue to emerge and the search for a cure
the NSAA correlated better with the 6MWT than with other continues, the need for norm referenced functional outcomes
timed function tests [60]. While it can be informative, there that are appropriate for the neuromuscular population arises.
are some limitations of the use of the 6MWT in patients Further, newborn screening for these rare diseases and the
with DMD. Younger boys with DMD may show an increase impact of early treatment will definitely change the health
in distance walked in six minutes despite the progressive outcomes of patients. To date, norm referenced functional
nature of their disease making interpretation of longitudinal outcomes such as the Bayley III and the Peabody have
data challenging [61-62]. Henricson and others reported on been used in clinical trials in patients with SMA treated
the concept of converting 6MWT data to a percent-predicted pre-symptomatically or at an early symptom onset. An
value to help interpret results in the context of maturation international alliance of clinicians is investigating the most
[63]. appropriate set of outcomes that should be used to monitor the
The 100-meter timed test (100 m) was introduced as an development of patients with SMA that have been treated pre-
alternative test of mobility that uses a distinct distance symptomatically with DMTs. This will most likely include
and allows the child to run to limit the ceiling effect norm referenced motor function measures to follow a child’s
seen in walking tests [32]. An initial natural history study development over time as compared to same aged peers. The
examined boys aged three to eight years using the 100 m need for disease specific outcomes may continue as well
[64]. Results in this cohort revealed boys with DMD take for comparison with natural history in untreated patients.
a significantly longer time to complete the 100 m when Determining the appropriate mix of outcomes will continue
compared to normative data based on age, gender, and size. to be a challenge.
The authors suggest this supports the theory that the 100 m The need for training physiotherapists outside of clinical
would have limited risk for a ceiling effect as a test of centers of excellence is now recommended as the expanding

1033
L.L. Nelson and S.T. Iannaccone Neuromuscular Disorders 31 (2021) 1028–1037

requirement for evaluations by third parties for continued use [3] Miller RG, Moore DH, Dronsky V, Bradley W, Barohn R, Bryan W,
of DMTs. A novel comprehensive education program is in the et al. A placebo-controlled trial of gabapentin in spinal muscular
early stages of development with the goal of addressing unmet atrophy. J Neurol Sci 2001;191:127–31.
[4] Main M, Kairon H, Mercuri E, Muntoni F. The Hammersmith functional
needs for education and resources for any physiotherapist motor scale for children with spinal muscular atrophy: a scale to test
working with patients with SMA [66]. While this effort is ability and monitor progress in children with limited ambulation. Eur J
focused solely on SMA, it will likely prove useful as a Paediatr Neurol 2003;7:155–9 pmid:12865054.
template for other NMD to establish educational resources [5] Glanzman AM, O’Hagen JM, McDermott MP, Martens WB,
Flickinger J, Riley S, et al. Validation of the expanded hammersmith
for novice and community based therapists.
functional motor scale in spinal muscular atrophy type II and III. J
During the recent Covid-19 pandemic, remote functional Child Neurol Dec 2011;26(12):1499–507 Epub 2011 Sep 21. PMID:
assessments became an idea whose time had come. As the 21940700. doi:10.1177/0883073811420294.
volume of in-person assessments and elective or non-urgent [6] Finkel RS. Electrophysiological and motor function scale association
care was reduced due to quarantine, telemedicine (TM) was in a pre-symptomatic infant with spinal muscular atrophy type I.
Neuromuscul Disord 2013;23(2):112–15 FebEpub 2012 Nov 10. PMID:
widely used as an alternative for ambulatory clinical practice.
23146148. doi:10.1016/j.nmd.2012.09.006.
Virtual clinical assessment can have significant limitations [7] Bishop KM, Montes J, Finkel RS. Motor milestone assessment of infants
with respect to functional examination of patients including with spinal muscular atrophy using the hammersmith infant neurological
the lack of standardization for conducting the assessment. Exam-Part 2: experience from a nusinersen clinical study. Muscle Nerve
Nevertheless, attempts have been made to collect data in a Jan 2018;57(1):142–6 Epub 2017 Jun 14. PMID: 28556387. doi:10.
1002/mus.25705.
remote environment. In a study published on establishing a
[8] Kolb SJ, Coffey CS, Yankey JW, Krosschell K, Arnold WD,
telerehabilitation program for patients with DMD, the authors Rutkove SB, et al. Natural history of infantile-onset spinal muscular
outlined home motor assessment tasks that could be easily atrophy. Ann Neurol Dec 2017;82(6):883–91 Epub 2017 Dec 8. PMID:
performed by caregivers within the home [67]. Intermittent 29149772; PMCID: PMC5776712. doi:10.1002/ana.25101.
TM assessments may reduce burden of travel of in-person [9] Glanzman AM, McDermott MP, Montes J, Martens WB, Flickinger J,
visits, both clinically and for research purposes, an important Riley S, et al. Validation of the Children’s Hospital of Philadelphia
Infant Test of Neuromuscular Disorders (CHOP INTEND). Pediatr
consideration for participants in RCTs. Use of intermittent Phys Ther 2011;23(4):322–6 WinterPMID: 22090068. doi:10.1097/PEP.
TM visits may be beneficial in reducing exposure during 0b013e3182351f04.
cold and flu season when patients with NMD are especially [10] Mazzone E, De Sanctis R, Fanelli L, Bianco F, Main M, van den
susceptible. There may be a need for discussion and possible Hauwe M, et al. Hammersmith functional motor scale and motor
function measure-20 in non ambulant SMA patients. Neuromuscul
development of valid remote functional assessments for future
Disord Apr 2014;24(4):347–52 Epub 2014 Jan 16. PMID: 24491485.
use. doi:10.1016/j.nmd.2014.01.003.
Motor development and motor function assessment has [11] Mayhew A, Cano S, Scott E, Eagle M, Bushby K, Muntoni F. North star
proven to be a challenging construct. However, in a clinical network for paediatric neuromuscular disease. Moving towards
relatively short time, the NMD network has accomplished meaningful measurement: rasch analysis of the North star ambulatory
assessment in Duchenne muscular dystrophy. Dev Med Child Neurol
an enormous undertaking of establishing assessment protocols
Jun 2011;53(6):535–42 10.1111/j.1469-8749.2011.03939.x. Epub 2011
for rare disease. Continued worldwide collaboration of expert Mar 17. PMID: 21410696.
investigators, CEs, regulatory agencies, family advocacy [12] Mayhew AG, Cano SJ, Scott E, Eagle M, Bushby K, Manzur A,
groups, statisticians and patients will be instrumental in et al. Detecting meaningful change using the North star ambulatory
further advancement of scales used in NMDs. assessment in Duchenne muscular dystrophy. Dev Med Child Neurol
Nov 2013;55(11):1046–52 Epub 2013 Aug 5. PMID: 23909763. doi:10.
1111/dmcn.12220.
Declaration of Competing Interests [13] Pane M, Mazzone ES, Sivo S, Sormani MP, Messina S, D’Amico A,
et al. Long term natural history data in ambulant boys with
Duchenne muscular dystrophy: 36-month changes. PLoS One Oct
The authors declare that they have no known competing 1 2014;9(10):e108205 Erratum in: PLoS One. 2015;10(3):e0121882.
financial interests or personal relationships that could have Erratum in: PLoS One. 2015;10(12):e0144079. PMID: 25271887;
appeared to influence the work reported in this paper. PMCID: PMC4182715. doi:10.1371/journal.pone.0108205.
[14] Mayhew A, Mazzone ES, Eagle M, Duong T, Ash M, Decostre V,
et al. Development of the performance of the upper limb module
References for Duchenne muscular dystrophy. Dev Med Child Neurol Nov
2013;55(11):1038–45 Epub 2013 Aug 1. PMID: 23902233. doi:10.1111/
[1] McDonald CM, Henricson EK, Abresch RT, Han JJ, Escolar DM, dmcn.12213.
Florence JM, et al. The cooperative international neuromuscular research [15] McDonald CM, Henricson EK, Abresch RT, Florence J, Eagle M,
group Duchenne natural history study-a longitudinal investigation in Gappmaier E, et al. The 6-minute walk test and other clinical endpoints
the era of glucocorticoid therapy: design of protocol and the methods in Duchenne muscular dystrophy: reliability, concurrent validity, and
used. Muscle Nerve 2013 May 16;48(1):32–54 Epub PMID: 23677550; minimal clinically important differences from a multicenter study.
PMCID: PMC4147958. doi:10.1002/mus.23807. Muscle Nerve 2013;48(3):357–68 [PubMed: 23674289]. doi:10.1002/
[2] Kaufmann P, McDermott MP, Darras BT, Finkel RS, Sproule DM, mus.23905.
Kang PB, et al. Pediatric Neuromuscular Clinical Research network [16] Ramsey D, Scoto M, Mayhew A, Main M, Mazzone ES, Montes J,
for spinal muscular atrophy (PNCR). Prospective cohort study of spinal et al. Revised Hammersmith scale for spinal muscular atrophy:
muscular atrophy types 2 and 3. Neurology 2012 Oct 30;79(18):1889– a SMA specific clinical outcome assessment tool. PLoS One
97 Epub 2012 Oct 17. PMID: 23077013; PMCID: PMC3525313. 2017;12(2):e0172346. doi:10.1371/journal. pone.0172346.
doi:10.1212/WNL.0b013e318271f7e4.

1034
L.L. Nelson and S.T. Iannaccone Neuromuscular Disorders 31 (2021) 1028–1037

[17] de Lattre C, Payan C, Vuillerot C, Rippert P, de Castro D, Bérard C, [32] Alfano LN, Miller NF, Berry KM, Yin H, Rolf KE, Flanigan KM,
et al. Motor function measure: validation of a short form for young et al. The 100-meter timed test: normative data in healthy males and
children with neuromuscular diseases. Arch Phys Med Rehabil Nov comparative pilot outcome data for use in Duchenne muscular dystrophy
2013;94(11):2218–26 Epub 2013 Apr 18. PMID: 23602884. doi:10. clinical trials. Neuromuscul Disord May 2017;27(5):452–7 Epub 2017
1016/j.apmr.2013.04.001. Feb 17. PMID: 28279570. doi:10.1016/j.nmd.2017.02.007.
[18] Dunaway Young S, Montes J, Kramer SS, Marra J, Salazar R, Cruz R, [33] Pera MC, Coratti G, Forcina N, Mazzone ES, Scoto M, Montes J, et al.
et al. Six-minute walk test is reliable and valid in spinal muscular Content validity and clinical meaningfulness of the HFMSE in spinal
atrophy. Muscle Nerve Nov 2016;54(5):836–42 Epub 2016 May 13. muscular atrophy. BMC Neurol Feb 23 2017;17(1):39 PMID: 28231823;
PMID: 27015431. doi:10.1002/mus.25120. PMCID: PMC5324197. doi:10.1186/s12883- 017- 0790- 9.
[19] Montes J, McDermott MP, Mirek E, Mazzone ES, Main M, [34] Scott OM, Hyde A, Goddard C, Dubowitz V. Quantitation of muscle
Glanzman AM, et al. Ambulatory function in spinal muscular function in children: a prospective study in Duchenne muscular
atrophy: age-related patterns of progression. PLoS One Jun 26 dystrophy. Muscle Nerve 1982;5:291–301.
2018;13(6):e0199657 PMID: 29944707; PMCID: PMC6019250. doi:10. [35] J.W.D. Lab. Adult test of neuromuscular disorders (ATEND) wheelchair
1371/journal.pone.0199657. based assessment. https://med.stanford.edu/day-lab/atend.html, 2021.
[20] Montes J, Dunaway S, Garber CE, Chiriboga CA, De Vivo DC, Rao AK. [accessed 21 June 2021].
Leg muscle function and fatigue during walking in spinal muscular [36] De Sanctis R, Coratti G, Pasternak A, Montes J, Pane M, Mazzone ES,
atrophy type 3. Muscle Nerve Jul 2014;50(1):34–9 Epub 2014 May et al. Developmental milestones in type I spinal muscular atrophy.
5. PMID: 24122959. doi:10.1002/mus.24081. Neuromuscul Disord Nov 2016;26(11):754–9 Epub 2016 Oct 5. PMID:
[21] Cano SJ, Mayhew A, Glanzman AM, Krosschell KJ, Swoboda KJ, 27769560; PMCID: PMC5091285. doi:10.1016/j.nmd.2016.10.002.
Main M, et al. Rasch analysis of clinical outcome measures in spinal [37] Krosschell K, Maczulski J, Crawford T, Scott C, Swoboda K.
muscular atrophy. Muscle Nerve Mar 2014;49(3):422–30 Epub 2013 Jul A modified Hammersmith functional motor scale for use in
26. PMID: 23836324; PMCID: PMC4376296. doi:10.1002/mus.23937. multi-center research on spinal muscular atrophy. Neuromuscul Disord
[22] Ricotti V, Ridout DA, Pane M, Main M, Mayhew A, Mercuri E, et al. 2006;16:417–26.
The NorthStar ambulatory assessment in Duchenne muscular dystrophy: [38] Mazzone E, Bianco F, Martinelli D, Glanzman AM, Messina S, De
considerations for the design of clinical trials. J Neurol Neurosurg Sanctis R, et al. Assessing upper limb function in nonambulant SMA
Psychiatry 2016;87(2):149–55 FebEpub 2015 Mar 2. PMID: 25733532; patients: development of a new module. Neuromuscul Disord Jun
PMCID: PMC4752678. doi:10.1136/jnnp- 2014- 309405. 2011;21(6):406–12 Epub 2011 Mar 21. PMID: 21421316. doi:10.1016/
[23] Jacobs MB, James MK, Lowes LP, Alfano LN, Eagle M, Muni Lofra R, j.nmd.2011.02.014.
et al. Assessing dysferlinopathy patients over three years with a new [39] Mazzone ES, Mayhew A, Montes J, Ramsey D, Fanelli L, Dunaway YS,
motor scale. Ann Neurol May 2021;89(5):967–78 Epub 2021 Feb 26. et al. Revised upper limb module for spinal muscular atrophy:
PMID: 33576057. doi:10.1002/ana.26044. development of a New Module. Muscle Nerve 2017;55:869–74.
[24] Krosschell KJ, Scott CB, Maczulski JA, Lewelt AJ, Reyna SP, [40] Pera MC, Coratti G, Mazzone ES, Montes J, Scoto M, De Sanctis R,
Swoboda KJ. Project Cure SMA. Reliability of the Modified et al. Revised upper limb module for spinal muscular atrophy: 12 month
Hammersmith functional motor scale in young children with spinal changes. Muscle Nerve Apr 2019;59(4):426–30 Epub 2019 Feb 7.
muscular atrophy. Muscle Nerve Aug 2011;44(2):246–51 Epub 2011 Jun PMID: 30677148. doi:10.1002/mus.26419.
22. PMID: 21698647; PMCID: PMC3136587. doi:10.1002/mus.22040. [41] Darras BT, Chiriboga CA, Iannaccone ST, Swoboda KJ, Montes J,
[25] Krosschell KJ, Bosch M, Nelson L, Duong T, Lowes LP, Alfano LN, Mignon L, et al. Nusinersen in later-onset spinal muscular atrophy:
et al. Motor function test reliability during the NeuroNEXT long-term results from the phase 1/2 studies. Neurology May 21
spinal muscular atrophy infant biomarker study. J Neuromuscul Dis 2019;92(21):e2492–506 Epub 2019 Apr 24. PMID: 31019106; PMCID:
2018;5(4):509–21 PMID: 30223401; PMCID: PMC8112280. doi:10. PMC6541434. doi:10.1212/WNL.0000000000007527.
3233/JND-180327. [42] Montes J, McDermott MP, Martens WB, Dunaway S, Glanzman AM,
[26] Glanzman AM, Mazzone E, Main M, Pelliccioni M, Wood J, Riley S, et al. Six-minute walk test demonstrates motor fatigue
Swoboda KJ, et al. The Children’s Hospital of Philadelphia Infant Test in spinal muscular atrophy. Neurology Mar 9 2010;74(10):833–
of Neuromuscular Disorders (CHOP INTEND): test development and 8 PMID: 20211907; PMCID: PMC2839195. doi:10.1212/WNL.
reliability. Neuromuscul Disord Mar 2010;20(3):155–61 Epub 2010 Jan 0b013e3181d3e308.
13. PMID: 20074952; PMCID: PMC3260046. doi:10.1016/j.nmd.2009. [43] Pera MC, Luigetti M, Pane M, Coratti G, Forcina N, Fanelli L, et al.
11.014. 6MWT can identify type 3 SMA patients with neuromuscular junction
[27] O’Hagen JM, Glanzman AM, McDermott MP, Ryan PA, Flickinger J, dysfunction. Neuromuscul Disord Oct 2017;27(10):879–82 Epub 2017
Quigley J, et al. An expanded version of the Hammersmith Functional Jul 14. PMID: 28803817. doi:10.1016/j.nmd.2017.07.007.
Motor Scale for SMA II and III patients. Neuromuscul Disord [44] Bartels B, Habets LE, Stam M, Wadman RI, Wijngaarde CA,
2007;17(9–10):693–7 Epub 2007/07/31. pmid:17658255. Schoenmakers MAGC, et al. Assessment of fatigability in patients with
[28] Glanzman AM, Mazzone ES, Young SD, Gee R, Rose K, Mayhew A, spinal muscular atrophy: development and content validity of a set of
et al. Evaluator training and reliability for SMA Global Nusinersen endurance tests. BMC Neurol Feb 9 2019;19(1):21 PMID: 30738436;
Trials1. J Neuromuscul Dis 2018;5(2):159–66 PMID: 29865090; PMCID: PMC6368708. doi:10.1186/s12883- 019- 1244- 3.
PMCID: PMC6030668. doi:10.3233/JND-180301. [45] Bartels B, de Groot JF, Habets LE, Wijngaarde CA, Vink W,
[29] Mazzone E, Messina S, Vasco G. Reliability of the North Star Stam M, et al. Fatigability in spinal muscular atrophy: validity and
ambulatory assessment in a multicentric setting. Neuromuscul Disord reliability of endurance shuttle tests. Orphanet J Rare Dis Mar 23
2009;19:458–61. 2020;15(1):75 PMID: 32293503; PMCID: PMC7092552. doi:10.1186/
[30] Pane M, Mazzone ES, Sivo S, Fanelli L, De Sanctis R, D’Amico A, s13023- 020- 1348- 2.
et al. The 6 min walk test and performance of upper limb [46] Bérard C, Payan C, Hodgkinson I, Fermanian JM.F.M. Collaborative
in ambulant duchenne muscular dystrophy boys. PLoS Curr Study Group. A motor function measure for neuromuscular
Oct 7 2014;6 ecurrents.md.a93d9904d57dcb08936f2ea89bca6fe610.1371/ diseases. Construction and validation study. Neuromuscul Disord Jul
currents.md.a93d9904d57dcb08936f2ea89bca6fe6 PMID: 25642376; 2005;15(7):463–70 PMID: 16106528. doi:10.1016/j.nmd.2005.03.004.
PMCID: PMC4208936. [47] Vuillerot C, Payan C, Iwaz J, Ecochard R, Bérard C. MFM Spinal
[31] McDonald CM, Henricson EK, Han JJ, Abresch RT, Nicorici A, Muscular Atrophy Study Group. Responsiveness of the motor function
Elfring GL, et al. The 6-minute walk test as a new outcome measure in measure in patients with spinal muscular atrophy. Arch Phys Med
Duchenne muscular dystrophy. Muscle Nerve Apr 2010;41(4):500–10 Rehabil Aug 2013;94(8):1555–61 Epub 2013 Feb 1. PMID: 23380348.
PMID: 19941337. doi:10.1002/mus.21544. doi:10.1016/j.apmr.2013.01.014.

1035
L.L. Nelson and S.T. Iannaccone Neuromuscular Disorders 31 (2021) 1028–1037

[48] Trundell D, Le Scouiller S, Le Goff L, Gorni K, Vuillerot C. Assessment outcomes in boys with Duchenne muscular dystrophy and
of the validity and reliability of the 32-item Motor Function Measure typically developing controls: longitudinal comparisons and
in individuals with Type 2 or non-ambulant Type 3 spinal muscular clinically-meaningful changes over one year. PLoS Curr. Jul 8
atrophy. PLoS One Sep 18 2020;15(9):e0238786 PMID: 32946459; 2013;5 :ecurrents.md.9e17658b007eb79fcd6f723089f79e06PMID:
PMCID: PMC7500661. doi:10.1371/journal.pone.0238786. 23867975; PMCID: PMC3712467. doi:10.1371/currents.md.
[49] Trundell D, Le Scouiller S, Gorni K, Seabrook T, Vuillerot CSMA MFM 9e17658b007eb79fcd6f723089f79e06.
Study Group. Validity and reliability of the 32-item motor function [62] McDonald CM, Henricson EK, Han JJ, Abresch RT, Nicorici A,
measure in 2- to 5-year-olds with neuromuscular disorders and 2- to 25- Atkinson L, et al. The 6-minute walk test in Duchenne/Becker
year-olds with spinal muscular atrophy. Neurol Ther Dec 2020;9(2):575– muscular dystrophy: longitudinal observations. Muscle Nerve Dec
84 Epub 2020 Aug 27. PMID: 32856191; PMCID: PMC7606363. 2010;42(6):966–74 [PubMed: 21038378].
doi:10.1007/s40120- 020- 00206- 3. [63] Henricson E, Abresch R, Han JJ, Nicorici A, Goude Keller E, Elfring G,
[50] Bartels B, de Groot JF, Habets LE, Wadman RI, Asselman FL, et al. Percent-predicted 6-minute walk distance in duchenne muscular
Nieuwenhuis EES, et al. Correlates of fatigability in patients with spinal dystrophy to account for maturational influences. PLoS Curr Jan 25
muscular atrophy. Neurology Feb 9 2021;96(6):e845–52 Epub 2020 Nov 2012;4:RRN1297 PMID: 22306689; PMCID: PMC3269886. doi:10.
20. PMID: 33219141. doi:10.1212/WNL.0000000000011230. 1371/currents.RRN1297.
[51] Chabanon A, Seferian AM, Daron A, Péréon Y, Cances C, Vuillerot C, [64] Miller NF, Alfano LN, Iammarino MA, Connolly AM, Moore-
et al. Prospective and longitudinal natural history study of patients Clingenpeel M, Powers BR, et al. Natural history of steroid-treated
with Type 2 and 3 spinal muscular atrophy: baseline data NatHis- young boys with Duchenne muscular dystrophy using the NSAA, 100
SMA study. PLoS One Jul 26 2018;13(7):e0201004 PMID: 30048507; m, and timed functional tests. Pediatr Neurol Dec 2020;113:15–20 Epub
PMCID: PMC6062049. doi:10.1371/journal.pone.0201004. 2020 Aug 27. PMID: 32979653. doi:10.1016/j.pediatrneurol.2020.08.
[52] Mercuri E, Coratti G, Messina S, Ricotti V, Baranello G, D’Amico A, 013.
et al. Revised north star ambulatory assessment for young boys with [65] Mayhew AG, Coratti G, Mazzone ES, Klingels K, James M, Pane M,
Duchenne muscular dystrophy. PLoS One Aug 5 2016;11(8):e0160195 et al. Performance of upper limb module for Duchenne muscular
PMID: 27494024; PMCID: PMC4975396. doi:10.1371/journal.pone. dystrophy. Dev Med Child Neurol May 2020;62(5):633–9 Epub 2019
0160195. Sep 19. PMID: 31538331. doi:10.1111/dmcn.14361.
[53] Mendell JR, Rodino-Klapac LR, Sahenk Z, Roush K, Bird L, Lowes LP, [66] STEP IN SMA Education. https://www.stepinsma.org/education, 2021.
et al. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann [accessed 25 Jun 2021].
Neurol Nov 2013;74(5):637–47 Epub 2013 Sep 10. PMID: 23907995. [67] Sobierajska-Rek A, Mański Ł, Jabłońska-Brudło J, Śledzińska K,
doi:10.1002/ana.23982. Ucińska A, Wierzba J. Establishing a telerehabilitation program
[54] Mendell JR, Goemans N, Lowes LP, Alfano LN, Berry K, Shao J, et al. for patients with Duchenne muscular dystrophy in the COVID-19
Longitudinal effect of eteplirsen versus historical control on ambulation pandemic. Wien Klin Wochenschr Apr 2021;133(7–8):344–50 Epub
in Duchenne muscular dystrophy. Ann Neurol Feb 2016;79(2):257–71 2020 Dec 21. PMID: 33346889; PMCID: PMC7750780. doi:10.1007/
Epub 2016 Jan 8. PMID: 26573217; PMCID: PMC5064753. doi:10. s00508- 020- 01786- 8.
1002/ana.24555. [68] Krosschell KJ, Kissel JT, Townsend EL, Simeone SD, Zhang RZ,
[55] Goemans N, Mercuri E, Belousova E, Komaki H, Dubrovsky A, Reyna SP, et al. Clinical trial of L-Carnitine and valproic acid in spinal
McDonald CM, et al. A randomized placebo-controlled phase 3 trial muscular atrophy type I. Muscle Nerve Feb 2018;57(2):193–9 Epub
of an antisense oligonucleotide, drisapersen, in Duchenne muscular 2017 Sep 18. PMID: 28833236. doi:10.1002/mus.25776.
dystrophy. Neuromuscul Disord Jan 2018;28(1):4–15 Epub 2017 Dec [69] Mercuri E, Messina S, Battini R, Berardinelli A, Boffi P, Bono R,
6. PMID: 29203355. doi:10.1016/j.nmd.2017.10.004. et al. Reliability of the Hammersmith functional motor scale for spinal
[56] Alfano LN, Charleston JS, Connolly AM, Cripe L, Donoghue C, muscular atrophy in a multicentric study. Neuromuscul Disord Feb
Dracker R, et al. Long-term treatment with eteplirsen in nonambulatory 2006;16(2):93–8 Epub 2006 Jan 20. PMID: 16427782. doi:10.1016/j.
patients with Duchenne muscular dystrophy. Medicine (Baltimore) Jun nmd.2005.11.010.
2019;98(26):e15858 PMID: 31261494; PMCID: PMC6617421. doi:10. [70] Finkel RS, McDermott MP, Kaufmann P, Darras BT, Chung WK,
1097/MD.0000000000015858. Sproule DM, et al. Observational study of spinal muscular atrophy type
[57] Victor RG, Sweeney HL, Finkel R, McDonald CM, Byrne B, Eagle M, I and implications for clinical trials. Neurology Aug 26 2014;83(9):810–
et al. A phase 3 randomized placebo-controlled trial of tadalafil for 17 Epub 2014 Jul 30. PMID: 25080519; PMCID: PMC4155049. doi:10.
Duchenne muscular dystrophy. Neurology Oct 24 2017;89(17):1811–20 1212/WNL.0000000000000741.
Epub 2017 Sep 29. PMID: 28972192; PMCID: PMC5664308. doi:10. [71] Mercuri E, Lucibello S, Perulli M, Coratti G, de Sanctis R, Pera MC,
1212/WNL.0000000000004570. et al. Longitudinal natural history of type I spinal muscular atrophy:
[58] McDonald CM, Campbell C, Torricelli RE, Finkel RS, Flanigan KM, a critical review. Orphanet J Rare Dis Apr 5 2020;15(1):84 PMID:
Goemans N, et al. Ataluren in patients with nonsense mutation 32248834; PMCID: PMC7132885. doi:10.1186/s13023- 020- 01356- 1.
Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, [72] Mercuri E, Finkel R, Montes J, Mazzone ES, Sormani MP, Main M,
double-blind, placebo-controlled, phase 3 trial. Lancet Sep 23 et al. Patterns of disease progression in type 2 and 3 SMA: implications
2017;390(10101):1489–98 Epub 2017 Jul 17. PMID: 28728956. doi:10. for clinical trials. Neuromuscul Disord Feb 2016;26(2):126–31 Epub
1016/S0140- 6736(17)31611- 2. 2015 Dec 3. PMID: 26776503; PMCID: PMC4762230. doi:10.1016/j.
[59] Shieh PB, Mcintosh J, Jin F, Souza M, Elfring G, Narayanan S, nmd.2015.10.006.
et al. Deflazacort versus prednisone/prednisolone for maintaining [73] Kaufmann P, McDermott MP, Darras BT, Finkel R, Kang P, Oskoui M,
motor function and delaying loss of ambulation: a post HOC analysis et al. Observational study of spinal muscular atrophy type 2 and 3:
from the ACT DMD trial. Muscle Nerve Nov 2018;58(5):639–45 Epub functional outcomes over 1 year. Arch Neurol Jun 2011;68(6):779–86
2018 Sep 27. PMID: 30028519; PMCID: PMC6767037. doi:10.1002/ Epub 2011 Feb 14. PMID: 21320981; PMCID: PMC3839315. doi:10.
mus.26191. 1001/archneurol.2010.373.
[60] Mazzone E, Martinelli D, Berardinelli A, Messina S, D’Amico A, [74] Mazzone E, Bianco F, Main M, van den Hauwe M, Ash M, de
Vasco G, et al. North Star Ambulatory Assessment, 6-minute walk test Vries R, et al. Six minute walk test in type III spinal muscular atrophy:
and timed items in ambulant boys with Duchenne muscular dystrophy. a 12 month longitudinal study. Neuromuscul Disord Aug
Neuromuscul Disord Nov 2010;20(11):712–16 Epub 2010 Jul 14. 2013;23(8):624–8 Epub 2013 Jul 1. PMID: 23809874. doi:10.1016/j.
PMID: 20634072. doi:10.1016/j.nmd.2010.06.014. nmd.2013.06.001.
[61] Henricson E, Abresch R, Han JJ, Nicorici A, Goude Keller E, [75] Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, DeVivo DC,
de Bie E, et al. The 6-minute walk test and person-reported et al. Treatment of infantile-onset spinal muscular atrophy with

1036
L.L. Nelson and S.T. Iannaccone Neuromuscular Disorders 31 (2021) 1028–1037

nusinersen: a phase 2, open-label, dose-escalation study. Lancet cbe611fe-cda9-4d98-9574-0ac18e109daa. PMID: 23326337; PMCID:
2016;388:3017–26. PMC3543414. doi:10.1371/journal.pone.0052512.
[76] Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, [86] McDonald CM, Henricson EK, Abresch RT, Florence JM, Eagle M,
et al. Nusinersen versus Sham control in infantile-onset spinal muscular Gappmaier E, et al. The 6-minute walk test and other endpoints in
atrophy. N Engl J Med Nov 2 2017;377(18):1723–32 PMID: 29091570. Duchenne muscular dystrophy: longitudinal natural history observations
doi:10.1056/NEJMoa1702752. over 48 weeks from a multicenter study. Muscle Nerve Sep
[77] Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, 2013;48(3):343–56 Epub 2013 Jun 26. PMID: 23681930; PMCID:
Prior TW, et al. Single-dose gene-replacement therapy for spinal PMC3824082. doi:10.1002/mus.23902.
muscular atrophy. N Engl J Med 2017;377(18):1713–22. [87] Mazzone E, Vasco G, Sormani MP, Torrente Y, Berardinelli A,
[78] De Vivo DC, Bertini E, Swoboda KJ, Hwu WL, Crawford TO, Messina S, et al. Functional changes in Duchenne muscular
Finkel RS, et al. Nusinersen initiated in infants during the dystrophy: a 12-month longitudinal cohort study. Neurology Jul 19
presymptomatic stage of spinal muscular atrophy: interim efficacy 2011;77(3):250–6 Epub 2011 Jul 6. PMID: 21734183. doi:10.1212/
and safety results from the Phase 2 NURTURE study. Neuromuscul WNL.0b013e318225ab2e.
Disord Nov 2019;29(11):842–56 Epub 2019 Sep 12. PMID: 31704158; [88] Ricotti V, Selby V, Ridout D, Domingos J, Decostre V, Mayhew A,
PMCID: PMC7127286. doi:10.1016/j.nmd.2019.09.007. et al. Respiratory and upper limb function as outcome measures
[79] Al-Zaidy SA, Kolb SJ, Lowes L, Alfano LN, Shell R, Church KR, in ambulant and non-ambulant subjects with Duchenne muscular
et al. AVXS-101 (Onasemnogene Abeparvovec) for SMA1: comparative dystrophy: a prospective multicentre study. Neuromuscul Disord Apr
study with a prospective natural history Cohort. J Neuromuscul Dis 2019;29(4):261–8 Epub 2019 Feb 19. PMID: 30852071. doi:10.1016/j.
2019;6(3):307–17 PMID: 31381526. doi:10.3233/JND-190403. nmd.2019.02.002.
[80] Mercuri E, Darras BT, Chiriboga CA, Day JW, Campbell C, [89] Mercuri E, Signorovitch JE, Swallow E, Song J, Ward SJDMD Italian
Connolly AM, et al. Nusinersen versus Sham control in later-onset Group; Trajectory Analysis Project (cTAP). Categorizing natural history
spinal muscular atrophy. N Engl J Med Feb 15 2018;378(7):625–35 trajectories of ambulatory function measured by the 6-minute walk
PMID: 29443664. doi:10.1056/NEJMoa1710504. distance in patients with Duchenne muscular dystrophy. Neuromuscul
[81] Chiriboga CA, Swoboda KJ, Darras BT, Iannaccone ST, Montes J, Disord 2016;26(9):576–83 [PubMed: 27423700]. doi:10.1016/j.nmd.
De Vivo DC, et al. Results from a phase 1 study of nusinersen 2016.05.016.
(ISIS-SMN(Rx)) in children with spinal muscular atrophy. Neurology [90] Arora H, Willcocks RJ, Lott DJ, Harrington AT, Senesac CR,
2016;86:890–7. Zilke KL, et al. Longitudinal timed function tests in Duchenne muscular
[82] Bertini E, Dessaud E, Mercuri E, Muntoni F, Kirschner J, Reid C, dystrophy: imaging DMD cohort natural history. Muscle Nerve Nov
et al. Safety and efficacy of olesoxime in patients with type 2 or non- 2018;58(5):631–8 Epub 2018 Jul 24. PMID: 29742798; PMCID:
ambulatory type 3 spinal muscular atrophy: a randomised, double-blind, PMC6660165. doi:10.1002/mus.26161.
placebo-controlled phase 2 trial. Lancet Neurol Jul 2017;16(7):513–22 [91] Ricotti V, Ridout DA, Scott E, Quinlivan R, Robb SA, Manzur AY,
Epub 2017 Apr 28. Erratum in: Lancet Neurol. 2017 Aug;16(8):584. et al. Long-term benefits and adverse effects of intermittent versus daily
PMID: 28460889. doi:10.1016/S1474- 4422(17)30085- 6. glucocorticoids in boys with Duchenne muscular dystrophy. J Neurol
[83] Montes J, Dunaway Young S, Mazzone ES, Pasternak A, Neurosurg Psychiatry 2013;84:698–705.
Glanzman AM, Finkel RS, et al. Nusinersen improves walking [92] Taylor M, Jefferies J, Byrne B, Lima J, Ambale-Venkatesh B,
distance and reduces fatigue in later-onset spinal muscular atrophy. Ostovaneh MR, et al. Cardiac and skeletal muscle effects in the
Muscle Nerve Oct 2019;60(4):409–14 Epub 2019 Jul 27. PMID: randomized HOPE-Duchenne trial. Neurology Feb 19 2019;92(8):e866–
31298747; PMCID: PMC6771553. doi:10.1002/mus.26633. 78 Epub 2019 Jan 23. PMID: 30674601; PMCID: PMC6396968.
[84] Montes J, Goodwin AM, McDermott MP, Uher D, Hernandez FM, doi:10.1212/WNL.0000000000006950.
Coutts K, et al. Diminished muscle oxygen uptake and [93] Pane M, Fanelli L, Mazzone ES, Olivieri G, D’Amico A, Messina S,
fatigue in spinal muscular atrophy. Ann Clin Transl Neurol et al. Benefits of glucocorticoids in non-ambulant boys/men with
2021;8(5):1086–95. Duchenne muscular dystrophy: a multicentric longitudinal study
[85] Mazzone ES, Pane M, Sormani MP, Scalise R, Berardinelli A, using the performance of upper limb test. Neuromuscul Disord Oct
Messina S, et al. 24 month longitudinal data in ambulant boys with 2015;25(10):749–53 Epub 2015 Jul 17. PMID: 26248957; PMCID:
Duchenne muscular dystrophy. PLoS One 2013;8(1):e52512 Epub 2013 PMC4597096. doi:10.1016/j.nmd.2015.07.009.
Jan 11. Erratum in: PLoS One. 2013;8(11). doi:10.1371/annotation/

1037