A qualitative, mixed-method approach to reaching consensus on function, fatigue, and fatigability outcomes in teens and adults living with spinal muscular atrophy

A qualitative, mixed-method approach to reaching consensus on function, fatigue, and fatigability outcomes in teens and adults living with spinal muscular atrophy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A qualitative, mixed-method approach to reaching consensus on function, fatigue, and fatigability outcomes in teens and adults living with spinal muscular atrophy Jacqueline Glascock, Lisa T Belter, Meghan Moore Burk, Jessica J Tingey, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6917745/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Oct, 2025 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted 5 You are reading this latest preprint version Abstract Background: Spinal muscular atrophy (SMA) is a neuromuscular disease caused by mutations in the survival motor neuron gene, SMN1 . Loss of SMN1 function results in deficiency of the SMN protein leading to motor neuron death, muscle wasting, and progressive loss of motor function. Two disease modifying therapies have been approved for teens and adults in the United States, with many more potential treatments in the drug development pipeline. As treatment options for teens and adults with SMA increase, a validated core set of outcome measures is needed to assess motor function, fatigue, and fatigability. The aim of this study was to determine which type of outcome measures best captures changes in disease status in teens and adults with SMA. Results: In the first phase of this two-part study, a working group of key opinion leaders in SMA research and clinical care was surveyed using a modified Delphi method. The working group concluded that a patient-reported outcome measure based on activities of daily living (ADLs) would be the best way to capture changes in function, fatigue, and fatigability that are meaningful to both clinicians and teens and adults living with SMA. In the second phase of the study, two discussion groups of adults (non-ambulatory or ambulatory) were interviewed for their perspectives about which ADLs are most important to them, and about how fatigue and fatigability affect their abilities to perform these ADLs. Both discussion groups prioritized ADLs that related to independence and dignity. Non-ambulatory and ambulatory participants also reported that fatigue and fatigability are a major factor in their ability to perform ADLs. Conclusion: SMA key opinion leaders and adults with SMA agreed that ADLs would be sensitive and impactful outcomes in the assessment of function and fatigue. The findings of this study form a foundation for reaching consensus around a core set of outcome measures for assessing disease status, fatigue, and fatigability in teens and adults with SMA in the U.S. activities of daily living ADLs clinician-reported outcome measure CROM fatigue fatigability patient-reported outcome measure PROM spinal muscular atrophy SMA Figures Figure 1 Figure 2 Figure 3 BACKGROUND Spinal muscular atrophy (SMA) Spinal muscular atrophy (SMA) is an autosomal recessive disease that was, until recently, the leading genetic cause of mortality in children under the age of two years. [ 1 – 3 ] In 95% of cases, SMA is caused by a biallelic mutation in the survival motor neuron 1 gene ( SMN1 ). [ 4 – 6 ] Mutation of the SMN1 gene results in deficiency of the survival motor neuron protein (SMN), which has a variety of functions throughout the body and is especially important in the brainstem and spinal cord. [ 7 – 9 ] Untreated SMA is characterized by progressive motor neuron loss that may result in limb and truncal muscle weakness, scoliosis, contractures, and respiratory complications. [ 10 – 19 ] In the most severe forms of SMA, symptoms can be present at birth and progress rapidly, and early diagnosis and treatment with a disease modifying therapy (DMT) are necessary to achieve optimal outcomes. [ 20 – 23 ] With less severe types of SMA, symptom onset may occur later in life, and loss of function may be more gradual. [ 12 , 24 – 28 ] Like SMN1 , the survival motor neuron 2 gene ( SMN2) also encodes the SMN protein. Although much of the protein produced by SMN2 is truncated and dysfunctional, SMN2 can act as a partial “back-up” for the mutated SMN1 gene in people with SMA. As such, SMN2 serves as a critical disease modifying gene. [ 29 , 30 ] SMA phenotype has historically been classified into five types, 0–4, which are determined by the age of symptom onset and maximum motor function achieved. [ 11 , 12 , 30 , 31 ] However, the recent availability of DMTs for SMA has dramatically impacted the clinical course of the disease and led to a shift in classification based on SMN2 copy number and motor function. [ 32 ] In 2016, the United States (U. S.) Food and Drug Administration (FDA) approved the antisense oligonucleotide, nusinersen , for use in children and adults with SMA. [ 33 ] Next, a gene therapy, onasemnogene abeparvovec , was approved by the FDA in 2019 for use in children under the age of two. [ 34 ] Finally, the RNA splicing modifier, risdiplam , was approved by the FDA for patients older than 2 months in 2020 and for patients of any age in 2022. [ 35 ] Each of these “SMN-dependent” therapies works by restoring SMN protein levels, which protects motor neurons and preserves muscle function. [ 20 – 23 ] However, due to disease phenotype heterogeneity, and variability in disease onset and the timing of therapeutic intervention, treatment response varies widely. Therefore, critical treatment needs remain unmet within the SMA community. For example, teens and adults with SMA who do not receive DMT until later in their disease progression may experience less dramatic benefits from treatment. [ 36 – 38 ] To meet remaining treatment needs, the SMA drug pipeline is burgeoning with studies of new potential, SMN-independent treatments, as well as novel protocols for approved SMN-dependent treatments. [ 39 ] In the future, it is likely that a combination of SMN-dependent and SMN-independent therapies will be used to achieve optimal patient outcomes. [ 40 – 42 ] Clinical outcome measures for SMA A clinical outcome measure is an endpoint that assesses how disease progression and treatment affect how a patient feels, functions, or survives. [ 43 ] The measure may be clinician-reported, in which changes in function are measured by a trained healthcare professional, or patient-reported, in which changes in abilities are described by the patient. Myriad clinician-reported outcome measures (CROMs) and patient-reported outcome measures (PROMs) have been utilized in SMA research and clinical care. For example, a literature review and clinician survey performed by Slayter et. al in 2021 [ 44 ] identified 17 different CROMs that had been used or were still in use internationally in the evaluation of adults with SMA. Similarly, a recent scoping review of PROMs for SMA determined that between 2016 and 2022, 31 unique PROMs were utilized in studies conducted internationally with adults living with SMA and other neuromuscular conditions. [ 45 ] Of these 31 PROMs, few included a comprehensive set of health domains, and only two were developed explicitly for people with SMA. In addition to changes in motor function, fatigue and fatigability are often reported as major concerns by teens and adults with SMA [ 46 – 48 ]. Fatigue and fatigability are major aspects of daily life for teens and adults with SMA, yet the symptoms are multidimensional and difficult to measure. [ 48 – 51 ] Although the nomenclature for fatigue and fatigability is varied and ill-defined, the emerging trend is to separate the concepts into two subtypes, performance fatigue/fatigability (also called functional fatigue/fatigability) and perceived fatigue/fatigability. [ 50 – 52 ] Performance fatigue and fatigability can be defined as lack of endurance, or the inability to complete or repeat a specific physical task within a given time frame. Perceived fatigue and fatigability are a person’s subjective feeling of reduced capacity to initiate, complete, and repeat tasks. Outcome measures for performance and perceived fatigue and fatigability have not yet been validated specifically for SMA patients in the U.S. [ 50 , 51 , 53 ] It is estimated that in the U.S., approximately 60% of people with SMA are teens or adults. [ 54 ] As more teens and adults with a broad range of SMA phenotypes receive investigational and FDA-approved treatments in the U.S., a standardized set of clinical outcomes is needed to measure changes in motor function, fatigue, and fatigability in teens and adults. The establishment of core clinical outcomes for SMA would facilitate comparisons of research data across studies and provide a consistent standard of care across the nation. [ 55 ] Cure SMA is the largest SMA patient advocacy organization based in the U.S. that funds and directs research for SMA. [ 56 ] In this study, Cure SMA convened 1) a working group of key opinion leaders (KOL Working Group) SMA comprising researchers, health care providers, and biotechnology industry representatives, and 2) two discussion groups comprising either non-ambulatory adults (Non-ambulatory Discussion Group) or ambulatory adults (Ambulatory Discussion Group) living with SMA. The aim of the study was to build consensus on which clinical outcomes best capture changes in disease status and motor function in teens and adults with SMA in the U.S. as a first step in establishing a set of core outcome measures for use in research and clinical care. METHODS Overview A two-phase, mixed-methods study was utilized to build consensus around which are the most valuable CROMs for teens and adults with SMA. (Fig. 1 ) In the planning stages of the study, two physical therapists (PTs) with expertise in SMA were consulted on study design and content. These PTs also participated as a Steering Committee in the KOL Working Group phase of the study. A third-party consultant, The Kith Collective, coordinated, organized, and conducted discussion group meetings with guidance from Cure SMA. PTs and Kith Collective employees were compensated for their time, KOLs participated as volunteers, and discussion group participants received a gift card ( $ 50) for their participation. Phase 1: KOL Working group KOL Working Group objectives were to 1) identify clinically meaningful outcomes in teens and adults with SMA not assessed by existing outcome measures, 2) identify key outcomes within core functional domains for assessing disease progression and functional ability in teens and adults with SMA, and 3) identify types of outcomes that best capture major and subtle functional changes in teens and adults with SMA. The KOL Working Group was composed of two Steering Committee members and 12 KOLs. KOLs were invited by email to participate based on their expertise in SMA clinical care and research. (Additional File 1) For logistical simplicity, invitations were restricted to KOLs residing in the U.S. A modified Delphi method was utilized to achieve consensus. The process consisted of a 30-minute kick-off call on February 9, 2022, followed by six, 90-minute KOL Working Group meetings occurring between March 9, 2022, and October 11, 2022; all meetings were held over Zoom. To prepare the KOLs for discussions, peer-reviewed articles were gathered by Cure SMA staff on the following topics as they relate to outcome measures for SMA: bulbar function, fatigue and fatigability, activity limitations/disease burden, respiratory function, and general function. At the kick-off call, Cure SMA distributed briefing packets containing the background reading. Before each of the remaining six KOL Working Group meetings, the participants completed a 5-minute, anonymous, multiple choice/open response survey. (See Additional File 2 for all Working Group surveys.) Pre-call surveys were sent one week prior to the next meeting and were to be completed by the day before the next meeting. Cure SMA staff reviewed and distilled survey results between meetings, then presented and discussed findings with the KOLs at the following meeting. Survey results were also utilized by Cure SMA to generate a new survey in advance of the next meeting to work toward consensus on core outcomes. Each Zoom meeting was recorded, and minutes were distributed by email the following week. At the conclusion of Phase 1 of the study, key questions that emerged during the Delphi process were identified by Cure SMA and the Kith Collective. These questions informed the discussion guide (Additional File 3) for the next phase of the study. Discussion Group Discussion group objectives were 1) to understand which health outcomes matter most to adults with SMA, and 2) to understand how fatigue and fatigability affect abilities to perform Activities of Daily Living (ADLs). An eligibility survey (Additional File 4) was created and shared via email with teens and adults with SMA that reside in the U.S. as identified through the Cure SMA Membership Database. [ 57 ] Eligibility survey responses were received from 261 individuals and were organized into a perspectives matrix created by Cure SMA staff. Responses to demographic and patient experience questions were used to facilitate diverse enrollment. (Additional File 5) Twenty-three persons with SMA were invited to participate in the discussion groups; informed consent was obtained from 10 individuals. Participants were divided into two discussion groups based upon whether the individual was non-ambulatory or ambulatory. The Non-ambulatory Discussion Group contained six adults with SMA, and the Ambulatory Discussion Group four adults with SMA. (Additional File 6) Due to limited response to recruitment, neither discussion sub-group contained teen participants. For each discussion group, a 30-minute introductory meeting was held, followed by a 90-minute main meeting. All meetings, led by the Kith Collective, were held over Zoom and recorded. During the introduction meeting, the background and intent of the study was described, and participants were introduced to the concepts of ADLs and fatigue. In advance of the main meeting, participants were asked to consider a list of sample ADLs and to think about other activities that were important to them. (Additional File 7) This exercise was meant to prepare participants for upcoming discussions in the main meeting. Prior to initiation, WIRB-Copernicus Group Institutional Review Board (WCG IRB) reviewed and approved the study (IRB Tracking Number: 20226344). All respondents were informed via the informed consent document that findings may be published. Only de-identified results are included within the manuscript. All procedures performed involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. During the sessions, notes were taken by Kith Collective and Cure SMA staff and used to identify themes in participant feedback, as was chat feedback from those participants that elected to provide written responses. RESULTS Phase 1: KOL Working Group Through reiterative surveys and discussions, KOL Working Group participants worked toward consensus on the most meaningful outcomes for measuring function and disease status in teens and adults with SMA. First, KOL Working Group participants identified clinically relevant outcomes, within each of five domains, that were not captured by existing outcome measures for non-ambulatory and ambulatory teens and adults with SMA. (Table 1 ) As the group discussed these outcomes, two themes emerged: 1) ADLs may be utilized as meaningful outcomes for assessing function in non-ambulatory and ambulatory teens and adults with SMA, and 2) fatigue and fatigability are major aspects of SMA that may affect abilities to perform ADLs. Table 1 Domains and outcomes not captured by existing outcome measures for teens and adults with SMA Domain Outcome Bulbar function (encompassing swallow, voice, vocal capacity, phonation, speech) • Ability to capture slow disease progression/early deficits/incremental changes/increased sensitivity to longitudinal change • Jaw range of motion • Tongue strength • Bite strength • Chewing fatigue/endurance of chewing • Ability to be understood when speaking • Ability to maintain good nutrition • Risk of aspiration • Swallowing Fatigue and fatigability • Ability to complete meals, time to finish meals • Functional metrics/current tools have reduced carryover to true functional activities • Ability to function for entire day • Assessment of sleep • Respiratory function Cognition • Neurodevelopmental scores/neurophysiological evaluation • School readiness functions • Prospective natural history or evaluation of cognition in teens/adults is an area of need Gross motor function/range of motion/strength • Ability to self-transfer, nocturnal rotation • Wheelchair-based assessments (i.e., ATEND) • Impact on daily function • Ability to manage assistive devices Fine motor function • Functions related to use of social media/computer tasks/communication (typing, texting, etc.) • Ability to manage assistive devices (wheelchair joystick) • Ability to feed self • Grasp and grip Survey 1 results (n = 9): KOL Working Group participants were asked, “When thinking about outcomes for teens and adults with SMA, which outcomes/items in [domain] not captured by currently existing outcomes do you feel would be clinically meaningful?”. Activities of daily living (ADLs) As discussions unfolded, KOL Working Group participants agreed on the need for specific, finite outcomes that are sensitive enough to detect both major and minor changes in function. The group reasoned that teens and adults with SMA are likely to experience subtle changes in function over time, whether from disease progression or treatment, and these subtle changes may profoundly impact participation in daily activities and quality of life. Consensus began to develop that ADLs were likely to be the most meaningful type of outcome for teens and adults with SMA because these age groups tend to describe differences in disease status (i.e., improvements or reductions in function) through changes in their abilities to complete everyday tasks. KOL Working Group participants were asked to rank outcomes within five domains in terms of which would be most clinically meaningful in assessing teen and adult functional status. (Table 2 ) In discussion, KOL Working Group participants also noted that transfers, socialization and communication, transportation, toileting, and the ability to move outside the home were additional important domains for both non-ambulatory and ambulatory people with SMA. Table 2 KOL Working Group key outcomes for assessing functional ability in teens and adults with SMA Domain (number of respondents) Outcomes Overall Rank Score No. of Rankings Bulbar Function (n = 6) (max score = 30) Risk of aspiration 1 22 6 Swallowing/dysphagia 2 19 5 Ability to maintain good nutrition 3 16 5 Perceived Fatigue (n = 5) (max score = 25) Time on ventilation 1 13 4 Ability to complete age-appropriate play/specific tasks during the day 2 12 3 How long can one perform a task before fatigue limits it 3 11 4 Functional (Performance) Fatigue (n = 5) (max score = 25) Ability to function for entire day 1 24 5 Ability to complete meals/time to finish meals 2 16 4 Ability to drive power chair 3 8 3 Cognition/Language/Communication (n = 4) (max score = 20) Ability to communicate 1 20 4 Intelligibility (especially, if muscle weakness is impeding intelligibility) 2 10 3 School assessments/school readiness 3 8 3 Gross Motor Function/ Range of Motion/Strength (n = 5) (max score = 25) Ability to manage assistive devices (wheelchair joystick) 1 18 5 Functions related to use of social media/computer tasks/communication (typing, texting, etc.) 2 15 5 Strength to make transfers outside of home 3 10 3 Fine Motor Function (n = 5) (max score = 25) Ability to manage assistive devices (wheelchair joystick) 1 22 5 Functions related to use of social media/computer tasks/communication (typing, texting, etc.) 2 21 5 Ability to feed self 3 8 2 Survey 2 results: KOL Working Group participants were asked to rank up to five outcomes in each domain according to clinical relevance. The three highest-ranked patient outcomes in each domain are shown in this table. Outcomes were given a value of 1 through 5 based on ranking, with the highest-ranked outcomes given a value of 5 and the lowest a value of 1. Therefore, the maximum possible score (max score) for each outcome was 5 times the number of respondents who ranked that outcome. ADLs = activities of daily living; KOL Working Group = key opinion leader working group. KOL Working Group participants then weighed the utility of ADLs against other types of outcomes used to assess function in teens and adults with SMA. (Table 3 ) KOL Working Group participants concluded that ADLs may be leveraged to simultaneously assess gross motor functions and detect minor functional changes that might be missed by other types of outcomes. Group participants noted that using an outcome measure based on ADLs alongside a CROM and/or a biomarker [ 58 – 60 ] was likely to give the most broad and detailed information about disease status in teens and adults with SMA. Table 3 Outcome types ranked by ability to capture functional status in teens and adults with SMA SURVEY 3 RESULTS (n = 3) Outcome Type Overall rank Score (max = 15) No. of Rankings Activities of daily living (ADLs) 1 15 3 Gross motor milestones 2 11 3 Write-in responses 1 3 9 3 Compound muscle action potential (CMAP) 4 5 2 Other biomarker 5 1 1 SURVEY 4 RESULTS (n = 7) Outcome Type Overall rank Score (max = 28) No. of Rankings Gross motor milestones 1 28 7 Activities of daily living (ADLs) 2 28 6 Compound muscle action potential (CMAP) 3 20 7 Write-in responses 2 4 13 6 Other biomarker 3 5 10 6 In Surveys 3 and 4, KOL Working Group participants were asked to rank types of outcomes in terms of their utility in assessing functional status in teens and adults with SMA. Survey 3 results: 1 Write-in responses: The Moore Scale (Moore Scale = EVOLVE-SMA [ 61 ]); respiratory function; access to needed equipment; time spent on medical/therapeutic interventions; if time for care interferes with other desired activities. Survey 4 results: 2 Write-in responses: specific evaluations that assess ADLs and gross motor milestones; HFMSE, RULM scores, and 6MWT; patient reported measures of participation (school, work, community), social function; mouth opening; assessments which might be informative would be use/change of respiratory supports; changes in PT/OT status and need for additional supports (wheelchair, etc.); change in need for nutritional support; new surgeries (progressive scoliosis, etc.). 3 Other biomarker response: MUNE. Outcomes were given a value of 1 through 5 based on ranking, with the highest-ranked outcomes given a value of 5 and the lowest a value of 1. Therefore, the maximum possible score (max score) for each outcome was 5 times the number of respondents who ranked that outcome. ADLs = activities of daily living; 6MWT = Six Minute Walk Test; HFMSE = Hammersmith Functional Motor Scale Expanded; MUNE = motor unit number estimation; OT = occupational therapist; PT = physical therapist; RULM = Revised Upper Limb Module. Having determined that ADLs were potentially the most useful type of outcomes for assessing function in teens and adults with SMA, KOL Working Group participants discussed the most effective methods for gathering information on individuals’ ability to perform these tasks. For both non-ambulatory and ambulatory individuals with SMA, a majority of group members agreed that information would be most clinically meaningful if it was reported by the patient or their caregiver, and if it described smaller tasks required for specific ADLs. (Fig. 2 a) A majority of KOL Working Group participants also indicated that questions about ADLs should be tailored to detect changes in function over time for both non-ambulatory and ambulatory teens and adults with SMA. (Fig. 2 b) In discussion, the group agreed that when asking teen and adult patients with SMA about ADLs, it would be important to note if the patient requires assistive technology, a specialized environment, or the assistance of another person to achieve the activity. Fatigue and fatigability As Phase 1 of the study progressed, KOL Working Group participants repeatedly remarked that fatigue and fatigability are major issues with non-ambulatory and ambulatory teens and adults with SMA, and that these phenomena are difficult to describe and measure. The working group discussed existing outcome measures of fatigue and fatigability, noting that none had been validated for SMA. The KOL Working Group concurred that ADLs could be utilized as outcomes to measure changes in fatigue and fatigability. A majority of KOL Working Group participants indicated that an ADL-based outcome measure should use a variety of questions when querying patients about changes in daily fatigue and fatigability. (Fig. 3 a) KOL Working Group participants noted that both non-ambulatory and ambulatory patients with SMA report a “refractory period” of fatigue after heavy exertion. When the group ranked methods of assessing this refractory period, a majority preferred measuring the amount of rest time needed after overexertion for both non-ambulatory and ambulatory patients with SMA. For non-ambulatory patients with SMA, a majority also favored comparing ADLs based on amount of rest time needed. (Fig. 3 b) Discussion group questions Phase 1 results of this study yielded consensus among KOL Working Group participants that ADLs may be utilized as outcomes to assess both function, and fatigue and fatigability in non-ambulatory and ambulatory teens and adults with SMA. KOL Working Group participants agreed that gathering input from individuals with SMA was an essential next step in developing a core list of ADLs. Using Phase 1 data and feedback, Cure SMA developed the following questions around which to build discussion guides for the patient focus groups surveyed in Phase 2. In addition to the sample ADL domains discussed by the KOL Working Group, would discussion group participants like any additional domains included in an outcome measure? Which ADLs would discussion group participants most like to have stabilized? e.g., “I want to make sure I have enough strength to continue to use the bathroom independently.” What do discussion group participants feel would be the best way to show/tell their provider about their fatigue/changes in fatigue? e.g., “What do you wish your doctor knew about your fatigue?” Phase 2: Discussion Group Non-ambulatory Discussion Group Activities of Daily Living The first objective of the Non-ambulatory Discussion Group was to obtain feedback from participants about which ADLs were most important to them. Non-ambulatory Discussion Group participants were asked to review a list of ADLs (Additional File 7) and indicate other ADLs of importance that were not included. Transitioning between indoors and outdoors, caring for and interacting with pets, and using one’s voice were noted as key ADLs by Non-ambulatory Discussion Group participants. Many aspects of voice use were discussed by the subgroup. Participants explained how, in addition to facilitating communication, their voices play important roles in using verbal command to operate items ranging from a light switch to a power wheelchair. I do everything with my voice. As the group discussed ADLs that were meaningful to them, the need to customize ADLs to the person being assessed became a major theme. Group participants noted that the abilities of adults to perform ADLs varies widely depending on age, stage of disease progression, and physical accommodations. A second theme emerged as several group participants noted that many of the most important ADLs to them were those that fell beyond self-care and household chores and extended into work, relationships, hobbies, and other forms of self-expression. I don’t see any work, I don’t see any recreation, I don’t see any going out in the community or anything like that. And to me that’s all more part of a day than all these things. All these things are part of everyday, but the list here sounds like we get dressed, we take a pill, we eat something and that’s all we do all day…There’s a lot more in there with that. For me, what’s most important is art and music. I play instruments and do art, and so losing that would really affect my quality of life. This is kind of unusual, but it is important to me, and I kind of made it a category of its own called ‘emotional.’ Like hugging people, I miss not being able to physically hug people. Physically interacting with people. The group also concurred that abilities to perform ADLs can vary from day to day and are influenced by environmental factors like cold, which impacts fine motor skills. Drawing/painting/3D printing. Tasks of repair and maintenance that might be simple for an able-bodied person—some days I can do them and some days not. All those tasks are simple for an able-bodied person, but for someone with a disability—sometimes I can do it on my own, and sometimes I need assistance, depending on my ability level that day. Many NGD participants had already lost abilities to do more routine ADLs independently and relied on help from others or assistive devices to perform self-care and household chores. As such, getting access to help from (family or paid) caregivers was itself an essential ADL. As long as the proper supports are there, it is probably what I fret about most, is losing my ton of support. I think that’s really the key—it’s caregivers and access to caregivers—because we could make a list five times this length, but at the end of the day, as long as you have reliable caregivers and access to help a lot of these things don’t matter as much. However, other Non-ambulatory Discussion Group participants considered needing assistance to complete an ADL an extra burden. One participant explained it was frustrating to have to wait for 5 to 30 minutes for help to arrive before they could accomplish a task. A fourth theme that formed was the desire to maintain independence and dignity. Many of the ADLs that were most important to group participants fell into the domains of maintaining one’s own comfort, health, hygiene, and safety. One Non-ambulatory Discussion Group participant said that retaining the ability to make their own healthcare decisions was very important to them. Another said they feared losing the ability to breath on their own, because the loss would entail “so much more dependence and complications.” …This is kind of embarrassing, but crying, being able to wipe your own face and blow your nose, it’s embarrassing, but it’s important. The group was then asked by the moderator, “How hard or easy do you think it would be to measure your overall health status based on your ability to perform ADLs over the course of time?” Non-ambulatory Discussion Group participants agreed that changes in ability to perform ADLs were more likely to reflect changes in function than in overall health status. Several participants explained that they thought of their overall health status as independent from SMA. It all goes back to how we see ourselves as normal. From the perspective of medical professionals, we are unhealthy.” They continued, ““What do you mean by healthy? Because, we don’t think we’re not healthy. We’ve embraced our disability. Just because I can’t feed myself anymore, I don’t think I’m less healthy. .. Being able to type on a keyboard, I don’t see that as a measure of my health. Non-ambulatory Discussion Group participants added that although abilities will vary day to day, these variations may not reflect a change in overall health status. Non-ambulatory Discussion Group participants were shown an example of the type of scale that may be used in a questionnaire asking about ADLs. The scale included the following rating options: Unable – can’t do, doesn’t know how, or is too young; Hard – does with a lot of help, extra time or effort; A little hard – does with a little help, extra time, or effort; and Easy – does with not help, extra time or effort, or a person’s skills are past this level. The moderator asked, “If you are asked to rate your ability to perform various ADLs using a scale like this, would you find it easier to rate the broad domain like ‘feeding oneself’ or would you want to be able to break that task into different parts?” The majority agreed that asking detailed questions in which ADLs had been broken down into smaller tasks would likely produce more accurate answers because people with SMA have different adaptive strategies. We can do a lot of this stuff but will probably do it a little differently. For example, feeding ourselves, you know, some of us can pick it up and just go for it, others may have to hold the fork a different way, or you know, use a different utensil, use both arms—so I think breaking it up would be the way to go. You can make a phone call, but can you get a phone? That’s why being specific is important. A third group participant noted that breaking ADLs into smaller tasks would clarify whether the respondent was able to perform the ADL independently or required assistance. They extrapolated, When I hear these questions coming from a perspective, like a medical research perspective, I assume they want to know, can I do these things myself? And the answer to that is, ‘No.’ But can I do them? Well, yes, I do them every day, with peoples’ help. So, the way I judge it is, ‘Can you do it with someone’s help?’ And I would answer, ‘Yes.’ But I would think I would give you a wrong idea of what I can do. However, one group participant thought that broader ADLs domains would be easier to rate. They explained, My life is pretty defined by what I can do by myself and what I can’t do by myself, so this makes it a little easier to kind of categorize it in my brain. Table 4 Summary of feedback from Non-ambulatory Discussion Group participants* Topic Major theme Subtheme ADLs ADLs should be customized to the individual. People with SMA have different ranges of abilities. People with SMA have different lifestyles and priorities. ADLs should encompass activities beyond self-care and household chores. Work, hobbies, relationships, and interacting with the community are all important domains. Abilities to perform ADLs can vary from day to day and in different situations. Preserving abilities to perform ADLs that enable independence and dignity is critical. ADLs should be utilized to assess a person’s functional status rather than overall health. ADL assessments should ask detailed questions. Abilities to perform ADLs may sometimes depend on assistive devices, environmental adaptations, or help from a family member or caregiver. Maintaining one’s own comfort, health, hygiene, and safety are key to preserving independence and dignity. Some people with SMA may think of their overall health as separate from SMA. Some people with SMA may consider themselves disabled but not unhealthy. People with SMA may have different ways of accomplishing the same task, which would be revealed by more detailed questions. Fatigue and Its Impact on ADLs Fatigue is a major factor of daily life. Fatigue reduces abilities to perform ADLs. Fatigue impacts relationships and social lives. Fatigue levels fluctuate. Physical, cognitive/intellectual, and emotional/social fatigue are intertwined. Patterns of fatigue generally correlate with levels of exertion. Fatigue fluctuates in patterns that are unique to the individual. Depression and pain can increase fatigue. Environmental conditions like cold can increase fatigue. For some patients, treatment seems to have reduced fatigue or improved recovery from fatigue. Physical fatigue has a greater impact but affects interest in and ability to interact socially and with the environment. Whether or not one talks to one’s doctor about fatigue depends on the doctor and the patient. All three types of fatigue affect abilities to perform ADLs. Some people with SMA may not consider their doctor to be an expert in fatigue. Some people with SMA initiate conversations about fatigue with their doctors to get medical help with or advice about managing fatigue. The topic of fatigue sometimes comes up naturally during a visit to the doctor. ADLs = activities of daily living; *n = 6 Impact of fatigue and fatigability on ADLs The second objective of the Non-ambulatory Discussion Group was to gather input from non-ambulatory adults with SMA about how fatigue and fatigability affect their abilities to perform ADLs. (Table 4 ) On a scale of 1–5 (1 = “hardly ever” and 5 = “all the time”), participants were asked to indicate the degree to which fatigue is present in their everyday lives. (All but one participant indicated that fatigue is an element of daily life.) Of the six Non-ambulatory Discussion Group participants, two answered “5,” one answered “4,” two answered “3,” and one selected “NA.” Participants were then asked, if their fatigue level fluctuates during the day and if they identified a pattern. There was a general theme among responses that fatigue levels do follow a pattern; however, the pattern varied between people. One participant remarked that their energy was typically highest in the morning and throughout the day. Another mentioned that their fatigue varied throughout the day and week, but that they “bounced back” from fatigue more quickly since being on treatment. A third participant remarked that the weather greatly impacted their fatigue because they have a fused spine, and their pain increases in cold weather, which in turn increases their fatigue. They explained that depression also notably increases their fatigue, and that their fatigue decreases when the depression is successfully treated. Several other participants agreed that weather also affects their fatigue levels. One participant explained that as they have gotten older and lost function, their fatigue patterns have become very predictable: the busier their day, the more fatigue they experience. But, 20 years ago, I experienced nothing even close to what I have now…I dread when people ask me to do anything past 5 o’clock because if they don’t have SMA, it’s embarrassing to tell them, ‘I’m just too tired.’ I almost am so fatigued that I hurt. It’s almost like a pain, because it is so significant. Non-ambulatory Discussion Group participants were then asked which type of fatigue – physical, cognitive/intellectual, or emotional/social – is most troublesome. The majority ranked physical fatigue as having the greatest affect, but the group agreed that the different types are intertwined. Sometimes my friendships kind of fall to the wayside because I’m just interacting with people all day, and asking for help, it physically and emotionally is exhausting. If I didn’t have the physical fatigue, I would not have the social fatigue. A third Non-ambulatory Discussion Group participant explained that it would be important for healthcare providers to be specific when inquiring about how fatigue affects ADLs, because although their emotional fatigue affects their abilities to perform ADLs, it was likely caused by depression rather than SMA. Next, participants were asked, “How many of you have had the experience of talking either to your primary care doctor or specialist about fatigue?” The group reported mixed experiences. I thought [the question] was funny. I’ve never had a conversation with my doctor about fatigue. I guess I just think it comes with the territory and what can they do about it? If I were to feel the need to discuss [fatigue], probably one of the last people I would feel the need to discuss it with would be my doctor. This participant explained that he liked his doctor but wouldn’t think of his doctor as being an expert on fatigue. However, a third participant had the opposite perspective: I have a lot of different doctors, and I’ve talked to pretty much all of them about fatigue…Because in some way or another, it affects every specialty doctor that I see, for whatever reason that I see them. Similarly, another participant described a productive experience they had talking with their doctor about fatigue when they began working full-time. They had received many physical accommodations at their new workplace, but they had not been given a long enough lunch break: I was getting tired having to feed myself and rush eating during the 30 minutes. Plus, I didn’t have any downtime. .. I don’t think they realized that was also a physical activity. In addition to providing an accommodation letter, the participant’s doctor also discussed strategies for managing workplace fatigue to alleviate the need for reduced hours. Through referral to specialists, the participant was able to get both medical help and practical advice that improved their workday fatigue. During the discussion session, participants were asked, “What do you wish your doctor understood about the fatigue experience?” Although there were no immediate responses, one participant said: …The fatigue is just so, it’s so debilitating for me, and it’s become that way more and more as I get older. And maybe part of that’s from, like, menopause, and that kind of thing but. .. it’s so terrible and devastating for me that it’s not so much what can I accomplish, but it’s how fatigue plays into that and. .. how it limits me. Ambulatory Discussion Group Results Activities of Daily Living The first objective of the Ambulatory Discussion Group was to gather input from participants about which abilities to perform ADLs were most important to them to maintain. (Table 5 ) Ambulatory Discussion Group participants were asked to review a list of ADLs (Additional File 7) and indicate other ADLs of importance that were not included. Picking things up off the floor, emptying the dishwasher, using the toilet away from home, and running errands were noted as key ADLs by Ambulatory Discussion Group participants. Ambulatory Discussion Group participants also shared strategies and tools—like shower chairs, toilet doughnuts, and pinchers—they used to accomplish ADLs as motor abilities waned. Adaptation became a theme throughout the conversation. The group was asked which ADLs they were most concerned about retaining the ability to perform. ADLs related to maintaining independence and preserving dignity—such as driving, feeding oneself, and taking care of one’s own hygiene and appearance—were of importance. To go wherever you want, whenever you want, and then the day that you know you can't. It's just, it, this disease, has robbed, robbed me. You know, I feel like, ‘Give me my life back.’ I think the shower, showering, bathing, toileting, you know, keeping clean, maintaining your appearance is probably on the top of the list for most of us. It'd be difficult to be at somebody else's mercy. Two Ambulatory Discussion Group participants had siblings with SMA, and the participants had watched their siblings lose abilities to perform ADLs related to preserving independence and dignity. These participants expressed concern about becoming similarly dependent on others. Navigating new environments and environmental hazards inside and outside the home was also a theme of the discussion. Fear of falling, which could lead to a debilitating injury, was prominent for several of the participants. It's not on the list, but one thing that I see in daily living for me is the fear of falling. I live in fear of falling, because if I fall, I can break a hip… So, I might be overboard in it, but I look at every little thing. I'm always looking down for an acorn, a pebble, anything that's uneven—a slight little thing that can cause you to fall. It's starting to rule my life. The participant went on to explain that they were careful to choose certain types of footwear and were selective about the type of chair they sat in to decrease their likelihood of falling. Ambulatory Discussion Group participants were then asked, “How hard or easy do you think it would be to measure your overall health status based on your ability to perform ADLs over the course of time?” The moderator added that Non-ambulatory Discussion Group participants had shared that they often adapted methods of completing tasks to compensate for loss of function. One participant noted they own multiple identical assistive tools, such as “grabbers,” so that they can keep one in each room of the house. The same participant said that among other household adaptations, they had replaced their heavy dishware with lighter plates and cups. “We figure out a way to do it, but we do things differently or we find things that work great for us.” Another participant concurred, giving the example of having learned to break down the task of unloading the dishwasher into several discrete steps as she has lost muscle strength, rather than transferring dishes directly from the washer to the shelf. A third Ambulatory Discussion Group participant said, “ I look back over my life, and the whole thing is like an adaptation. Even before I knew I had SMA, I had different ways than other people of doing things because I had weakness…. doing things over my head and things like that. And you just adapt here and adapt there and you figure out all these little cheats, so to speak. When they diagnosed me, I looked back and I thought, ‘Oh my gosh, now I know why everybody else does it like this. And I do it [like that].’” The Ambulatory Discussion Group were then shown an example of a ranking scale that comprised the following choices: Unable – can’t do, doesn’t know how, or is too young; Hard – does with a lot of help, extra time or effort; A little hard – does with a little help, extra time, or effort; and Easy – does with not help, extra time or effort, or a person’s skills are past this level. The moderator asked, “If you are asked to rate your ability to perform various ADLs using a scale like this, would you find it easier to rate the broad domain like ‘feeding oneself,’ or would you want to be able to break the task into different parts?” Participants agreed that tasks broken down into smaller parts would be more likely to detect adaptations to accomplish ADLs as functional status changed. Table 5 Summary of feedback from Ambulatory Discussion Group participants* Topic Major theme Subtheme ADLs Maintaining independence and preserving dignity are of the upmost importance. Preserving abilities to perform activities like driving and toileting is very important. Adaptation is a key strategy for coping with loss of function. As function declines, some tasks can still be performed but require different strategies, specific assistive tools, or help from others to accomplish. ADLs need to be detailed enough to detect adaptations that had occurred because of functional decline. Environmental conditions impact abilities to perform ADLs. New environments with unknown accommodations and hazards are stressful. Falling inside and outside the home is a major concern—furniture, ice, uneven surfaces, and crowds are all potential threats to stability. Inclement weather reduces ability and willingness to participate in activities outside the home. Cold weather can also negatively affect mobility/dexterity and increase pain. Fatigue and Its Impact on ADLs Some ADLs are related to caring for others. Fatigue is an aspect of daily life. Parents with SMA must adapt to perform parenting ADLs. Cooking for others as well as oneself may be an ADL for some people with SMA. Fatigue levels are variable throughout the day. Patterns of fatigue vary between participants. Physical fatigue is the most prominent type. Physical fatigue has the greatest impact on ADLs and can precipitate cognitive/intellectual and emotional/social fatigue. Environmental stressors like cold weather, wind, and obstacles can affect both physical and emotional/social fatigue. Healthcare professionals generally do not recognize that fatigue is a component of SMA. Healthcare professionals may be unfamiliar with SMA and attribute fatigue to other causes. Even an SMA specialist may have a hard time appreciating the nature and level of a patient’s fatigue. ADLs = activities of daily living; *n = 4 Impact of fatigue and fatigability on ADLs The second objective of the discussion was to gather input from ambulatory adults with SMA about how fatigue affected their abilities to perform ADLs. (Table 6) On a scale of 1–5 (1 = “hardly ever” and 5 = “all the time.”), Ambulatory Discussion Group participants were asked to indicate the degree to which fatigue is present in their everyday lives. Two participants answered “5,” and two answered “NA.” Upon further discussion, it became clear that fatigue was a factor for each participant but presented in different forms and patterns for each individual. Whereas one participant felt very energized in the morning but “crashed” after their midday meal, another felt notable, painful fatigue throughout each day. A third participant’s fatigue fluctuated daily depending on sleep quality and the needs of their daughter. The fourth participant felt less fatigue in the afternoon than in the morning. Ambulatory Discussion Group participants were asked which of the following types of fatigue were most troublesome: physical, cognitive/intellectual, or emotional/social. Participants unanimously agreed that physical fatigue was the most troublesome. However, there was also discussion about how physical fatigue could precipitate emotional/social fatigue. One participant explained, I feel like my emotional and social fatigue is based off of my physical fatigue. If I'm tired, then it's, physical. I don't want to go and have to worry about somewhere not being accessible or being in a social situation and being down here when everybody's up here—because I use my electric wheelchair most of the time. When participants were asked if fatigue was something they talked to their doctors about, responses varied widely. One participant said they talked to all their doctors about fatigue and received different responses depending on the doctor. Another participant was evaluated for depression when they told their doctor they were experiencing fatigue. A third participant said that although their doctor is a specialist in SMA and will address fatigue by doing bloodwork and looking for ways to support them, they still hesitate to bring up the topic. I think sometimes it's hard. I don't know if other people feel this way, but all my doctors at the neurology clinic, none of them have SMA, right? So sometimes it's hard. It's like, ‘Do I even attempt to explain? Because they're not going to understand it. .. So sometimes it's like, ‘Is it even worth the effort to describe it or to communicate it? Because I don't think it's ever going to be fully understood. The moderator asked Ambulatory Discussion Group participants what they wished their doctor understood about the fatigue experience. Respondents broadly indicated they wished their doctor knew more about SMA since the lack of familiarity impacts perceived ability to adequately care for SMA-related needs, and the physician’s ability to take the limitations of the disease into account when addressing needs unrelated to SMA. One participant noted their concerns are often attributed to their age, or even to menopause. Another participant remarked that their doctor had taken the time to educate himself about SMA: I think the main thing is that when you do go to a doctor that they at least take the time to get the basic knowledge of [SMA]…. to help us live our lives the best that we can. So, I guess it's education, just educate themselves a little bit more. Ambulatory Discussion Group participants were invited to share other factors that increased fatigue. Inclement weather, pain, and poor sleep quality were again mentioned as contributing factors. Conversely, one participant noted that treatment seemed to temporarily reduce their fatigue. Discussion As more therapeutic options become accessible to teens and adults with SMA [ 62 ], it is important to establish a standardized set of core outcomes to measure disease progression and treatment response. Efforts to standardize outcome measures for teens and adults with SMA are underway in Canada and throughout Europe [ 44 , 63 – 67 ], but a core set of outcome measures has not yet been defined in the U.S. In the present study, we surveyed a working group of key opinion leaders in clinical research and care, as well as two discussion groups comprised of non-ambulatory adults or ambulatory adults with SMA, for their perspectives on what type of outcomes could capture disease status and treatment effects in a manner that is meaningful both clinically and to the individual. The study objective was to begin to build consensus toward a standardized set of outcome measures for teens and adults with SMA. Activities of daily living (ADLs) The KOL Working Group reached consensus that ADLs are the best type of outcome to detect clinically relevant functional changes in teens and adults with SMA. KOL Working Group participants ranked ADLs that facilitate personal autonomy as most meaningful, and discussion group participants concurred that ADLs related to dignity and independence are of the upmost importance to maintain. The KOL Working Group and discussion groups also agreed that when used as outcomes, ADLs should be small, specific tasks selected to detect subtle changes in function that affect individuals’ unique lifestyles. Thus far, U.S. research studies assessing SMA disease progression or treatment effects in teens and adults have utilized predominantly CROMs such as the Hammersmith Functional Motor Scale Expanded (HFMSE), the 32-item Motor Function Measure (MFM32), the Revised Upper Limb Module (RULM), the 6 Minute Walk Test (6MWT); and the 10 Meter Walk/Run Test (10MWRT) [ 68 – 72 ]. A few studies have also included PROMs [ 73 , 74 ], and several groups are actively developing novel CROMs [ 75 ] and PROMs [ 61 ], some of which were unpublished at the time of this writing. Whereas clinician-reported measures are utilized, by definition, in a clinical setting, PROMs have the potential to detect functional changes that are impactful to people with SMA as they go about their everyday lives. PROMs based on abilities to perform ADLs are commonly employed to assess disease status in adults with other neuromuscular diseases such as multiple sclerosis (MS) [ 76 ], amyotrophic lateral sclerosis (ALS) [ 77 ], and myasthenia gravis (MG) [ 78 ]. Since the present study was completed, several studies have also investigated the use of ADLs as outcomes to track disease progression and treatment response in teens and adults with SMA. For example, Sadjadi et al. (2023) [ 1 ] evaluated the modified Spinal Muscular Atrophy Functional Rating Scale (SMAFRS) as an ADL-based outcome measure for non-ambulatory and ambulatory adults, and Slayter et al. (2023) [ 2 ] included the SMAFRS in their eight-measure toolkit created to assess disease progression in adults. In addition, the Spinal Muscular Atrophy Independence Scale Upper Limb Module (SMAIS-ULM) has recently been developed as an ADL-based PROM for individuals who are 12 years of age or older, and for caregivers of children who are older than 2 years of age. [ 79 ] Finally, Lefton-Greif et al (2025) [ 80 ] developed and partially validated a scale for bulbar function assessment in adults with SMA based in part on ADLs such as completing meals, swallowing pills, and communicating with family members. These studies demonstrate a trend in using outcome measures comprised of ADLs in assessing disease status and treatment response in teens and adults with SMA. In Phase 1 of the study, the KOL Working Group did note that an outcome measure consisting of ADLs might be most powerful when combined with a clinical measure such as a biomarker. While recent research has found that molecular biomarkers reflecting neurodegeneration are not as useful in teens and adults with SMA as they are in children [ 59 , 81 , 82 ], electrophysiological outcome measures such as compound muscle action potential (CMAP) show promise as biomarkers in teens and adults with SMA [ 59 , 65 , 69 , 83 , 84 ]. Indeed, when asked to rank which type of outcome measure would best capture disease state in teens and adults with SMA, KOL Working Group participants ranked CMAP and ADLs as equally useful. Fatigue and fatigability Several clinician-reported, performance-based outcome measures have been utilized to assess performance fatigue and fatigability in teens and adults with SMA. For example, the 6MWT [ 85 – 89 ] has been the gold standard for quantifying lower limb performance fatigue and fatigability in ambulatory individuals with SMA [ 37 , 69 , 90 – 93 ]. The Endurance Shuttle Nine Hole Peg Test (ESNHPT) has been used for distal arm and hand performance fatigue and fatigability, and the Endurance Shuttle Box and Block Test (ESBBT) has been utilized to assess upper arm performance fatigue and fatigability. [ 94 – 96 ] These and other clinician-reported, performance-based outcome measures of fatigue and fatigability are advantageous in that they are objective. However, they have several limitations. First, they measure the ability to perform specific tasks, and these tasks may not be varied or sensitive enough to reveal subtle but important changes in fatigue that affect overall quality of life. [ 97 ] Second, people with very severe forms of SMA may not be able to complete standard performance-based tests, creating floor effects. [ 98 , 99 ] Similarly, ceiling effects on existing performance-based assessments will likely become more salient as more people with SMA receive DMTs and other treatments, diversifying and broadening the natural history of the disease. Third, performance-based fatigue and fatigability assessments are a snapshot of performance in a clinic at a specific time point and are subject to variations based on recent activity and other variables. Finally, results from clinician-reported, performance-based outcome measures tend to correlate with disease severity and with results from functional assessments like the RULM and HFMSE. [ 37 , 100 , 101 ] In contrast, results from performance fatigue and fatigability assessments have generally not correlated with levels of perceived fatigue assessed within the same studies. That is, improvements in performance fatigue do not correlate with improvements in perceived fatigue when the two are measured side-by-side. [ 48 , 97 , 100 ] Furthermore, levels of perceived fatigue generally do not correlate with either disease severity or motor function. [ 48 , 102 ] These findings support the idea that performance fatigue/fatigability and perceived fatigue/fatigability are separate, albeit interrelated, phenomena, and that perceived fatigue/fatigability are better assessed by separate, PROMs. KOL Working Group and discussion group participants agreed that fatigue and fatigability are components of everyday life that affect abilities to perform ADLs. Despite this agreement, participants in both discussion groups reported that most healthcare professionals do not recognize the significance of fatigue and fatigability in the context of SMA. This communication gap may in part result from the fact that a PROM for fatigue and fatigability in SMA has not yet been validated. Myriad PROMs have been used to assess perceived fatigue in teens and adults with SMA, such as the Fatigue Severity Scale (FSS) [ 91 , 103 ], the Pediatric Quality of Life Multidimensional Fatigue Scale (PedsQL MFS) [ 48 ], the Multi-Dimensional Fatigue Inventory (MFI) [ 53 ], and the Spinal Muscular Atrophy Health Index (SMA-HI) sleep and fatigue modules [ 104 ]. These instruments query individuals about perceived levels of fatigue and fatigability experienced over durations ranging from the past week to the prior month. However, more recent research [ 105 ] has validated the use of a fatigue and fatigability scale comprised of ADLs. This new questionnaire, the PROfuture, was developed in Spain for people with SMA who are older than 14 years of age. Furthermore, Rodriguez-Torres et al. (2025) [ 106 ] recently developed a novel PROM, the SMA EFFORT, for evaluating perceived physical fatigue in teens and adults across four categories: 1) exercise/recreation, 2) mobility, 3) ADLs, and 4) postural control. The new developments support the idea that ADLs can serve as outcomes for a standardized measure of fatigue and fatigability in teens and adults with SMA living in the U.S. Limitations Input from the KOL Working Group represented perspectives from experts in SMA research and clinical care. Primary care physicians, physical therapists, neurologists, and other clinical care providers who are not as familiar with SMA may have contributed unique and valuable viewpoints to the study. Similarly, the non-ambulatory and ambulatory discussion groups were small and represented a limited range of demographics. In particular, the discussion groups did not include teen participants owing to lack of response during recruitment. Although limited by sample size, this study can serve as a starting point for a broader discussion on how to develop a core set of outcome measures for function, fatigue, and fatigability in teens and adults with SMA in the U.S. Conclusion The findings of this study provide insight into which type of outcomes are meaningful to SMA researchers and clinicians, as well as adults with SMA, when assessing function, fatigue, and fatigability. The working group and discussion groups agreed that PROMs based on ADLs may be most effective at detecting changes in disease progression, motor function, and fatigue and fatiguability that impact abilities to perform everyday tasks that matter most to people with SMA. The groups also concurred that ADLs which impact one’s independence and dignity are of the highest priority to maintain and monitor. Furthermore, the working group and discussion groups each acknowledged that fatigue and fatigability are major aspects of daily life that affect abilities to perform ADLs, but that there is currently no effective way to measure or communicate about fatigue and fatigability. Critical treatment needs remain unmet within the SMA community, particularly among teens and adults with SMA who do not receive DMT until later in disease progression. As novel treatment options and protocols become available for these populations, a standardized core set of outcome measures will be required to assess disease status and treatment response. These results may form a foundation for the development of core outcome measures for function and fatigue in teens and adults with SMA. Declarations Ethics approval and consent to participate Prior to initiation, WIRB-Copernicus Group Institutional Review Board (WCG IRB) reviewed and approved the study (IRB Tracking Number: 20226344). All respondents were informed via the informed consent document that findings may be published. Only de-identified results are included within the manuscript. All procedures performed involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Consent for publication Not applicable. Competing Interests None of the authors have competing interests to declare. Funding The authors acknowledge the Cure SMA Industry Collaboration (SMA-IC) for funding support to conduct this research study and pay the journal’s Rapid Service Fee. The SMA-IC was established in 2016 to leverage the experience, expertise, and resources of pharmaceutical and biotechnology companies, as well as other nonprofit organizations involved in the development of SMA therapeutics to more effectively address a range of scientific, clinical, and regulatory challenges. Current members include Cure SMA Biogen, Novartis, Scholar Rock, Genentech/Roche Pharmaceuticals, NMD Pharma, and SMA Europe. Funding for this research was provided by the 2021 SMA-IC which included Novartis Gene Therapies, Biogen, Genentech/Roche, and Scholar Rock. Author contributions JG, MAC, LTB, and MMB played key roles in the conception and design of the study. JG, MAC, and LTB were involved in the acquisition and analysis of data. JJT drafted the manuscript; JG, MAC, LTB, and MMB provided gave critical feedback during manuscript development. Acknowledgements The authors would like to thank Discussion Group participants for generously giving their time and insight during Phase 2 of this study. The authors would also like to thank the following key opinion leaders for donating their time and expertise as Working Group participants in Phase 1 of the study: Imran Tanvir (Genentech), Robert Goldstein (formerly with Biogen), Sandra Reyna (Novartis Gene Therapies), Nily Osman (formerly with Scholar Rock), Nicole Gusset (SMA Europe), Bakri Elsheikh (The Ohio State University), Richard Shell (Nationwide Children’s Hospital), Maureen Lefton-Greif (Johns Hopkins Medicine), Katlyn McGrattan (University of Minnesota), Lindsay Alfano (The Ohio State University), Hank Mayer (Children’s Hospital of Philadelphia), and Thomas Crawford (Johns Hopkins Medicine). Finally, the authors would like to thank Leslie Nelson (University of Texas Southwestern Medical Center) and Meghan Moore Burk (Children’s Hospital Colorado) for their contributions as consultants on study design. Availability of data and materials All data generated or analysed during this study are included in this published article and its supplementary information files. References Bach JR, Baird JS, Plosky D, Navado J, Weaver B. Spinal muscular atrophy type 1: Management and outcomes. Pediatr Pulmonol. 2002;34(1):16–22. Borkowska J, Rudnik-Schoneborn S, Hausmanowa-Petrusewicz I, Zerres K. Early infantile form of spinal muscular atrophy (werdnig-hoffmann disease) with prolonged survival. Folia Neuropathol. 2002;40(1):19–26. Chung BH, Wong VC, Ip P. Spinal muscular atrophy: Survival pattern and functional status. Pediatrics. 2004;114(5):e548–53. Milligan JN, Blasco-Perez L, Costa-Roger M, Codina-Sola M, Tizzano EF. 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Safety and treatment effects of nusinersen in longstanding adult 5q-SMA type 3 - a prospective observational study. J Neuromuscul Dis. 2019;6(4):453–65. Belter L, Peterson I, Jarecki J. Evaluating perceived fatigue within an adult spinal muscular atrophy population. Neurol Ther. 2023;12(6):2161–75. Mattsson M, Möller B, Lundberg I, Gard G, Boström C. Reliability and validity of the fatigue severity scale in swedish for patients with systemic lupus erythematosus. Scand J Rheumatol. 2008;37(4):269–77. Mazzella A, Cruz R, Belter L et al. Assessing perspectives of disease burden and clinically meaningful changes using the spinal muscular atrophy health index in adolescents and young adults. Muscle Nerve. 2022. Domine MCCM, de Lemus M, Castellano IP, Ñungo-Garzón NC, Sevilla-Mantecón T, Vázquez-Costa JF. Physical fatigue and perceived fatigability in adolescents and adults with spinal muscular atrophy: A pilot study. Neurol Perspect. 2022;2(4):199–208. Rodriguez-Torres R, Kanner CH, Gay EL, et al. Development of the SMA EFFORT: A new approach to characterize perceived physical fatigability in spinal muscular atrophy. J Neuromuscul Dis. 2025;12(1):22143602241313326. Supplementary Files AdditionalFile1.pdf AdditionalFile2.pdf AdditionalFile3.pdf AdditionalFile4.pdf AdditionalFile5.xlsx AdditionalFile6.pdf AdditionalFile7.pdf Cite Share Download PDF Status: Published Journal Publication published 17 Oct, 2025 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted Editorial decision: Major revision 27 Jul, 2025 Reviewers agreed at journal 27 Jun, 2025 Reviewers invited by journal 20 Jun, 2025 Editor assigned by journal 20 Jun, 2025 First submitted to journal 19 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6917745","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":473910335,"identity":"18c56ae1-6651-4822-a0ae-21e3ecb3e600","order_by":0,"name":"Jacqueline Glascock","email":"","orcid":"","institution":"Cure SMA","correspondingAuthor":false,"prefix":"","firstName":"Jacqueline","middleName":"","lastName":"Glascock","suffix":""},{"id":473910336,"identity":"df0507b5-20e6-42a2-bdda-b845ae34cc78","order_by":1,"name":"Lisa T Belter","email":"","orcid":"","institution":"Cure 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leader\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6917745/v1/dffc935f412aaff9a56dbf6a.png"},{"id":85350154,"identity":"fe840821-63a4-40e6-b998-17704a55d43b","added_by":"auto","created_at":"2025-06-25 02:49:50","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":187619,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ea \u003c/strong\u003eKOL Working Group participants indicated which information would best aid in assessing disease status.\u003c/p\u003e\n\u003cp\u003e*Write-in responses for non-ambulatory and ambulatory patients were: \"Surrogate markers of function needed to complete ADLs\" and \"Would also note improvement in fatigue/fatigability,\" respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eb \u003c/strong\u003eKOL Working Group participants indicated which method would best aid in assessing disease status.\u003c/p\u003e\n\u003cp\u003e*Write-in comments for non-ambulatory and ambulatory patients were \"Would also monitor fatigue and fatigability \" and \"Would also note improvement in fatigue and fatigability,\" respectively.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6917745/v1/a4af9b8d757ddd0c9587f035.png"},{"id":85349824,"identity":"ec506f80-3c7e-45cc-8c41-18991819fcb4","added_by":"auto","created_at":"2025-06-25 02:41:50","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":130343,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ea \u003c/strong\u003eKOL Working Group participants indicated which language would be most useful in asking how fatigue affects ADLs.\u003c/p\u003e\n\u003cp\u003e*Write-in answers for both non-ambulatory and ambulatory patients with SMA: \"Might ask about task becoming too difficult or taking more time to complete\" and 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02:33:50","extension":"pdf","order_by":13,"title":"","display":"","copyAsset":false,"role":"supplement","size":108222,"visible":true,"origin":"","legend":"","description":"","filename":"AdditionalFile6.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6917745/v1/6fc54d17a1518a3eb0a9c7e4.pdf"},{"id":85349064,"identity":"6f198c27-06ec-4737-b1b1-0b60aa132f0d","added_by":"auto","created_at":"2025-06-25 02:33:50","extension":"pdf","order_by":14,"title":"","display":"","copyAsset":false,"role":"supplement","size":58484,"visible":true,"origin":"","legend":"","description":"","filename":"AdditionalFile7.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6917745/v1/582193cd0cb8fcefbe058f1f.pdf"}],"financialInterests":"","formattedTitle":"A qualitative, mixed-method approach to reaching consensus on function, fatigue, and fatigability outcomes in teens and adults living with spinal muscular atrophy","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003e \u003cem\u003eSpinal muscular atrophy\u003c/em\u003e (SMA)\u003c/p\u003e \u003cp\u003eSpinal muscular atrophy (SMA) is an autosomal recessive disease that was, until recently, the leading genetic cause of mortality in children under the age of two years. [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e–\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] In 95% of cases, SMA is caused by a biallelic mutation in the survival motor neuron 1 gene (\u003cem\u003eSMN1\u003c/em\u003e). [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e–\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] Mutation of the \u003cem\u003eSMN1\u003c/em\u003e gene results in deficiency of the survival motor neuron protein (SMN), which has a variety of functions throughout the body and is especially important in the brainstem and spinal cord. [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e–\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] Untreated SMA is characterized by progressive motor neuron loss that may result in limb and truncal muscle weakness, scoliosis, contractures, and respiratory complications. [\u003cspan additionalcitationids=\"CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e–\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] In the most severe forms of SMA, symptoms can be present at birth and progress rapidly, and early diagnosis and treatment with a disease modifying therapy (DMT) are necessary to achieve optimal outcomes. [\u003cspan additionalcitationids=\"CR21 CR22\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e–\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] With less severe types of SMA, symptom onset may occur later in life, and loss of function may be more gradual. [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan additionalcitationids=\"CR25 CR26 CR27\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e–\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] Like \u003cem\u003eSMN1\u003c/em\u003e, the survival motor neuron 2 gene (\u003cem\u003eSMN2)\u003c/em\u003e also encodes the SMN protein. Although much of the protein produced by \u003cem\u003eSMN2\u003c/em\u003e is truncated and dysfunctional, \u003cem\u003eSMN2\u003c/em\u003e can act as a partial “back-up” for the mutated \u003cem\u003eSMN1\u003c/em\u003e gene in people with SMA. As such, \u003cem\u003eSMN2\u003c/em\u003e serves as a critical disease modifying gene. [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eSMA phenotype has historically been classified into five types, 0–4, which are determined by the age of symptom onset and maximum motor function achieved. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] However, the recent availability of DMTs for SMA has dramatically impacted the clinical course of the disease and led to a shift in classification based on \u003cem\u003eSMN2\u003c/em\u003e copy number and motor function. [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] In 2016, the United States (U. S.) Food and Drug Administration (FDA) approved the antisense oligonucleotide, \u003cem\u003enusinersen\u003c/em\u003e, for use in children and adults with SMA. [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] Next, a gene therapy, \u003cem\u003eonasemnogene abeparvovec\u003c/em\u003e, was approved by the FDA in 2019 for use in children under the age of two. [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] Finally, the RNA splicing modifier, \u003cem\u003erisdiplam\u003c/em\u003e, was approved by the FDA for patients older than 2 months in 2020 and for patients of any age in 2022. [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e] Each of these “SMN-dependent” therapies works by restoring SMN protein levels, which protects motor neurons and preserves muscle function. [\u003cspan additionalcitationids=\"CR21 CR22\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e–\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] However, due to disease phenotype heterogeneity, and variability in disease onset and the timing of therapeutic intervention, treatment response varies widely. Therefore, critical treatment needs remain unmet within the SMA community. For example, teens and adults with SMA who do not receive DMT until later in their disease progression may experience less dramatic benefits from treatment. [\u003cspan additionalcitationids=\"CR37\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e–\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] To meet remaining treatment needs, the SMA drug pipeline is burgeoning with studies of new potential, SMN-independent treatments, as well as novel protocols for approved SMN-dependent treatments. [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e] In the future, it is likely that a combination of SMN-dependent and SMN-independent therapies will be used to achieve optimal patient outcomes. [\u003cspan additionalcitationids=\"CR41\" citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e–\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]\u003c/p\u003e\n\u003ch3\u003eClinical outcome measures for SMA\u003c/h3\u003e\n\u003cp\u003eA clinical outcome measure is an endpoint that assesses how disease progression and treatment affect how a patient feels, functions, or survives. [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e] The measure may be clinician-reported, in which changes in function are measured by a trained healthcare professional, or patient-reported, in which changes in abilities are described by the patient. Myriad clinician-reported outcome measures (CROMs) and patient-reported outcome measures (PROMs) have been utilized in SMA research and clinical care. For example, a literature review and clinician survey performed by Slayter et. al in 2021 [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e] identified 17 different CROMs that had been used or were still in use internationally in the evaluation of adults with SMA. Similarly, a recent scoping review of PROMs for SMA determined that between 2016 and 2022, 31 unique PROMs were utilized in studies conducted internationally with adults living with SMA and other neuromuscular conditions. [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e] Of these 31 PROMs, few included a comprehensive set of health domains, and only two were developed explicitly for people with SMA. In addition to changes in motor function, fatigue and fatigability are often reported as major concerns by teens and adults with SMA [\u003cspan additionalcitationids=\"CR47\" citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e–\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. Fatigue and fatigability are major aspects of daily life for teens and adults with SMA, yet the symptoms are multidimensional and difficult to measure. [\u003cspan additionalcitationids=\"CR49 CR50\" citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e–\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e] Although the nomenclature for fatigue and fatigability is varied and ill-defined, the emerging trend is to separate the concepts into two subtypes, performance fatigue/fatigability (also called functional fatigue/fatigability) and perceived fatigue/fatigability. [\u003cspan additionalcitationids=\"CR51\" citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e–\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e] \u003cem\u003ePerformance fatigue and fatigability\u003c/em\u003e can be defined as lack of endurance, or the inability to complete or repeat a specific physical task within a given time frame. \u003cem\u003ePerceived fatigue and fatigability\u003c/em\u003e are a person’s subjective feeling of reduced capacity to initiate, complete, and repeat tasks. Outcome measures for performance and perceived fatigue and fatigability have not yet been validated specifically for SMA patients in the U.S. [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eIt is estimated that in the U.S., approximately 60% of people with SMA are teens or adults. [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e] As more teens and adults with a broad range of SMA phenotypes receive investigational and FDA-approved treatments in the U.S., a standardized set of clinical outcomes is needed to measure changes in motor function, fatigue, and fatigability in teens and adults. The establishment of core clinical outcomes for SMA would facilitate comparisons of research data across studies and provide a consistent standard of care across the nation. [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eCure SMA is the largest SMA patient advocacy organization based in the U.S. that funds and directs research for SMA. [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e] In this study, Cure SMA convened 1) a working group of key opinion leaders (KOL Working Group) SMA comprising researchers, health care providers, and biotechnology industry representatives, and 2) two discussion groups comprising either non-ambulatory adults (Non-ambulatory Discussion Group) or ambulatory adults (Ambulatory Discussion Group) living with SMA. The aim of the study was to build consensus on which clinical outcomes best capture changes in disease status and motor function in teens and adults with SMA in the U.S. as a first step in establishing a set of core outcome measures for use in research and clinical care.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"METHODS","content":"\u003ch2\u003eOverview\u003c/h2\u003e\u003cp\u003e A two-phase, mixed-methods study was utilized to build consensus around which are the most valuable CROMs for teens and adults with SMA. (Fig.\u0026nbsp; \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e ) In the planning stages of the study, two physical therapists (PTs) with expertise in SMA were consulted on study design and content. These PTs also participated as a Steering Committee in the KOL Working Group phase of the study. A third-party consultant, The Kith Collective, coordinated, organized, and conducted discussion group meetings with guidance from Cure SMA. PTs and Kith Collective employees were compensated for their time, KOLs participated as volunteers, and discussion group participants received a gift card (\u003cspan\u003e$\u003c/span\u003e50) for their participation. \u003c/p\u003e\n\u003ch3\u003ePhase 1: KOL Working group\u003c/h3\u003e\n\u003cp\u003eKOL Working Group objectives were to 1) identify clinically meaningful outcomes in teens and adults with SMA not assessed by existing outcome measures, 2) identify key outcomes within core functional domains for assessing disease progression and functional ability in teens and adults with SMA, and 3) identify types of outcomes that best capture major and subtle functional changes in teens and adults with SMA. The KOL Working Group was composed of two Steering Committee members and 12 KOLs. KOLs were invited by email to participate based on their expertise in SMA clinical care and research. (Additional File 1) For logistical simplicity, invitations were restricted to KOLs residing in the U.S. A modified Delphi method was utilized to achieve consensus. The process consisted of a 30-minute kick-off call on February 9, 2022, followed by six, 90-minute KOL Working Group meetings occurring between March 9, 2022, and October 11, 2022; all meetings were held over Zoom. To prepare the KOLs for discussions, peer-reviewed articles were gathered by Cure SMA staff on the following topics as they relate to outcome measures for SMA: bulbar function, fatigue and fatigability, activity limitations/disease burden, respiratory function, and general function. At the kick-off call, Cure SMA distributed briefing packets containing the background reading. Before each of the remaining six KOL Working Group meetings, the participants completed a 5-minute, anonymous, multiple choice/open response survey. (See Additional File 2 for all Working Group surveys.) Pre-call surveys were sent one week prior to the next meeting and were to be completed by the day before the next meeting.\u003c/p\u003e \u003cp\u003eCure SMA staff reviewed and distilled survey results between meetings, then presented and discussed findings with the KOLs at the following meeting. Survey results were also utilized by Cure SMA to generate a new survey in advance of the next meeting to work toward consensus on core outcomes. Each Zoom meeting was recorded, and minutes were distributed by email the following week. At the conclusion of Phase 1 of the study, key questions that emerged during the Delphi process were identified by Cure SMA and the Kith Collective. These questions informed the discussion guide (Additional File 3) for the next phase of the study.\u003c/p\u003e\n\u003ch3\u003eDiscussion Group\u003c/h3\u003e\n\u003cp\u003eDiscussion group objectives were 1) to understand which health outcomes matter most to adults with SMA, and 2) to understand how fatigue and fatigability affect abilities to perform Activities of Daily Living (ADLs). An eligibility survey (Additional File 4) was created and shared via email with teens and adults with SMA that reside in the U.S. as identified through the Cure SMA Membership Database. [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e] Eligibility survey responses were received from 261 individuals and were organized into a perspectives matrix created by Cure SMA staff. Responses to demographic and patient experience questions were used to facilitate diverse enrollment. (Additional File 5) Twenty-three persons with SMA were invited to participate in the discussion groups; informed consent was obtained from 10 individuals. Participants were divided into two discussion groups based upon whether the individual was non-ambulatory or ambulatory. The Non-ambulatory Discussion Group contained six adults with SMA, and the Ambulatory Discussion Group four adults with SMA. (Additional File 6) Due to limited response to recruitment, neither discussion sub-group contained teen participants.\u003c/p\u003e \u003cp\u003e For each discussion group, a 30-minute introductory meeting was held, followed by a 90-minute main meeting. All meetings, led by the Kith Collective, were held over Zoom and recorded. During the introduction meeting, the background and intent of the study was described, and participants were introduced to the concepts of ADLs and fatigue. In advance of the main meeting, participants were asked to consider a list of sample ADLs and to think about other activities that were important to them. (Additional File 7) This exercise was meant to prepare participants for upcoming discussions in the main meeting. Prior to initiation, WIRB-Copernicus Group Institutional Review Board (WCG IRB) reviewed and approved the study (IRB Tracking Number: 20226344). All respondents were informed via the informed consent document that findings may be published. Only de-identified results are included within the manuscript. All procedures performed involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. During the sessions, notes were taken by Kith Collective and Cure SMA staff and used to identify themes in participant feedback, as was chat feedback from those participants that elected to provide written responses.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePhase 1: KOL Working Group\u003c/h2\u003e \u003cp\u003e Through reiterative surveys and discussions, KOL Working Group participants worked toward consensus on the most meaningful outcomes for measuring function and disease status in teens and adults with SMA. First, KOL Working Group participants identified clinically relevant outcomes, within each of five domains, that were not captured by existing outcome measures for non-ambulatory and ambulatory teens and adults with SMA. (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) As the group discussed these outcomes, two themes emerged: 1) ADLs may be utilized as meaningful outcomes for assessing function in non-ambulatory and ambulatory teens and adults with SMA, and 2) fatigue and fatigability are major aspects of SMA that may affect abilities to perform ADLs.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDomains and outcomes not captured by existing outcome measures for teens and adults with SMA\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDomain\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBulbar function (encompassing swallow, voice, vocal capacity, phonation, speech)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026bull; Ability to capture slow disease progression/early deficits/incremental changes/increased sensitivity to longitudinal change\u003c/p\u003e \u003cp\u003e\u0026bull; Jaw range of motion\u003c/p\u003e \u003cp\u003e\u0026bull; Tongue strength\u003c/p\u003e \u003cp\u003e\u0026bull; Bite strength\u003c/p\u003e \u003cp\u003e\u0026bull; Chewing fatigue/endurance of chewing\u003c/p\u003e \u003cp\u003e\u0026bull; Ability to be understood when speaking\u003c/p\u003e \u003cp\u003e\u0026bull; Ability to maintain good nutrition\u003c/p\u003e \u003cp\u003e\u0026bull; Risk of aspiration\u003c/p\u003e \u003cp\u003e\u0026bull; Swallowing\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFatigue and fatigability\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026bull; Ability to complete meals, time to finish meals\u003c/p\u003e \u003cp\u003e\u0026bull; Functional metrics/current tools have reduced carryover to true functional activities\u003c/p\u003e \u003cp\u003e\u0026bull; Ability to function for entire day\u003c/p\u003e \u003cp\u003e\u0026bull; Assessment of sleep\u003c/p\u003e \u003cp\u003e\u0026bull; Respiratory function\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCognition\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026bull; Neurodevelopmental scores/neurophysiological evaluation\u003c/p\u003e \u003cp\u003e\u0026bull; School readiness functions\u003c/p\u003e \u003cp\u003e\u0026bull; Prospective natural history or evaluation of cognition in teens/adults is an area of need\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGross motor function/range of motion/strength\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026bull; Ability to self-transfer, nocturnal rotation\u003c/p\u003e \u003cp\u003e\u0026bull; Wheelchair-based assessments (i.e., ATEND)\u003c/p\u003e \u003cp\u003e\u0026bull; Impact on daily function\u003c/p\u003e \u003cp\u003e\u0026bull; Ability to manage assistive devices\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFine motor function\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026bull; Functions related to use of social media/computer tasks/communication (typing, texting, etc.)\u003c/p\u003e \u003cp\u003e\u0026bull; Ability to manage assistive devices (wheelchair joystick)\u003c/p\u003e \u003cp\u003e\u0026bull; Ability to feed self\u003c/p\u003e \u003cp\u003e\u0026bull; Grasp and grip\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eSurvey 1 results (n\u0026thinsp;=\u0026thinsp;9): KOL Working Group participants were asked, \u0026ldquo;When thinking about outcomes for teens and adults with SMA, which outcomes/items in [domain] not captured by currently existing outcomes do you feel would be clinically meaningful?\u0026rdquo;.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eActivities of daily living (ADLs)\u003c/h3\u003e\n\u003cp\u003eAs discussions unfolded, KOL Working Group participants agreed on the need for specific, finite outcomes that are sensitive enough to detect both major and minor changes in function. The group reasoned that teens and adults with SMA are likely to experience subtle changes in function over time, whether from disease progression or treatment, and these subtle changes may profoundly impact participation in daily activities and quality of life. Consensus began to develop that ADLs were likely to be the most meaningful type of outcome for teens and adults with SMA because these age groups tend to describe differences in disease status (i.e., improvements or reductions in function) through changes in their abilities to complete everyday tasks. KOL Working Group participants were asked to rank outcomes within five domains in terms of which would be most clinically meaningful in assessing teen and adult functional status. (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) In discussion, KOL Working Group participants also noted that transfers, socialization and communication, transportation, toileting, and the ability to move outside the home were additional important domains for both non-ambulatory and ambulatory people with SMA.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eKOL Working Group key outcomes for assessing functional ability in teens and adults with SMA\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDomain\u003c/p\u003e \u003cp\u003e(number of respondents)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOutcomes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOverall Rank\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eScore\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo. of Rankings\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBulbar Function\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e(max score\u0026thinsp;=\u0026thinsp;30)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRisk of aspiration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSwallowing/dysphagia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbility to maintain good nutrition\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePerceived Fatigue\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e(max score\u0026thinsp;=\u0026thinsp;25)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTime on ventilation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbility to complete age-appropriate play/specific tasks during the day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHow long can one perform a task before fatigue limits it\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFunctional (Performance) Fatigue\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e(max score\u0026thinsp;=\u0026thinsp;25)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbility to function for entire day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbility to complete meals/time to finish meals\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbility to drive power chair\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCognition/Language/Communication (n\u0026thinsp;=\u0026thinsp;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e(max score\u0026thinsp;=\u0026thinsp;20)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbility to communicate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntelligibility (especially, if muscle weakness is impeding intelligibility)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSchool assessments/school readiness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGross Motor Function/\u003c/p\u003e \u003cp\u003eRange of Motion/Strength\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e(max score\u0026thinsp;=\u0026thinsp;25)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbility to manage assistive devices (wheelchair joystick)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFunctions related to use of social media/computer tasks/communication (typing, texting, etc.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStrength to make transfers outside of home\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFine Motor Function\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e(max score\u0026thinsp;=\u0026thinsp;25)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbility to manage assistive devices (wheelchair joystick)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFunctions related to use of social media/computer tasks/communication (typing, texting, etc.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbility to feed self\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eSurvey 2 results: KOL Working Group participants were asked to rank up to five outcomes in each domain according to clinical relevance. The three highest-ranked patient outcomes in each domain are shown in this table. Outcomes were given a value of 1 through 5 based on ranking, with the highest-ranked outcomes given a value of 5 and the lowest a value of 1. Therefore, the maximum possible score (max score) for each outcome was 5 times the number of respondents who ranked that outcome. ADLs\u0026thinsp;=\u0026thinsp;activities of daily living; KOL Working Group\u0026thinsp;=\u0026thinsp;key opinion leader working group.\u003c/p\u003e \u003cp\u003eKOL Working Group participants then weighed the utility of ADLs against other types of outcomes used to assess function in teens and adults with SMA. (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) KOL Working Group participants concluded that ADLs may be leveraged to simultaneously assess gross motor functions and detect minor functional changes that might be missed by other types of outcomes. Group participants noted that using an outcome measure based on ADLs alongside a CROM and/or a biomarker [\u003cspan additionalcitationids=\"CR59\" citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e] was likely to give the most broad and detailed information about disease status in teens and adults with SMA.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOutcome types ranked by ability to capture functional status in teens and adults with SMA\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSURVEY 3 RESULTS (n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOutcome Type\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eOverall rank\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eScore (max\u0026thinsp;=\u0026thinsp;15)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eNo. of Rankings\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eActivities of daily living (ADLs)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGross motor milestones\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWrite-in responses\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCompound muscle action potential (CMAP)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther biomarker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSURVEY 4 RESULTS (n\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOutcome Type\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eOverall rank\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eScore (max\u0026thinsp;=\u0026thinsp;28)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eNo. of Rankings\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGross motor milestones\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eActivities of daily living (ADLs)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCompound muscle action potential (CMAP)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWrite-in responses\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther biomarker\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn Surveys 3 and 4, KOL Working Group participants were asked to rank types of outcomes in terms of their utility in assessing functional status in teens and adults with SMA. Survey 3 results: \u003csup\u003e1\u003c/sup\u003eWrite-in responses: The Moore Scale (Moore Scale\u0026thinsp;=\u0026thinsp;EVOLVE-SMA [\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e]); respiratory function; access to needed equipment; time spent on medical/therapeutic interventions; if time for care interferes with other desired activities. Survey 4 results: \u003csup\u003e2\u003c/sup\u003eWrite-in responses: specific evaluations that assess ADLs and gross motor milestones; HFMSE, RULM scores, and 6MWT; patient reported measures of participation (school, work, community), social function; mouth opening; assessments which might be informative would be use/change of respiratory supports; changes in PT/OT status and need for additional supports (wheelchair, etc.); change in need for nutritional support; new surgeries (progressive scoliosis, etc.). \u003csup\u003e3\u003c/sup\u003eOther biomarker response: MUNE. Outcomes were given a value of 1 through 5 based on ranking, with the highest-ranked outcomes given a value of 5 and the lowest a value of 1. Therefore, the maximum possible score (max score) for each outcome was 5 times the number of respondents who ranked that outcome. ADLs\u0026thinsp;=\u0026thinsp;activities of daily living; 6MWT\u0026thinsp;=\u0026thinsp;Six Minute Walk Test; HFMSE\u0026thinsp;=\u0026thinsp;Hammersmith Functional Motor Scale Expanded; MUNE\u0026thinsp;=\u0026thinsp;motor unit number estimation; OT\u0026thinsp;=\u0026thinsp;occupational therapist; PT\u0026thinsp;=\u0026thinsp;physical therapist; RULM\u0026thinsp;=\u0026thinsp;Revised Upper Limb Module.\u003c/p\u003e \u003cp\u003eHaving determined that ADLs were potentially the most useful type of outcomes for assessing function in teens and adults with SMA, KOL Working Group participants discussed the most effective methods for gathering information on individuals\u0026rsquo; ability to perform these tasks. For both non-ambulatory and ambulatory individuals with SMA, a majority of group members agreed that information would be most clinically meaningful if it was reported by the patient or their caregiver, and if it described smaller tasks required for specific ADLs. (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003ea) A majority of KOL Working Group participants also indicated that questions about ADLs should be tailored to detect changes in function over time for both non-ambulatory and ambulatory teens and adults with SMA. (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003eb) In discussion, the group agreed that when asking teen and adult patients with SMA about ADLs, it would be important to note if the patient requires assistive technology, a specialized environment, or the assistance of another person to achieve the activity.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eFatigue and fatigability\u003c/h3\u003e\n\u003cp\u003eAs Phase 1 of the study progressed, KOL Working Group participants repeatedly remarked that fatigue and fatigability are major issues with non-ambulatory and ambulatory teens and adults with SMA, and that these phenomena are difficult to describe and measure. The working group discussed existing outcome measures of fatigue and fatigability, noting that none had been validated for SMA. The KOL Working Group concurred that ADLs could be utilized as outcomes to measure changes in fatigue and fatigability. A majority of KOL Working Group participants indicated that an ADL-based outcome measure should use a variety of questions when querying patients about changes in daily fatigue and fatigability. (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e3\u003c/span\u003ea) KOL Working Group participants noted that both non-ambulatory and ambulatory patients with SMA report a \u0026ldquo;refractory period\u0026rdquo; of fatigue after heavy exertion. When the group ranked methods of assessing this refractory period, a majority preferred measuring the amount of rest time needed after overexertion for both non-ambulatory and ambulatory patients with SMA. For non-ambulatory patients with SMA, a majority also favored comparing ADLs based on amount of rest time needed. (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e3\u003c/span\u003eb)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eDiscussion group questions\u003c/h2\u003e \u003cp\u003ePhase 1 results of this study yielded consensus among KOL Working Group participants that ADLs may be utilized as outcomes to assess both function, and fatigue and fatigability in non-ambulatory and ambulatory teens and adults with SMA. KOL Working Group participants agreed that gathering input from individuals with SMA was an essential next step in developing a core list of ADLs. Using Phase 1 data and feedback, Cure SMA developed the following questions around which to build discussion guides for the patient focus groups surveyed in Phase 2.\u003c/p\u003e \u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eIn addition to the sample ADL domains discussed by the KOL Working Group, would discussion group participants like any additional domains included in an outcome measure?\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eWhich ADLs would discussion group participants most like to have stabilized? e.g., \u0026ldquo;I want to make sure I have enough strength to continue to use the bathroom independently.\u0026rdquo;\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e What do discussion group participants feel would be the best way to show/tell their provider about their fatigue/changes in fatigue? e.g., \u0026ldquo;What do you wish your doctor knew about your fatigue?\u0026rdquo;\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePhase 2: Discussion Group\u003c/h2\u003e \u003cdiv id=\"Sec13\" class=\"Section3\"\u003e \u003ch2\u003eNon-ambulatory Discussion Group\u003c/h2\u003e \u003cdiv id=\"Sec14\" class=\"Section4\"\u003e \u003ch2\u003eActivities of Daily Living\u003c/h2\u003e \u003cp\u003eThe first objective of the Non-ambulatory Discussion Group was to obtain feedback from participants about which ADLs were most important to them. Non-ambulatory Discussion Group participants were asked to review a list of ADLs (Additional File 7) and indicate other ADLs of importance that were not included. Transitioning between indoors and outdoors, caring for and interacting with pets, and using one\u0026rsquo;s voice were noted as key ADLs by Non-ambulatory Discussion Group participants. Many aspects of voice use were discussed by the subgroup. Participants explained how, in addition to facilitating communication, their voices play important roles in using verbal command to operate items ranging from a light switch to a power wheelchair.\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eI do everything with my voice.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eAs the group discussed ADLs that were meaningful to them, the need to customize ADLs to the person being assessed became a major theme. Group participants noted that the abilities of adults to perform ADLs varies widely depending on age, stage of disease progression, and physical accommodations.\u003c/p\u003e \u003cp\u003eA second theme emerged as several group participants noted that many of the most important ADLs to them were those that fell beyond self-care and household chores and extended into work, relationships, hobbies, and other forms of self-expression.\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eI don\u0026rsquo;t see any work, I don\u0026rsquo;t see any recreation, I don\u0026rsquo;t see any going out in the community or anything like that. And to me that\u0026rsquo;s all more part of a day than all these things. All these things are part of everyday, but the list here sounds like we get dressed, we take a pill, we eat something and that\u0026rsquo;s all we do all day\u0026hellip;There\u0026rsquo;s a lot more in there with that.\u003c/p\u003e\u003cp\u003eFor me, what\u0026rsquo;s most important is art and music. I play instruments and do art, and so losing that would really affect my quality of life.\u003c/p\u003e\u003cp\u003eThis is kind of unusual, but it is important to me, and I kind of made it a category of its own called \u0026lsquo;emotional.\u0026rsquo; Like hugging people, I miss not being able to physically hug people. Physically interacting with people.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eThe group also concurred that abilities to perform ADLs can vary from day to day and are influenced by environmental factors like cold, which impacts fine motor skills.\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eDrawing/painting/3D printing. Tasks of repair and maintenance that might be simple for an able-bodied person\u0026mdash;some days I can do them and some days not.\u003c/p\u003e\u003cp\u003eAll those tasks are simple for an able-bodied person, but for someone with a disability\u0026mdash;sometimes I can do it on my own, and sometimes I need assistance, depending on my ability level that day.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eMany NGD participants had already lost abilities to do more routine ADLs independently and relied on help from others or assistive devices to perform self-care and household chores. As such, getting access to help from (family or paid) caregivers was itself an essential ADL.\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eAs long as the proper supports are there, it is probably what I fret about most, is losing my ton of support.\u003c/p\u003e\u003cp\u003eI think that\u0026rsquo;s really the key\u0026mdash;it\u0026rsquo;s caregivers and access to caregivers\u0026mdash;because we could make a list five times this length, but at the end of the day, as long as you have reliable caregivers and access to help a lot of these things don\u0026rsquo;t matter as much.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003e However, other Non-ambulatory Discussion Group participants considered needing assistance to complete an ADL an extra burden. One participant explained it was frustrating to have to wait for 5 to 30 minutes for help to arrive before they could accomplish a task.\u003c/p\u003e \u003cp\u003eA fourth theme that formed was the desire to maintain independence and dignity. Many of the ADLs that were most important to group participants fell into the domains of maintaining one\u0026rsquo;s own comfort, health, hygiene, and safety. One Non-ambulatory Discussion Group participant said that retaining the ability to make their own healthcare decisions was very important to them. Another said they feared losing the ability to breath on their own, because the loss would entail \u0026ldquo;so much more dependence and complications.\u0026rdquo;\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003e\u0026hellip;This is kind of embarrassing, but crying, being able to wipe your own face and blow your nose, it\u0026rsquo;s embarrassing, but it\u0026rsquo;s important.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003e The group was then asked by the moderator, \u0026ldquo;How hard or easy do you think it would be to measure your overall health status based on your ability to perform ADLs over the course of time?\u0026rdquo; Non-ambulatory Discussion Group participants agreed that changes in ability to perform ADLs were more likely to reflect changes in function than in overall health status. Several participants explained that they thought of their overall health status as independent from SMA.\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eIt all goes back to how we see ourselves as normal. From the perspective of medical professionals, we are unhealthy.\u0026rdquo; They continued, \u0026ldquo;\u0026ldquo;What do you mean by healthy? Because, we don\u0026rsquo;t think we\u0026rsquo;re not healthy. We\u0026rsquo;ve embraced our disability.\u003c/p\u003e\u003cp\u003eJust because I can\u0026rsquo;t feed myself anymore, I don\u0026rsquo;t think I\u0026rsquo;m less healthy. .. Being able to type on a keyboard, I don\u0026rsquo;t see that as a measure of my health.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eNon-ambulatory Discussion Group participants added that although abilities will vary day to day, these variations may not reflect a change in overall health status.\u003c/p\u003e \u003cp\u003e Non-ambulatory Discussion Group participants were shown an example of the type of scale that may be used in a questionnaire asking about ADLs. The scale included the following rating options: Unable \u0026ndash; can\u0026rsquo;t do, doesn\u0026rsquo;t know how, or is too young; Hard \u0026ndash; does with a lot of help, extra time or effort; A little hard \u0026ndash; does with a little help, extra time, or effort; and Easy \u0026ndash; does with not help, extra time or effort, or a person\u0026rsquo;s skills are past this level. The moderator asked, \u0026ldquo;If you are asked to rate your ability to perform various ADLs using a scale like this, would you find it easier to rate the broad domain like \u0026lsquo;feeding oneself\u0026rsquo; or would you want to be able to break that task into different parts?\u0026rdquo; The majority agreed that asking detailed questions in which ADLs had been broken down into smaller tasks would likely produce more accurate answers because people with SMA have different adaptive strategies.\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eWe can do a lot of this stuff but will probably do it a little differently. For example, feeding ourselves, you know, some of us can pick it up and just go for it, others may have to hold the fork a different way, or you know, use a different utensil, use both arms\u0026mdash;so I think breaking it up would be the way to go.\u003c/p\u003e\u003cp\u003eYou can make a phone call, but can you get a phone? That\u0026rsquo;s why being specific is important.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003e A third group participant noted that breaking ADLs into smaller tasks would clarify whether the respondent was able to perform the ADL independently or required assistance. They extrapolated,\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eWhen I hear these questions coming from a perspective, like a medical research perspective, I assume they want to know, can I do these things myself? And the answer to that is, \u0026lsquo;No.\u0026rsquo; But can I do them? Well, yes, I do them every day, with peoples\u0026rsquo; help. So, the way I judge it is, \u0026lsquo;Can you do it with someone\u0026rsquo;s help?\u0026rsquo; And I would answer, \u0026lsquo;Yes.\u0026rsquo; But I would think I would give you a wrong idea of what I can do.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eHowever, one group participant thought that broader ADLs domains would be easier to rate. They explained,\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eMy life is pretty defined by what I can do by myself and what I can\u0026rsquo;t do by myself, so this makes it a little easier to kind of categorize it in my brain.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of feedback from Non-ambulatory Discussion Group participants*\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTopic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMajor theme\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSubtheme\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eADLs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eADLs should be customized to the individual.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePeople with SMA have different ranges of abilities.\u003c/p\u003e \u003cp\u003ePeople with SMA have different lifestyles and priorities.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eADLs should encompass activities beyond self-care and household chores.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWork, hobbies, relationships, and interacting with the community are all important domains.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbilities to perform ADLs can vary from day to day and in different situations.\u003c/p\u003e \u003cp\u003ePreserving abilities to perform ADLs that enable independence and dignity is critical.\u003c/p\u003e \u003cp\u003eADLs should be utilized to assess a person\u0026rsquo;s functional status rather than overall health.\u003c/p\u003e \u003cp\u003eADL assessments should ask detailed questions.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAbilities to perform ADLs may sometimes depend on assistive devices, environmental adaptations, or help from a family member or caregiver.\u003c/p\u003e \u003cp\u003eMaintaining one\u0026rsquo;s own comfort, health, hygiene, and safety are key to preserving independence and dignity.\u003c/p\u003e \u003cp\u003eSome people with SMA may think of their overall health as separate from SMA.\u003c/p\u003e \u003cp\u003eSome people with SMA may consider themselves disabled but not unhealthy.\u003c/p\u003e \u003cp\u003ePeople with SMA may have different ways of accomplishing the same task, which would be revealed by more detailed questions.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFatigue and Its Impact on ADLs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFatigue is a major factor of daily life.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFatigue reduces abilities to perform ADLs.\u003c/p\u003e \u003cp\u003eFatigue impacts relationships and social lives.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFatigue levels fluctuate.\u003c/p\u003e \u003cp\u003ePhysical, cognitive/intellectual, and emotional/social fatigue are intertwined.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePatterns of fatigue generally correlate with levels of exertion.\u003c/p\u003e \u003cp\u003eFatigue fluctuates in patterns that are unique to the individual.\u003c/p\u003e \u003cp\u003eDepression and pain can increase fatigue.\u003c/p\u003e \u003cp\u003eEnvironmental conditions like cold can increase fatigue.\u003c/p\u003e \u003cp\u003eFor some patients, treatment seems to have reduced fatigue or improved recovery from fatigue.\u003c/p\u003e \u003cp\u003ePhysical fatigue has a greater impact but affects interest in and ability to interact socially and with the environment.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWhether or not one talks to one\u0026rsquo;s doctor about fatigue depends on the doctor and the patient.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAll three types of fatigue affect abilities to perform ADLs.\u003c/p\u003e \u003cp\u003eSome people with SMA may not consider their doctor to be an expert in fatigue.\u003c/p\u003e \u003cp\u003eSome people with SMA initiate conversations about fatigue with their doctors to get medical help with or advice about managing fatigue.\u003c/p\u003e \u003cp\u003eThe topic of fatigue sometimes comes up naturally during a visit to the doctor.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eADLs\u0026thinsp;=\u0026thinsp;activities of daily living; *n\u0026thinsp;=\u0026thinsp;6\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003cem\u003eImpact of fatigue and fatigability on ADLs\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe second objective of the Non-ambulatory Discussion Group was to gather input from non-ambulatory adults with SMA about how fatigue and fatigability affect their abilities to perform ADLs. (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) On a scale of 1\u0026ndash;5 (1 = \u0026ldquo;hardly ever\u0026rdquo; and 5 = \u0026ldquo;all the time\u0026rdquo;), participants were asked to indicate the degree to which fatigue is present in their everyday lives. (All but one participant indicated that fatigue is an element of daily life.) Of the six Non-ambulatory Discussion Group participants, two answered \u0026ldquo;5,\u0026rdquo; one answered \u0026ldquo;4,\u0026rdquo; two answered \u0026ldquo;3,\u0026rdquo; and one selected \u0026ldquo;NA.\u0026rdquo; Participants were then asked, if their fatigue level fluctuates during the day and if they identified a pattern. There was a general theme among responses that fatigue levels do follow a pattern; however, the pattern varied between people. One participant remarked that their energy was typically highest in the morning and throughout the day. Another mentioned that their fatigue varied throughout the day and week, but that they \u0026ldquo;bounced back\u0026rdquo; from fatigue more quickly since being on treatment. A third participant remarked that the weather greatly impacted their fatigue because they have a fused spine, and their pain increases in cold weather, which in turn increases their fatigue. They explained that depression also notably increases their fatigue, and that their fatigue decreases when the depression is successfully treated. Several other participants agreed that weather also affects their fatigue levels. One participant explained that as they have gotten older and lost function, their fatigue patterns have become very predictable: the busier their day, the more fatigue they experience.\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eBut, 20 years ago, I experienced nothing even close to what I have now\u0026hellip;I dread when people ask me to do anything past 5 o\u0026rsquo;clock because if they don\u0026rsquo;t have SMA, it\u0026rsquo;s embarrassing to tell them, \u0026lsquo;I\u0026rsquo;m just too tired.\u0026rsquo; I almost am so fatigued that I hurt. It\u0026rsquo;s almost like a pain, because it is so significant.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eNon-ambulatory Discussion Group participants were then asked which type of fatigue \u0026ndash; physical, cognitive/intellectual, or emotional/social \u0026ndash; is most troublesome. The majority ranked physical fatigue as having the greatest affect, but the group agreed that the different types are intertwined.\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eSometimes my friendships kind of fall to the wayside because I\u0026rsquo;m just interacting with people all day, and asking for help, it physically and emotionally is exhausting.\u003c/p\u003e\u003cp\u003eIf I didn\u0026rsquo;t have the physical fatigue, I would not have the social fatigue.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eA third Non-ambulatory Discussion Group participant explained that it would be important for healthcare providers to be specific when inquiring about how fatigue affects ADLs, because although their emotional fatigue affects their abilities to perform ADLs, it was likely caused by depression rather than SMA.\u003c/p\u003e \u003cp\u003eNext, participants were asked, \u0026ldquo;How many of you have had the experience of talking either to your primary care doctor or specialist about fatigue?\u0026rdquo; The group reported mixed experiences.\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eI thought [the question] was funny. I\u0026rsquo;ve never had a conversation with my doctor about fatigue. I guess I just think it comes with the territory and what can they do about it?\u003c/p\u003e\u003cp\u003eIf I were to feel the need to discuss [fatigue], probably one of the last people I would feel the need to discuss it with would be my doctor.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eThis participant explained that he liked his doctor but wouldn\u0026rsquo;t think of his doctor as being an expert on fatigue. However, a third participant had the opposite perspective:\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eI have a lot of different doctors, and I\u0026rsquo;ve talked to pretty much all of them about fatigue\u0026hellip;Because in some way or another, it affects every specialty doctor that I see, for whatever reason that I see them.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eSimilarly, another participant described a productive experience they had talking with their doctor about fatigue when they began working full-time. They had received many physical accommodations at their new workplace, but they had not been given a long enough lunch break:\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eI was getting tired having to feed myself and rush eating during the 30 minutes. Plus, I didn\u0026rsquo;t have any downtime. .. I don\u0026rsquo;t think they realized that was also a physical activity.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eIn addition to providing an accommodation letter, the participant\u0026rsquo;s doctor also discussed strategies for managing workplace fatigue to alleviate the need for reduced hours. Through referral to specialists, the participant was able to get both medical help and practical advice that improved their workday fatigue.\u003c/p\u003e \u003cp\u003eDuring the discussion session, participants were asked, \u0026ldquo;What do you wish your doctor understood about the fatigue experience?\u0026rdquo; Although there were no immediate responses, one participant said:\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003e\u0026hellip;The fatigue is just so, it\u0026rsquo;s so debilitating for me, and it\u0026rsquo;s become that way more and more as I get older. And maybe part of that\u0026rsquo;s from, like, menopause, and that kind of thing but. .. it\u0026rsquo;s so terrible and devastating for me that it\u0026rsquo;s not so much what can I accomplish, but it\u0026rsquo;s how fatigue plays into that and. .. how it limits me.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eAmbulatory Discussion Group Results\u003c/h2\u003e \u003cdiv id=\"Sec16\" class=\"Section3\"\u003e \u003ch2\u003eActivities of Daily Living\u003c/h2\u003e \u003cp\u003e The first objective of the Ambulatory Discussion Group was to gather input from participants about which abilities to perform ADLs were most important to them to maintain. (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e) Ambulatory Discussion Group participants were asked to review a list of ADLs (Additional File 7) and indicate other ADLs of importance that were not included. Picking things up off the floor, emptying the dishwasher, using the toilet away from home, and running errands were noted as key ADLs by Ambulatory Discussion Group participants. Ambulatory Discussion Group participants also shared strategies and tools\u0026mdash;like shower chairs, toilet doughnuts, and pinchers\u0026mdash;they used to accomplish ADLs as motor abilities waned. Adaptation became a theme throughout the conversation. The group was asked which ADLs they were most concerned about retaining the ability to perform. ADLs related to maintaining independence and preserving dignity\u0026mdash;such as driving, feeding oneself, and taking care of one\u0026rsquo;s own hygiene and appearance\u0026mdash;were of importance.\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eTo go wherever you want, whenever you want, and then the day that you know you can't. It's just, it, this disease, has robbed, robbed me. You know, I feel like, \u0026lsquo;Give me my life back.\u0026rsquo;\u003c/p\u003e\u003cp\u003eI think the shower, showering, bathing, toileting, you know, keeping clean, maintaining your appearance is probably on the top of the list for most of us. It'd be difficult to be at somebody else's mercy.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eTwo Ambulatory Discussion Group participants had siblings with SMA, and the participants had watched their siblings lose abilities to perform ADLs related to preserving independence and dignity. These participants expressed concern about becoming similarly dependent on others.\u003c/p\u003e \u003cp\u003eNavigating new environments and environmental hazards inside and outside the home was also a theme of the discussion. Fear of falling, which could lead to a debilitating injury, was prominent for several of the participants.\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eIt's not on the list, but one thing that I see in daily living for me is the fear of falling. I live in fear of falling, because if I fall, I can break a hip\u0026hellip; So, I might be overboard in it, but I look at every little thing. I'm always looking down for an acorn, a pebble, anything that's uneven\u0026mdash;a slight little thing that can cause you to fall. It's starting to rule my life.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eThe participant went on to explain that they were careful to choose certain types of footwear and were selective about the type of chair they sat in to decrease their likelihood of falling.\u003c/p\u003e \u003cp\u003e Ambulatory Discussion Group participants were then asked, \u0026ldquo;How hard or easy do you think it would be to measure your overall health status based on your ability to perform ADLs over the course of time?\u0026rdquo; The moderator added that Non-ambulatory Discussion Group participants had shared that they often adapted methods of completing tasks to compensate for loss of function. One participant noted they own multiple identical assistive tools, such as \u0026ldquo;grabbers,\u0026rdquo; so that they can keep one in each room of the house. The same participant said that among other household adaptations, they had replaced their heavy dishware with lighter plates and cups.\u003c/p\u003e \u003cp\u003e \u003cem\u003e\u0026ldquo;We figure out a way to do it, but we do things differently or we find things that work great for us.\u0026rdquo;\u003c/em\u003e \u003c/p\u003e \u003cp\u003eAnother participant concurred, giving the example of having learned to break down the task of unloading the dishwasher into several discrete steps as she has lost muscle strength, rather than transferring dishes directly from the washer to the shelf. A third Ambulatory Discussion Group participant said,\u003c/p\u003e \u003cp\u003e\u0026ldquo;\u003cem\u003eI look back over my life, and the whole thing is like an adaptation. Even before I knew I had SMA, I had different ways than other people of doing things because I had weakness\u0026hellip;. doing things over my head and things like that. And you just adapt here and adapt there and you figure out all these little cheats, so to speak. When they diagnosed me, I looked back and I thought, \u0026lsquo;Oh my gosh, now I know why everybody else does it like this. And I do it [like that].\u0026rsquo;\u0026rdquo;\u003c/em\u003e\u003c/p\u003e \u003cp\u003eThe Ambulatory Discussion Group were then shown an example of a ranking scale that comprised the following choices: Unable \u0026ndash; can\u0026rsquo;t do, doesn\u0026rsquo;t know how, or is too young; Hard \u0026ndash; does with a lot of help, extra time or effort; A little hard \u0026ndash; does with a little help, extra time, or effort; and Easy \u0026ndash; does with not help, extra time or effort, or a person\u0026rsquo;s skills are past this level. The moderator asked, \u0026ldquo;If you are asked to rate your ability to perform various ADLs using a scale like this, would you find it easier to rate the broad domain like \u0026lsquo;feeding oneself,\u0026rsquo; or would you want to be able to break the task into different parts?\u0026rdquo; Participants agreed that tasks broken down into smaller parts would be more likely to detect adaptations to accomplish ADLs as functional status changed.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of feedback from Ambulatory Discussion Group participants*\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTopic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMajor theme\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSubtheme\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eADLs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMaintaining independence and preserving dignity are of the upmost importance.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePreserving abilities to perform activities like driving and toileting is very important.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdaptation is a key strategy for coping with loss of function.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAs function declines, some tasks can still be performed but require different strategies, specific assistive tools, or help from others to accomplish.\u003c/p\u003e \u003cp\u003eADLs need to be detailed enough to detect adaptations that had occurred because of functional decline.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEnvironmental conditions impact abilities to perform ADLs.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNew environments with unknown accommodations and hazards are stressful.\u003c/p\u003e \u003cp\u003eFalling inside and outside the home is a major concern\u0026mdash;furniture, ice, uneven surfaces, and crowds are all potential threats to stability.\u003c/p\u003e \u003cp\u003eInclement weather reduces ability and willingness to participate in activities outside the home.\u003c/p\u003e \u003cp\u003eCold weather can also negatively affect mobility/dexterity and increase pain.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFatigue and Its Impact on ADLs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSome ADLs are related to caring for others.\u003c/p\u003e \u003cp\u003eFatigue is an aspect of daily life.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eParents with SMA must adapt to perform parenting ADLs.\u003c/p\u003e \u003cp\u003eCooking for others as well as oneself may be an ADL for some people with SMA.\u003c/p\u003e \u003cp\u003eFatigue levels are variable throughout the day.\u003c/p\u003e \u003cp\u003ePatterns of fatigue vary between participants.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePhysical fatigue is the most prominent type.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePhysical fatigue has the greatest impact on ADLs and can precipitate cognitive/intellectual and emotional/social fatigue.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEnvironmental stressors like cold weather, wind, and obstacles can affect both physical and emotional/social fatigue.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHealthcare professionals generally do not recognize that fatigue is a component of SMA.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHealthcare professionals may be unfamiliar with SMA and attribute fatigue to other causes.\u003c/p\u003e \u003cp\u003eEven an SMA specialist may have a hard time appreciating the nature and level of a patient\u0026rsquo;s fatigue.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eADLs\u0026thinsp;=\u0026thinsp;activities of daily living; *n\u0026thinsp;=\u0026thinsp;4\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eImpact of fatigue and fatigability on ADLs\u003c/h2\u003e \u003cp\u003eThe second objective of the discussion was to gather input from ambulatory adults with SMA about how fatigue affected their abilities to perform ADLs. (Table\u0026nbsp;6) On a scale of 1\u0026ndash;5 (1 = \u0026ldquo;hardly ever\u0026rdquo; and 5 = \u0026ldquo;all the time.\u0026rdquo;), Ambulatory Discussion Group participants were asked to indicate the degree to which fatigue is present in their everyday lives. Two participants answered \u0026ldquo;5,\u0026rdquo; and two answered \u0026ldquo;NA.\u0026rdquo; Upon further discussion, it became clear that fatigue was a factor for each participant but presented in different forms and patterns for each individual. Whereas one participant felt very energized in the morning but \u0026ldquo;crashed\u0026rdquo; after their midday meal, another felt notable, painful fatigue throughout each day. A third participant\u0026rsquo;s fatigue fluctuated daily depending on sleep quality and the needs of their daughter. The fourth participant felt less fatigue in the afternoon than in the morning. Ambulatory Discussion Group participants were asked which of the following types of fatigue were most troublesome: physical, cognitive/intellectual, or emotional/social. Participants unanimously agreed that physical fatigue was the most troublesome. However, there was also discussion about how physical fatigue could precipitate emotional/social fatigue. One participant explained,\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eI feel like my emotional and social fatigue is based off of my physical fatigue. If I'm tired, then it's, physical. I don't want to go and have to worry about somewhere not being accessible or being in a social situation and being down here when everybody's up here\u0026mdash;because I use my electric wheelchair most of the time.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eWhen participants were asked if fatigue was something they talked to their doctors about, responses varied widely. One participant said they talked to all their doctors about fatigue and received different responses depending on the doctor. Another participant was evaluated for depression when they told their doctor they were experiencing fatigue. A third participant said that although their doctor is a specialist in SMA and will address fatigue by doing bloodwork and looking for ways to support them, they still hesitate to bring up the topic.\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eI think sometimes it's hard. I don't know if other people feel this way, but all my doctors at the neurology clinic, none of them have SMA, right? So sometimes it's hard. It's like, \u0026lsquo;Do I even attempt to explain? Because they're not going to understand it. .. So sometimes it's like, \u0026lsquo;Is it even worth the effort to describe it or to communicate it? Because I don't think it's ever going to be fully understood.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eThe moderator asked Ambulatory Discussion Group participants what they wished their doctor understood about the fatigue experience. Respondents broadly indicated they wished their doctor knew more about SMA since the lack of familiarity impacts perceived ability to adequately care for SMA-related needs, and the physician\u0026rsquo;s ability to take the limitations of the disease into account when addressing needs unrelated to SMA. One participant noted their concerns are often attributed to their age, or even to menopause. Another participant remarked that their doctor had taken the time to educate himself about SMA:\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eI think the main thing is that when you do go to a doctor that they at least take the time to get the basic knowledge of [SMA]\u0026hellip;. to help us live our lives the best that we can. So, I guess it's education, just educate themselves a little bit more.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eAmbulatory Discussion Group participants were invited to share other factors that increased fatigue. Inclement weather, pain, and poor sleep quality were again mentioned as contributing factors. Conversely, one participant noted that treatment seemed to temporarily reduce their fatigue.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eAs more therapeutic options become accessible to teens and adults with SMA [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e], it is important to establish a standardized set of core outcomes to measure disease progression and treatment response. Efforts to standardize outcome measures for teens and adults with SMA are underway in Canada and throughout Europe [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan additionalcitationids=\"CR64 CR65 CR66\" citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e], but a core set of outcome measures has not yet been defined in the U.S. In the present study, we surveyed a working group of key opinion leaders in clinical research and care, as well as two discussion groups comprised of non-ambulatory adults or ambulatory adults with SMA, for their perspectives on what type of outcomes could capture disease status and treatment effects in a manner that is meaningful both clinically and to the individual. The study objective was to begin to build consensus toward a standardized set of outcome measures for teens and adults with SMA.\u003c/p\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eActivities of daily living (ADLs)\u003c/h2\u003e \u003cp\u003eThe KOL Working Group reached consensus that ADLs are the best type of outcome to detect clinically relevant functional changes in teens and adults with SMA. KOL Working Group participants ranked ADLs that facilitate personal autonomy as most meaningful, and discussion group participants concurred that ADLs related to dignity and independence are of the upmost importance to maintain. The KOL Working Group and discussion groups also agreed that when used as outcomes, ADLs should be small, specific tasks selected to detect subtle changes in function that affect individuals\u0026rsquo; unique lifestyles. Thus far, U.S. research studies assessing SMA disease progression or treatment effects in teens and adults have utilized predominantly CROMs such as the Hammersmith Functional Motor Scale Expanded (HFMSE), the 32-item Motor Function Measure (MFM32), the Revised Upper Limb Module (RULM), the 6 Minute Walk Test (6MWT); and the 10 Meter Walk/Run Test (10MWRT) [\u003cspan additionalcitationids=\"CR69 CR70 CR71\" citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e]. A few studies have also included PROMs [\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e, \u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e], and several groups are actively developing novel CROMs [\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e] and PROMs [\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e], some of which were unpublished at the time of this writing. Whereas clinician-reported measures are utilized, by definition, in a clinical setting, PROMs have the potential to detect functional changes that are impactful to people with SMA as they go about their everyday lives. PROMs based on abilities to perform ADLs are commonly employed to assess disease status in adults with other neuromuscular diseases such as multiple sclerosis (MS) [\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e], amyotrophic lateral sclerosis (ALS) [\u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e], and myasthenia gravis (MG) [\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e]. Since the present study was completed, several studies have also investigated the use of ADLs as outcomes to track disease progression and treatment response in teens and adults with SMA. For example, Sadjadi et al. (2023) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] evaluated the modified Spinal Muscular Atrophy Functional Rating Scale (SMAFRS) as an ADL-based outcome measure for non-ambulatory and ambulatory adults, and Slayter et al. (2023) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] included the SMAFRS in their eight-measure toolkit created to assess disease progression in adults. In addition, the Spinal Muscular Atrophy Independence Scale Upper Limb Module (SMAIS-ULM) has recently been developed as an ADL-based PROM for individuals who are 12 years of age or older, and for caregivers of children who are older than 2 years of age. [\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e] Finally, Lefton-Greif et al (2025) [\u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e] developed and partially validated a scale for bulbar function assessment in adults with SMA based in part on ADLs such as completing meals, swallowing pills, and communicating with family members. These studies demonstrate a trend in using outcome measures comprised of ADLs in assessing disease status and treatment response in teens and adults with SMA.\u003c/p\u003e \u003cp\u003eIn Phase 1 of the study, the KOL Working Group did note that an outcome measure consisting of ADLs might be most powerful when combined with a clinical measure such as a biomarker. While recent research has found that molecular biomarkers reflecting neurodegeneration are not as useful in teens and adults with SMA as they are in children [\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e, \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e, \u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e], electrophysiological outcome measures such as compound muscle action potential (CMAP) show promise as biomarkers in teens and adults with SMA [\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e, \u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e, \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e, \u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e, \u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e]. Indeed, when asked to rank which type of outcome measure would best capture disease state in teens and adults with SMA, KOL Working Group participants ranked CMAP and ADLs as equally useful.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eFatigue and fatigability\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eSeveral clinician-reported, performance-based outcome measures have been utilized to assess performance fatigue and fatigability in teens and adults with SMA. For example, the 6MWT [\u003cspan additionalcitationids=\"CR86 CR87 CR88\" citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e] has been the gold standard for quantifying lower limb performance fatigue and fatigability in ambulatory individuals with SMA [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e, \u003cspan additionalcitationids=\"CR91 CR92\" citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR93\" class=\"CitationRef\"\u003e93\u003c/span\u003e]. The Endurance Shuttle Nine Hole Peg Test (ESNHPT) has been used for distal arm and hand performance fatigue and fatigability, and the Endurance Shuttle Box and Block Test (ESBBT) has been utilized to assess upper arm performance fatigue and fatigability. [\u003cspan additionalcitationids=\"CR95\" citationid=\"CR94\" class=\"CitationRef\"\u003e94\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR96\" class=\"CitationRef\"\u003e96\u003c/span\u003e] These and other clinician-reported, performance-based outcome measures of fatigue and fatigability are advantageous in that they are objective. However, they have several limitations. First, they measure the ability to perform specific tasks, and these tasks may not be varied or sensitive enough to reveal subtle but important changes in fatigue that affect overall quality of life. [\u003cspan citationid=\"CR97\" class=\"CitationRef\"\u003e97\u003c/span\u003e] Second, people with very severe forms of SMA may not be able to complete standard performance-based tests, creating floor effects. [\u003cspan citationid=\"CR98\" class=\"CitationRef\"\u003e98\u003c/span\u003e, \u003cspan citationid=\"CR99\" class=\"CitationRef\"\u003e99\u003c/span\u003e] Similarly, ceiling effects on existing performance-based assessments will likely become more salient as more people with SMA receive DMTs and other treatments, diversifying and broadening the natural history of the disease. Third, performance-based fatigue and fatigability assessments are a snapshot of performance in a clinic at a specific time point and are subject to variations based on recent activity and other variables. Finally, results from clinician-reported, performance-based outcome measures tend to correlate with disease severity and with results from functional assessments like the RULM and HFMSE. [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR100\" class=\"CitationRef\"\u003e100\u003c/span\u003e, \u003cspan citationid=\"CR101\" class=\"CitationRef\"\u003e101\u003c/span\u003e] In contrast, results from performance fatigue and fatigability assessments have generally \u003cem\u003enot\u003c/em\u003e correlated with levels of \u003cem\u003eperceived\u003c/em\u003e fatigue assessed within the same studies. That is, improvements in performance fatigue do not correlate with improvements in perceived fatigue when the two are measured side-by-side. [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR97\" class=\"CitationRef\"\u003e97\u003c/span\u003e, \u003cspan citationid=\"CR100\" class=\"CitationRef\"\u003e100\u003c/span\u003e] Furthermore, levels of perceived fatigue generally do not correlate with either disease severity or motor function. [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR102\" class=\"CitationRef\"\u003e102\u003c/span\u003e] These findings support the idea that performance fatigue/fatigability and perceived fatigue/fatigability are separate, albeit interrelated, phenomena, and that perceived fatigue/fatigability are better assessed by separate, PROMs.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003eKOL Working Group and discussion group participants agreed that fatigue and fatigability are components of everyday life that affect abilities to perform ADLs. Despite this agreement, participants in both discussion groups reported that most healthcare professionals do not recognize the significance of fatigue and fatigability in the context of SMA. This communication gap may in part result from the fact that a PROM for fatigue and fatigability in SMA has not yet been validated. Myriad PROMs have been used to assess perceived fatigue in teens and adults with SMA, such as the Fatigue Severity Scale (FSS) [\u003cspan citationid=\"CR91\" class=\"CitationRef\"\u003e91\u003c/span\u003e, \u003cspan citationid=\"CR103\" class=\"CitationRef\"\u003e103\u003c/span\u003e], the Pediatric Quality of Life Multidimensional Fatigue Scale (PedsQL MFS) [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e], the Multi-Dimensional Fatigue Inventory (MFI) [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e], and the Spinal Muscular Atrophy Health Index (SMA-HI) sleep and fatigue modules [\u003cspan citationid=\"CR104\" class=\"CitationRef\"\u003e104\u003c/span\u003e]. These instruments query individuals about perceived levels of fatigue and fatigability experienced over durations ranging from the past week to the prior month. However, more recent research [\u003cspan citationid=\"CR105\" class=\"CitationRef\"\u003e105\u003c/span\u003e] has validated the use of a fatigue and fatigability scale comprised of ADLs. This new questionnaire, the PROfuture, was developed in Spain for people with SMA who are older than 14 years of age. Furthermore, Rodriguez-Torres et al. (2025) [\u003cspan citationid=\"CR106\" class=\"CitationRef\"\u003e106\u003c/span\u003e] recently developed a novel PROM, the SMA EFFORT, for evaluating perceived physical fatigue in teens and adults across four categories: 1) exercise/recreation, 2) mobility, 3) ADLs, and 4) postural control. The new developments support the idea that ADLs can serve as outcomes for a standardized measure of fatigue and fatigability in teens and adults with SMA living in the U.S.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eInput from the KOL Working Group represented perspectives from experts in SMA research and clinical care. Primary care physicians, physical therapists, neurologists, and other clinical care providers who are not as familiar with SMA may have contributed unique and valuable viewpoints to the study. Similarly, the non-ambulatory and ambulatory discussion groups were small and represented a limited range of demographics. In particular, the discussion groups did not include teen participants owing to lack of response during recruitment. Although limited by sample size, this study can serve as a starting point for a broader discussion on how to develop a core set of outcome measures for function, fatigue, and fatigability in teens and adults with SMA in the U.S.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe findings of this study provide insight into which type of outcomes are meaningful to SMA researchers and clinicians, as well as adults with SMA, when assessing function, fatigue, and fatigability. The working group and discussion groups agreed that PROMs based on ADLs may be most effective at detecting changes in disease progression, motor function, and fatigue and fatiguability that impact abilities to perform everyday tasks that matter most to people with SMA. The groups also concurred that ADLs which impact one\u0026rsquo;s independence and dignity are of the highest priority to maintain and monitor. Furthermore, the working group and discussion groups each acknowledged that fatigue and fatigability are major aspects of daily life that affect abilities to perform ADLs, but that there is currently no effective way to measure or communicate about fatigue and fatigability. Critical treatment needs remain unmet within the SMA community, particularly among teens and adults with SMA who do not receive DMT until later in disease progression. As novel treatment options and protocols become available for these populations, a standardized core set of outcome measures will be required to assess disease status and treatment response. These results may form a foundation for the development of core outcome measures for function and fatigue in teens and adults with SMA.\u003c/p\u003e"},{"header":"Declarations","content":" \u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003ePrior to initiation, WIRB-Copernicus Group Institutional Review Board (WCG IRB) reviewed and approved the study (IRB Tracking Number: 20226344). All respondents were informed via the informed consent document that findings may be published. Only de-identified results are included within the manuscript. All procedures performed involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eCompeting Interests\u003c/h2\u003e \u003cp\u003eNone of the authors have competing interests to declare.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThe authors acknowledge the Cure SMA Industry Collaboration (SMA-IC) for funding support to conduct this research study and pay the journal\u0026rsquo;s Rapid Service Fee. The SMA-IC was established in 2016 to leverage the experience, expertise, and resources of pharmaceutical and biotechnology companies, as well as other nonprofit organizations involved in the development of SMA therapeutics to more effectively address a range of scientific, clinical, and regulatory challenges. Current members include Cure SMA Biogen, Novartis, Scholar Rock, Genentech/Roche Pharmaceuticals, NMD Pharma, and SMA Europe. Funding for this research was provided by the 2021 SMA-IC which included Novartis Gene Therapies, Biogen, Genentech/Roche, and Scholar Rock.\u003c/p\u003e\u003ch2\u003eAuthor contributions\u003c/h2\u003e \u003cp\u003eJG, MAC, LTB, and MMB played key roles in the conception and design of the study. JG, MAC, and LTB were involved in the acquisition and analysis of data. JJT drafted the manuscript; JG, MAC, LTB, and MMB provided gave critical feedback during manuscript development.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eThe authors would like to thank Discussion Group participants for generously giving their time and insight during Phase 2 of this study. The authors would also like to thank the following key opinion leaders for donating their time and expertise as Working Group participants in Phase 1 of the study: Imran Tanvir (Genentech), Robert Goldstein (formerly with Biogen), Sandra Reyna (Novartis Gene Therapies), Nily Osman (formerly with Scholar Rock), Nicole Gusset (SMA Europe), Bakri Elsheikh (The Ohio State University), Richard Shell (Nationwide Children\u0026rsquo;s Hospital), Maureen Lefton-Greif (Johns Hopkins Medicine), Katlyn McGrattan (University of Minnesota), Lindsay Alfano (The Ohio State University), Hank Mayer (Children\u0026rsquo;s Hospital of Philadelphia), and Thomas Crawford (Johns Hopkins Medicine). Finally, the authors would like to thank Leslie Nelson (University of Texas Southwestern Medical Center) and Meghan Moore Burk (Children\u0026rsquo;s Hospital Colorado) for their contributions as consultants on study design.\u003c/p\u003e\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e \u003cp\u003eAll data generated or analysed during this study are included in this published article and its supplementary information files.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBach JR, Baird JS, Plosky D, Navado J, Weaver B. Spinal muscular atrophy type 1: Management and outcomes. Pediatr Pulmonol. 2002;34(1):16\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBorkowska J, Rudnik-Schoneborn S, Hausmanowa-Petrusewicz I, Zerres K. Early infantile form of spinal muscular atrophy (werdnig-hoffmann disease) with prolonged survival. 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J Neuromuscul Dis. 2019;6(4):453\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBelter L, Peterson I, Jarecki J. Evaluating perceived fatigue within an adult spinal muscular atrophy population. Neurol Ther. 2023;12(6):2161\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMattsson M, M\u0026ouml;ller B, Lundberg I, Gard G, Bostr\u0026ouml;m C. Reliability and validity of the fatigue severity scale in swedish for patients with systemic lupus erythematosus. Scand J Rheumatol. 2008;37(4):269\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMazzella A, Cruz R, Belter L et al. Assessing perspectives of disease burden and clinically meaningful changes using the spinal muscular atrophy health index in adolescents and young adults. Muscle Nerve. 2022.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDomine MCCM, de Lemus M, Castellano IP, \u0026Ntilde;ungo-Garz\u0026oacute;n NC, Sevilla-Mantec\u0026oacute;n T, V\u0026aacute;zquez-Costa JF. Physical fatigue and perceived fatigability in adolescents and adults with spinal muscular atrophy: A pilot study. Neurol Perspect. 2022;2(4):199\u0026ndash;208.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRodriguez-Torres R, Kanner CH, Gay EL, et al. Development of the SMA EFFORT: A new approach to characterize perceived physical fatigability in spinal muscular atrophy. J Neuromuscul Dis. 2025;12(1):22143602241313326.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"activities of daily living, ADLs, clinician-reported outcome measure, CROM, fatigue, fatigability, patient-reported outcome measure, PROM, spinal muscular atrophy, SMA","lastPublishedDoi":"10.21203/rs.3.rs-6917745/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6917745/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Spinal muscular atrophy (SMA) is a neuromuscular disease caused by mutations in the survival motor neuron gene, \u003cem\u003eSMN1\u003c/em\u003e. Loss of \u003cem\u003eSMN1 \u003c/em\u003efunction results in deficiency of the SMN protein leading to motor neuron death, muscle wasting, and progressive loss of motor function. Two disease modifying therapies have been approved for teens and adults in the United States, with many more potential treatments in the drug development pipeline. As treatment options for teens and adults with SMA increase, a validated core set of outcome measures is needed to assess motor function, fatigue, and fatigability. The aim of this study was to determine which type of outcome measures best captures changes in disease status in teens and adults with SMA.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e In the first phase of this two-part study, a working group of key opinion leaders in SMA research and clinical care was surveyed using a modified Delphi method. The working group concluded that a patient-reported outcome measure based on activities of daily living (ADLs) would be the best way to capture changes in function, fatigue, and fatigability that are meaningful to both clinicians and teens and adults living with SMA. In the second phase of the study, two discussion groups of adults (non-ambulatory or ambulatory) were interviewed for their perspectives about which ADLs are most important to them, and about how fatigue and fatigability affect their abilities to perform these ADLs. Both discussion groups prioritized ADLs that related to independence and dignity. Non-ambulatory and ambulatory participants also reported that fatigue and fatigability are a major factor in their ability to perform ADLs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e SMA key opinion leaders and adults with SMA agreed that ADLs would be sensitive and impactful outcomes in the assessment of function and fatigue. The findings of this study form a foundation for reaching consensus around a core set of outcome measures for assessing disease status, fatigue, and fatigability in teens and adults with SMA in the U.S.\u003c/p\u003e","manuscriptTitle":"A qualitative, mixed-method approach to reaching consensus on function, fatigue, and fatigability outcomes in teens and adults living with spinal muscular atrophy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-25 02:33:45","doi":"10.21203/rs.3.rs-6917745/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2025-07-28T03:21:20+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-06-27T18:15:09+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-20T06:05:32+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-20T05:39:55+00:00","index":"","fulltext":""},{"type":"submitted","content":"Orphanet Journal of Rare Diseases","date":"2025-06-19T10:12:24+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"54503b5a-8a32-4677-a05e-ce4cbf7fdd7b","owner":[],"postedDate":"June 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-20T16:03:22+00:00","versionOfRecord":{"articleIdentity":"rs-6917745","link":"https://doi.org/10.1186/s13023-025-04047-x","journal":{"identity":"orphanet-journal-of-rare-diseases","isVorOnly":false,"title":"Orphanet Journal of Rare Diseases"},"publishedOn":"2025-10-17 15:58:09","publishedOnDateReadable":"October 17th, 2025"},"versionCreatedAt":"2025-06-25 02:33:45","video":"","vorDoi":"10.1186/s13023-025-04047-x","vorDoiUrl":"https://doi.org/10.1186/s13023-025-04047-x","workflowStages":[]},"version":"v1","identity":"rs-6917745","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6917745","identity":"rs-6917745","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}