Neurology
Addressing Unmet Needs and Functional Decline in Adults Living with SMA
This interactive case study was organized and funded by Scholar Rock.
Medical writing assistance was provided by Jessica Jinks and Alex Perkins, EMJ, London, UK.
1/23
These interactive case studies were developed with support from Andrej Marich, US Medical Director; Neuromuscular, Scholar Rock, Cambridge, Massachusetts, USA.
These are hypothetical patient cases and outcomes may not be reflective of clinical studies or real-life circumstances. This includes reference to agents that may be used off-label or for unlicensed indications. The mention of these agents and their uses is intended solely for educational purposes and should not be considered an endorsement or recommendation for their use outside approved indications. Please always consult guidelines and local prescribing information in your country of practice, as information may vary.
Prescribing Information for apitegromab can be found here. Adverse event reporting information can be found at the end of this case study.
Learning Objectives
By the end of this case study, participants should be able to:
2/23
Recognize
Persistent unmet needs experienced by adults with SMA despite treatment with SMN2-targeted therapies Signs of clinically meaningful functional decline that may not be fully captured by motor outcome measures alone
The impact of weakness, fatigue, and loss of function on activities of daily living, employment, and quality of life Caregiver burden and evolving support needs
Assess
Apply
A patient-centered approach to identifying treatment goals Shared decision-making strategies when discussing additional therapeutic options
Consider
The role of muscle-targeted treatment approaches as an extension of current SMA management
References and Abbreviations
References and Abbreviations SMA: spinal muscular atrophy; SMN: survival motor neuron.
3/23
Meet Stephan
Stephan is a 35-year-old man with Type III SMA who presents for routine follow-up. He was diagnosed at 6 years of age and remained ambulatory with assistive devices until 15 years of age. Since his mid-20s, he has been receiving SMN2-targeted treatment and has experienced a prolonged period of relative disease stability. While his formal motor function assessments have changed only gradually, increasing fatigue and perceived weakness are beginning to affect his independence, work responsibilities, and family life.
I feel like I'm gradually losing ground.
north
4/23
Patient Background and Past Medical History
Click through to learn more about Stephan:
Relevant past medical history
Home life and care needs
Adult aged 35 years Diagnosed with SMA at 6 years of age Type III SMA; he was ambulatory using assistive devices or braces until the age of 15 years Treated with SMN2-targeted treatment starting at age 26 years Has a history of femur fracture (x2), mild hip flexor and hamstring contractures, and scoliosis correction surgery (age 15 years)
He lives with his spouse, who provides some caregiving assistance, and his two children (ages 8 and 10 years). Currently employed as an operations manager at a non-profit organization.
5/23
Current Functional Status
Stephan has maintained a good degree of independence in many aspects of daily life, while relying on support for some activities. Flip the cards below to learn more.
Mobility
Transfers
Daily Living
Propels manual wheelchair for household and moderate community distances Requires a scooter or power chair for longer distances Unable to walk Unable to stand independently
Transfers between wheelchair and bed using an overhead grab bar Can achieve standing only with assistance from another person and upper limb support
Lives at home with his spouse and children Able to drive using adaptive vehicle Has access to pool and enjoys swimming Receives assistance from his spouse with some caregiving activities Remains employed full-time
6/23
Longitudinal Motor Assessment
How has Stephan's motor function changed over the past 10 years of SMN2-targeted treatment? Review his longitudinal assessment results below:
Time since starting SMN2-targeted therapy
HFMSE1
RULM1
Clinical interpretation
Year 0
35
21
Baseline assessment prior to treatment. Moderate motor impairment consistent with Type III SMA.
Year 2
38
22
Early treatment response. Small improvements in motor function suggest benefit from SMN2-targeted therapy.
Year 6
37
Overall stability. Motor assessments indicate maintenance of function over time.
Year 10
32
Gradual decline in HFMSE with preserved RULM. Motor assessments suggest only modest change.
Stephan’s motor function scores over time
Stephan’s motor function scores over time.
References and Abbreviations 1. Pierzchlewicz et al. Spinal muscular atrophy: the use of functional motor scales in the era of disease-modifying treatment. Child Neurol Open. 2021;8:2329048X211008725. HFMSE: Expanded Hammersmith Functional Motor Scale; RULM: Revised Upper Limb Module; SMA: spinal muscular atrophy; SMN: survival motor neuron.
7/23
QUESTION 1
Based on Stephan's HFMSE and RULM scores alone, which statement is most appropriate?
A
Stephan's disease is stable
B
Stephan's disease is improving
C
Stephan's disease is progressing
D
Additional clinical information is needed to determine Stephan's overall clinical status
Incorrect. HFMSE and RULM provide important information about motor function, but they do not capture all aspects of disease impact.1 Additional clinical information is needed before determining Stephan's overall clinical status. Select another option.
Incorrect. Although RULM improved during the first few years of treatment, these motor assessments alone are insufficient to determine Stephan's current overall clinical status.1 Select another option.
Incorrect. While HFMSE has shown a gradual decline in recent years, motor assessment scores alone do not provide enough information to determine Stephan's overall clinical status.1 Select another option.
Correct Answer: Although Stephan's motor assessments appear relatively stable, they do not provide a complete picture of his clinical status.1 Further assessment is required to understand his current symptoms and functional needs. Continue for more information.
References and Abbreviations 1. Pierzchlewicz et al. Spinal muscular atrophy: the use of functional motor scales in the era of disease-modifying treatment. Child Neurol Open. 2021;8:2329048X211008725. HFMSE: Hammersmith Functional Motor Scale Expanded; RULM: Revises Upper Limb Module.
8/23
Looking Beyond the Scores
Although Stephan's motor assessments suggest relative stability, his and his spouse's experiences reveal meaningful changes in his day-to-day function and indicate disease progression.
Stephan has become a lot more dependent on me, particularly when it comes to transfers into and out of his chair.
When I get home from work, I barely have enough energy to make dinner or spend time with my family.
Despite relative stability, Stephan describes:
Increasing fatigue throughout the day Progressive difficulty performing ADL A perception that his arms and hands are becoming weaker Greater shortness of breath when propelling his wheelchair Reduced participation in work and family activities
His spouse has also noticed meaningful changes:
More difficulty assisting transfers Increased caregiving burden Inability to enter and exit the shower without assistance Two falls during transfers within the past 2 years
References and Abbreviations ADL: activities of daily living.
9/23
QUESTION 2
Based on Stephan's profile, what is the most appropriate next step?
Continue routine follow-up
Increase the frequency of HFMSE assessments
Gather further information and perform additional assessments to better understand the factors contributing to his worsening symptoms
Conclude that his symptoms are explained by his motor scores
Correct Answer: Although Stephan's motor assessments suggest relative stability, his increasing fatigue, loss of function, and caregiver-reported changes indicate that additional evaluation is needed. Further respiratory, strength, and patient-centered assessments can help identify the factors contributing to his worsening symptoms and better characterize his overall disease burden.1-3 Continue for more information.
References and Abbreviations 1. Finkel RS et al. Diagnosis and management of spinal muscular atrophy: part 2: pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018;28(3):197-207. 2. Sansone VA et al. Measuring outcomes in adults with spinal muscular atrophy - challenges and future directions - meeting report. J Neuromuscul Dis. 2020;7(4):523-34. 3. Naqvi U et al., Muscle Strength Grading [Internet] (2025) Treasure Island: StatPearls. Available at: https://www.ncbi.nlm.nih.gov/books/NBK436008/. Last accessed: August 3, 2025. HFMSE: Hammersmith Functional Motor Scale Expanded.
10/23
Additional Clinical Assessment
To better understand the factors contributing to Stephan's worsening symptoms, additional respiratory, strength, and neurophysiological assessments were performed.
Although formal assessments demonstrate relative stability in some domains, there is evidence of declining respiratory function and persistent upper limb weakness that may be contributing to Stephan's reported fatigue, loss of endurance, and increasing difficulty with daily activities.
FVC1 Current: 74% of predicted value 3 years earlier: 81% predicted
PEF1 Stable over the past 5 years: 4.4 L/s
Respiratory Function:
MRC Strength Scale2
Upper Limb Assessment:
Deltoid: 3/5
Biceps: 4/5
Triceps: 4/5
EMG/Nerve Conduction Studies3
No significant interval change
Neurophysiology:
References and Abbreviations 1. Sansone VA et al. Measuring outcomes in adults with spinal muscular atrophy - challenges and future directions - meeting report. J Neuromuscul Dis. 2020;7(4):523-34. 2. Naqvi U et al,. Muscle Strength Grading [Internet] (2025) Treasure Island: StatPearls. Available at: https://www.ncbi.nlm.nih.gov/books/NBK436008/. Last accessed: August 3, 2025. 3. Arnold WD et al. Spinal muscular atrophy: diagnosis and management in a new therapeutic era. Muscle Nerve. 2015;51(2):157-67. EMG: electromyography; FVC: forced vital capacity; MRC: Medical Research Council; PEF: peak expiratory flow.
11/23
Additional Patient-Centered Investigations
Alongside routine clinical evaluation, several newer assessment tools can help capture disease burden and functional impact more comprehensively.1-3
Tool
What it helps assess
SMA-EFFORT1
Fatigue during everyday activities1
EVOLVE-SMA2
Functional ability (patient- or clinician-reported)2
SMA-FCS3
Gross motor function and risk of clinical outcomes3
References and Abbreviations 1. Rodrigues-Torres R 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. 2. Moore-Burk M et al. New SMA era: a broad-range tiered assessment of function for the evolving SMA phenotype (EVOLVE-SMA). J Neuromuscul Dis. 2026;13(4):748-68. 3. Howard JJ et al. The spinal muscular atrophy functional classification system. Dev Med Child Neurol. 2026;00:1-9. EVOLVE-SMA: Functional Ability Scale for Evolving Spinal Muscular Atrophy; SMA-EFFORT: Spinal Muscular Atrophy-Specific Patient-Reported Outcome Measure for Perceived Physical Fatigability; SMA-FCS: Spinal Muscular Atrophy Functional Classification System.
12/23
QUESTION 3
Which assessments should be considered alongside traditional motor outcome measures to better understand Stephan's disease burden? Select all that apply.
PROMs
SMA-EFFORT
EVOLVE-SMA
SMA-FCS
Fatigue and quality-of-life assessments
E
Bone density assessment
F
SUBMIT
Correct answer: All of the above. A comprehensive assessment of adults with SMA should combine traditional clinical assessments with patient-centered measures.1 Tools such as PROMs, SMA-EFFORT, EVOLVE-SMA, and SMA-FCS can complement motor outcome measures by providing additional insight into fatigue, function, independence, and quality of life, helping to better characterize overall disease burden.1-4
References and Abbreviations 1. Schroth M et al. Spinal muscular atrophy update in best practices: recommendations for treatment considerations. Neurol Clin Pract. 2025;15(1):e200374. 2. Rodrigues-Torres R et al. Development of the SMA EFFORT: a new approach to characterize perceived physical fatigability in spinal muscular atrophy. 3. Moore-Burk M et al. New SMA era: a broad-range tiered assessment of function for the evolving SMA phenotype (EVOLVE-SMA). J Neuromuscul Dis. 2026;13(4):748-68. 4. Howard JJ et al. The spinal muscular atrophy functional classification system. Dev Med Child Neurol. 2026;00:1-9. EVOLVE-SMA: Functional Ability Scale for Evolving Spinal Muscular Atrophy; SMA-EFFORT: Spinal Muscular Atrophy-Specific Patient-Reported Outcome Measure for Perceived Physical Fatigability; SMA-FCS: Spinal Muscular Atrophy Functional Classification System.
NEXT
13/23
Putting the Pieces Together
A comprehensive understanding of disease burden requires more than motor outcome measures alone. Clinical findings, patient experience, and caregiver perspectives should all inform assessment and management.1
Stable motor scores do not necessarily reflect stability in everyday life.2
References and Abbreviations 1. Schroth M et al. Spinal muscular atrophy update in best practices: recommendations for treatment considerations. Neurol Clin Pract. 2025;15(1):e200374. 2. Pierzchlewicz et al. Spinal muscular atrophy: the use of functional motor scales in the era of disease-modifying treatment. Child Neurol Open. 2021;8:2329048X211008725.
14/23
QUESTION 4
Based on Stephan's overall clinical picture, which statement best describes his current clinical status?
Stephan's disease is stable because his motor assessments have not changed greatly.
Although Stephan has benefited from long-term SMN2-targeted therapy, he continues to experience clinically meaningful disease burden and persistent unmet needs.
Stephan has no significant unmet clinical needs while receiving SMN2-targeted therapy.
Stephan's symptoms are unrelated to SMA progression.
Correct Answer: Stephan's case demonstrates that although long-term SMN2-targeted therapy has helped maintain motor function, he continues to experience fatigue, weakness, reduced endurance, and increasing functional limitations. These persistent unmet needs should be identified through comprehensive assessment and addressed through patient-centered management.1
References and Abbreviations 1. Schroth M et al. Spinal muscular atrophy update in best practices: recommendations for treatment considerations. Neurol Clin Pract. 2025;15(1):e200374. SMA: spinal muscular atrophy; SMN: survival motor neuron.
15/23
Identifying Stephan’s Unmet Needs
Despite long-term SMN2-targeted therapy and multidisciplinary care, Stephan continues to experience unmet needs that affect his independence, participation, and QoL. Click to reveal.
Persistent muscle weakness
Fatigue and reduced endurance
Increased difficulty with ADL
Reduced participation in work/family activities
Maintaining independence and QoL
Greater reliance on caregivers
References and Abbreviations ADL: activities of daily living; QoL: quality of life; SMN: survival motor neuron.
16/23
QUESTION 5
Which of the following treatment approaches best captures Stephan’s goals and clinical presentation?
Improve HFMSE and RULM scores
Restore independent household ambulation
Maintain independence, participation, and quality of life while addressing persistent unmet needs
Focus exclusively on preventing further motor decline
Try again While improvements in HFMSE and RULM scores are an important and commonly used indicator of improvement in function, HFMSE and RULM scores do not provide insight into some of the concerns that Stephan and his caregiver discussed in the visit.
Try again While maintaining independence represents an important goal for Stephan, restoring independent household ambulation is not a realistic goal to prioritize, given his current wheelchair dependence and the fact that available SMA therapies are not established to reverse lost motor function.
Correct Answer: Treatment goals should be developed through shared decision-making and reflect Stephan's priorities, persistent unmet needs, and overall clinical status.1 The aim is to maintain independence, participation, and QoL while addressing symptoms that continue to impact daily function.
Try again While preventing further decline is an important part of Stephan's care, focusing on this exclusively neglects other key aspects of his clinical picture, including his participation, quality of life, and the persistent unmet needs raised during the visit. Treatment goals should be broader and reflect his overall priorities, not motor function alone.
References and Abbreviations 1. Schroth M et al. Spinal muscular atrophy update in best practices: recommendations for treatment considerations. Neurol Clin Pract. 2025;15(1):e200374. HFMSE: Expanded Hammersmith Functional Motor Scale; QoL: quality of life; RULM: Revises Upper Limb Module.
17/23
Establishing Meaningful Treatment Goals
For Stephan, treatment may not be defined by improvements in motor scores alone. Equally important outcomes may include:
Improved strength and endurance
Greater independence with daily activities
Easier and safer transfers
Reduced fatigue
Maintaining participation in work and family life
References and Abbreviations 1. Schroth M et al. Spinal muscular atrophy update in best practices: recommendations for treatment considerations. Neurol Clin Pract. 2025;15(1):e200374.
Treatment goals should be individualized and developed through shared decision-making.1 Understanding what matters most to the patient and caregiver can help guide management decisions and identify opportunities to address ongoing unmet needs.1
18/23
Shared Decision-Making
Meaningful treatment goals should be individualized and reflect what matters most to the patient and caregiver, not solely changes in motor function measures.1
I’d like transfers to be easier and safer, while helping Stephan remain as independent as possible.
I want more strength and energy so I can stay independent, keep working, and spend time with my family.
Let's focus on what matters most to you, not just your motor scores.
Current SMA treatment recommendations emphasize incorporating patient preferences, quality of life, and functional goals into treatment decisions.1
References and Abbreviations 1. Schroth M et al. Spinal muscular atrophy update in best practices: recommendations for treatment considerations. Neurol Clin Pract. 2025;15(1):e200374. SMA: spinal muscular atrophy.
19/23
Developing a Comprehensive Management Plan
A holistic management approach may include…
Rehabilitation and Physical Therapy1
Respiratory Care2
Occupational Therapy and Assistive Technology1
Bone Health1
Psychosocial Support3,4
Treatment Optimization3,5
Strength and endurance optimization1 Transfer assessment and training1 Contracture prevention and management1 Fall prevention strategies1
Assessment and monitoring of respiratory function2 Review of airway clearance and respiratory support needs2
Home and workplace adaptations1 Transfer equipment and seating optimization1
Review current treatment goals3 Consider whether additional therapeutic strategies could address persistent unmet needs3,5
Caregiver support and education3 Work participation and vocational considerations4 Quality of life3
Fracture risk assessment1 Bone density monitoring1 Contracture and scoliosis surveillance1
Management of adult SMA extends beyond motor scores and pharmacological treatment.1 A multidisciplinary approach can help address the physical, functional, respiratory, psychosocial, and caregiver-related impacts of the disease.1-3
References and Abbreviations 1. Mercuri E et al. Diagnosis and management of spinal muscular atrophy: part 1: recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018;28(2):103-15. 2. Finkel RS et al. Diagnosis and management of spinal muscular atrophy: part 2: pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018;28(3):197-207. 3. Schroth M et al. Spinal muscular atrophy update in best practices: recommendations for treatment considerations. Neurol Clin Pract. 2025;15(1):e200374. 4. Wan HWY et al. Health, wellbeing and lived experiences of adults with SMA: a scoping systematic review. Orphanet J Rare Dis. 2020;15(1):70. 5. Finkel RS et al. Advancing treatment of spinal muscular atrophy through inhibition of the myostatin signaling pathway. Expert Rev Neurother. 2026;26(3):211-25. SMA: spinal muscular atrophy.
20/23
Considering Additional Therapeutic Strategies
Despite long-term treatment with an SMN2-targeted therapy, Stephan continues to experience: Progressive fatigue Weakness Reduced endurance Loss of functional independence
These ongoing challenges suggest that important unmet needs may remain, particularly at the level of skeletal muscle function. In addition to the multidisciplinary management plan consider whether an additional therapeutic strategy could help address these persistent unmet needs.
SMN2-targeted therapies Current SMN2-targeted therapies address the underlying SMN deficiency and support motor neuron health.1 These treatments have improved outcomes for patients with SMA by slowing progression, enhancing motor, respiratory, and feeding function, and reducing mortality.1 However, many people with SMA continue to experience persistent muscle weakness, fatigue, and functional limitations despite treatment.1
Muscle-targeted therapies Targeting skeletal muscle alongside ongoing SMN2-targeted therapy may be an option to consider.1
References and Abbreviations 1. Finkel RS et al. Advancing treatment of spinal muscular atrophy through inhibition of the myostatin signaling pathway. Expert Rev Neurother. 2026;26(3):211-25. SMA: spinal muscular atrophy; SMN: survival motor neuron.
21/23
Muscle-Targeted Therapy
A muscle-targeted approach may represent a potential therapeutic option for patients like Stephan.1 Click through to learn more about this strategy.
Myostatin is a key negative regulator of skeletal muscle growth. By inhibiting myostatin, it may be possible to enhance muscle mass and improve motor function.1
Apitegromab is a fully human monoclonal antibody that selectively binds promyostatin and latent myostatin, preventing the formation of mature myostatin.1 In the Phase III SAPPHIRE trial, apitegromab demonstrated significant improvements in motor function in patients with Type II and Type III SMA who were already receiving standard-of-care SMN2-targeted therapy.2
For patients like Stephan, who continue to experience persistent muscle weakness, fatigue, and reduced endurance despite optimized multidisciplinary care and long-term SMN2-targeted therapy, a muscle-targeted therapeutic strategy may represent an additional treatment option to consider.1
References and Abbreviations 1. Finkel RS et al. Advancing treatment of spinal muscular atrophy through inhibition of the myostatin signaling pathway. Expert Rev Neurother. 2026;26(3):211-25. 2. Crawford TO et al. Safety and efficacy of apitegromab in nonambulatory Type 2 or Type 3 spinal muscular atrophy (SAPPHIRE): a Phase 3, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2025;24(9):727-39. SMA: spinal muscular atrophy; SMN: survival motor neuron.
22/23
Key Messages
Persistent unmet needs may remain despite long-term SMN2-targeted therapy1 Stable motor scores do not necessarily reflect stable disease or the full impact of SMA on daily life2
Look beyond motor function by evaluating fatigue, strength, respiratory status, functional performance, participation, and quality of life2-6 Consider caregiver burden and evolving support needs as part of routine assessment6
Use shared decision-making to establish meaningful, patient-centered treatment goals6 Optimize multidisciplinary management to address the physical, functional, and psychosocial impacts of SMA7
For patients with persistent unmet needs despite optimized care, consider whether a muscle-targeted therapeutic approach may help address residual disease burden1,8
Comprehensive, patient-centered management extends beyond preserving motor function. It aims to help people with SMA maintain strength, independence, participation, and quality of life throughout their disease journey.
References and Abbreviations 1. Finkel RS et al. Advancing treatment of spinal muscular atrophy through inhibition of the myostatin signaling pathway. Expert Rev Neurother. 2026;26(3):211-25. 2. Pierzchlewicz et al. Spinal muscular atrophy: the use of functional motor scales in the era of disease-modifying treatment. Child Neurol Open. 2021;8:2329048X211008725. 3. Sansone VA et al. Measuring outcomes in adults with spinal muscular atrophy - challenges and future directions - meeting report. J Neuromuscul Dis. 2020;7(4):523-34. 4. Rodrigues-Torres R 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. 5. Naqvi U et al, Muscle Strength Grading [Internet] (2025) Treasure Island: StatPearls. Available at: https://www.ncbi.nlm.nih.gov/books/NBK436008/. Last accessed: August 3, 2025. 6. Schroth M et al. Spinal muscular atrophy update in best practices: recommendations for treatment considerations. Neurol Clin Pract. 2025;15(1):e200374. 7. Mercuri E et al. Diagnosis and management of spinal muscular atrophy: part 1: recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018;28(2):103-15. 8. Crawford TO et al. Safety and efficacy of apitegromab in nonambulatory Type 2 or Type 3 spinal muscular atrophy (SAPPHIRE): a Phase 3, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2025;24(9):727-39. SMA: spinal muscular atrophy; SMN: survival motor neuron.
Adverse event reporting details: To report SUSPECTED ADVERSE REACTIONS, contact Scholar Rock, Inc. at 1-855-MED-SRRK (1-855-633-7775) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
23/23
