Addressing MUSCLE in SMA
Bear, 9
Living with SMA
On an approved SMN-targeted therapy for 8 years
At the end of every motor neuron, there’s a muscle
The motor unit is the fundamental engine of motor function, comprising a lower motor neuron, a myofiber, and a neuromuscular junction that connects the two.13
Motor control and function depend not only on motor neuron signaling to muscle fibers, but also on the capacity of muscle to respond.17
In healthy muscle, muscle size is exquisitely tailored to need. In spinal muscular atrophy (SMA), this balance is pathologically tilted in favor of muscle atrophy13
SMN deficiency in the muscle impairs muscle development and maintenance, and electromyographic studies show that motor unit potentials are dependent on the duration of disease, with muscles in people with longer duration of disease showing marked perturbation of motor unit potentials.18,19
A unique aspect of SMA muscle is its heterogeneity. Atrophy is not uniform across muscle groups; some are relatively intact while others are more severely weakened. Even within the muscle, biopsies show patches of atrophic, normal, and hypertrophic myofibers, the latter presumably attempting to compensate for the loss of denervated myofibers. Unlike some other neuromuscular diseases, such as Duchenne muscular dystrophy, SMA muscle shows little necrosis or inflammation.13
Muscle biopsies in SMA Types 1, 2, and 3 show small atrophic fibers interspersed with normal or hypertrophic fibers13,20
SMA Type 1
(0.3 mo)
SMA Type 2
(29 mo)
SMA Type 3
(36 mo)
Hematoxylin & Eosin
Reprinted with permission.
Despite progressive muscle weakness, people with SMA have some remaining intact muscle. This provides a unique opportunity for research on muscle-targeted therapies in SMA.8,13-16
Muscle strength is INEXTRICABLY linked to motor function
Mckenna, 15
Living with SMA
On an approved
SMN-targeted
therapy for 7 years
Muscle weakness substantially impacts the essential functions of daily life beyond growth milestones and gross motor function11,21,22
For instance, it can affect airway clearance, bulbar function, and muscles controlling head stability, posture, and breathing.2,23,24
Multiple organs and physiologic functions are affected by muscle weakness
| Organ/ location affected | Muscle affected | Physiologic impact* |
|---|---|---|
| Airway23 | Intercostal muscles24 |
|
| Bulbar24 | Tongue, soft palate/ pharyngeal muscles, laryngeal muscles25 |
|
| Chewing24 | Temporalis, pterygoids, masseter27 |
|
| Cervical extension2 | Neck flexors24 |
|
| Chest and back2,28 | Intercostal muscles, axial skeletal muscles2,28 |
|
| Gross and fine motor function2 | Muscles controlling upper and lower limbs, eg, triceps and thigh adductors29 |
|
Weakness in two or more muscle groups can also contribute to impairments. Bulbar and chest weakness can contribute to speech impairment, poor posture, and scoliosis.24
SMN-targeted therapies were designed to address SMN protein deficiencies, but additional improvement in muscle strength may be needed
Response to SMN-targeted therapy does not restore motor function to normal levels, and in many cases response either plateaus or is lost.30-35 Furthermore, motor function improvements are not necessarily associated with improvements in bulbar or respiratory function.30 Nearly all children with SMA who receive respiratory support at baseline continue to require mechanical ventilation regardless of SMN-targeted therapy.36 Even when on treatment, patients with SMA can experience progressive muscle weakness and substantial fatigue.37 The need remains high for treatment options that help preserve muscle strength.
Despite improvement in motor function scores, one study showed that scoliosis progressed while on an SMN-targeted therapy28
| Patients | Baseline Cobb angle, degrees (range)* | Cobb angle at latest follow-up, degrees (range) |
|---|---|---|
| SMA Type 1 (n=8) | 26.3 (0-103) | 45.4 (0-108) |
| SMA Type 2 (n=7) | 45.0 (0-100) | 75.6 (24-141) |
| SMA Type 3 (n=8) | 6.5 (0-19) | 19.1 (0-41) |
This was a prospective study of 23 patients who received nusinersen at two SMA treatment institutes. Whole spine radiographs were performed before and after nusinersen initiation (6 and 12 months, with half-yearly or yearly follow-ups thereafter). Improvements were demonstrated by CHOP-INTEND and HINE for SMA Type 1 subjects, and HFMSE and RULM for Types 2 and 3. In general, all study groups showed improvements in motor function.28
Baseline scores assessed before nusinersen treatment. Median age at nusinersen initiation was 5.8 y ears (range 0.4-17.5). Median duration of follow-up was 3.4 years (range, 1.1-5.2).
VOICE OF THE CLINICIAN
“It is important to systematically assess the musculoskeletal system and to implement early prevention aimed at preventing scoliosis and contractures, as well as training to strengthen the muscles.”38
— Stępień et al., International Journal of Environmental Research and Public Health, 2021.
Losses beyond PHYSICAL movement
The effects of progressive muscle weakness on motor function may not be fully captured by a number on a scale. Patients with SMA report that physical limitations can impair daily activities, many of which are important for actively engaging in their interests, socializing, communicating, or pursuing their ambitions, like deciding which school to attend or where to travel next.10,11,21,22
Maintaining the ability to perform tasks such as holding a cup, opening a jar, buttoning pants, or tying a shoelace is very important to people with SMA. These abilities support functions such as drinking, eating, and dressing without assistance—all of which are key to remaining independent.10,11
Lyza, 22
Living with SMA
On an approved SMN-targeted therapy for 7 years
Activities of daily living become increasingly difficult with loss of motor function*10,11,22
DRESSING
Putting on shoes or pants, dressing upper and/or lower body
TOILETING
Using toilet independently, standing from sitting on toilet
PHYSICAL ACTIVITY
Taking a step, walking, exercising
SELF-CARE
Brushing hair, itching or scratching
MANUAL DEXTERITY
Picking up small items, holding objects, reaching for an object or touching floor
EATING/ DRINKING
Eating independently or while seated, picking up food, opening a wrapper
MOBILITY/ TRANSFERRING
Turning in bed, getting out of bed, standing after a fall or from sitting
WRITING/ TECHNOLOGY
Using a phone or device, writing or drawing with a pen
*Activities of daily living rated important by Type 2 and nonambulant Type 3 SMA patients.11
Adults with SMA face unique health challenges that require an evolution of treatment goals
For many people living with SMA, the goal is not only to maximize motor function scores, but also to have enough strength and endurance to sustain an activity, like cooking a meal.10 Some people living with SMA report that their muscles fatigue quickly,39-41 which can lead to sudden and unpredictable loss of function, so finishing tasks becomes frustrating, difficult, or not manageable.10
Workarounds highlight the functional deficits that directly impact people living with SMA, their determination to maintain their independence, and the unmet needs that remain10
DRESSING
Using a dressing stick
TOILETING
Avoiding liquids (intentional dehydration) to reduce urination frequency
PHYSICAL ACTIVITY
Using a backpack to store items to avoid frequent trips up or down stairs or to and from other rooms
SELF-CARE
Avoiding use of heavy items, like a blow dryer
MANUAL DEXTERITY
Lifting a pants leg with a hand to facilitate leg movement
EATING/ DRINKING
Using straws; avoiding difficult-to-chew foods
MOBILITY/ TRANSFERRING
Relying on caregivers
WRITING/ TECHNOLOGY
Using augmented or assistive communication technology
VOICE OF THE PATIENT
“Muscular atrophy can spread from the neck to the jaw and the face. One panelist—a mother of a seven-year-old boy with SMA Type 2—said that, in an effort to compensate for the gradual loss of jaw strength, her son uses his arm to support his chin and to help himself chew.”10
— Voice of the Patient Report, 2018.
Progressive muscle weakness requires workarounds, but another aspect of SMA does as well: debilitating fatigue.42
Hidden Impact
of Fatigue
Fatigue is one of the most debilitating, underaddressed, and misunderstood symptoms of SMA42-44
of patients with SMA report fatigue
Data from the Voice of Patient Report for Spinal Muscular Atrophy (n=47 of 66).10
Fatigue has two dimensions:
Subjective fatigue and fatigability are two different phenomena and are both experienced by people living with SMA. Fatigability limits the ability to sustain muscle activity. People living with SMA report struggles with conserving energy. This means people living with SMA may have to pick and choose when and how they expend their energy. Subjective fatigue, on the other hand, is not just limited to our bodies. It is an overall feeling of exhaustion that can impact mental well-being.10,42
VOICE OF THE PATIENT
“I hate feeling so fatigued on certain nights that I must stay in and not participate in everyday activities that allow me to live my life to the fullest.”10
— Patient with SMA Type 3, Voice of the Patient Report, 2018.
Although exercise is typically recommended for reducing muscle fatigue, exercise alone might not be a viable option for some people with SMA. Given the debilitating nature of fatigue in SMA, strategies to attenuate fatigue, such as new therapies with potential impacts on fatigue, strength, and performance are needed.2,3
Time lost is muscle lost
As time passes, not only are motor neurons lost, but muscle, abilities, and independence are all at risk of decline2,10,11
A variety of cross-sectional and longitudinal studies show muscle weakness is progressive and correlates with declines in motor function.46-48 A recent longitudinal study suggests that this is the case even in SMA Type 3 or 4.49 The study showed constant muscle strength decline among Types 3 and 4 patients without periods of slower progression or plateaus. The decline of muscle strength, even on a backdrop of apparent motor function stability,49 provides additional rationale for early treatment of SMA,50 potentially with approaches targeting muscle.8 As seen in studies of SMN-targeted therapies, the earlier the intervention, the better the outcome.50
In a 2018 study of people with SMA, muscle strength and motor function declined over time across all ages and SMA types46
MRC: Medical Research Council Scale for Muscle Strength.
VOICE OF THE PATIENT
“I don’t want to lose strength in my hand because then I will lose the independence to drive my own wheelchair. If I lose the ability to speak, I won’t be able to work.”10
— 29-year-old with SMA Type 2, Voice of the Patient Report, 2018.
Detecting muscle weakness in practice is challenging
Common assessment tools may not be sensitive enough to reflect lived patient experience
Despite repeated studies underscoring the correlation between muscle strength and motor function, progressive muscle loss can initially be overlooked.38,48,51,52 Common assessment tools are designed to detect overall motor function and may be less sensitive to changes in muscle strength.53,54
CHOP-INTEND, for example, typically does not correlate with patient or caregiver reports of improvement on therapy, possibly due to its inability to capture fine finger movements or ability to turn the head to the side—capabilities that are very meaningful to patients.53
In a study of 17 adult patients with Types 2 and 3 SMA, near-normal function of the upper extremities (as measured by the Nine Hole Peg Test, the Timed Test of in-Hand Manipulation, and Performance of Upper Limb scale) was seen in some patients, despite clear evidence of reduced muscle strength. The explanation for this discrepancy could be that such patients had enough reserve muscle torque to complete a task, engaged secondary muscle groups, or they used workarounds to complete the task, such as swinging movements to gain momentum or trunk movements to accelerate the arm.54
Motor function scales like the Hammersmith Functional Motor Scale–Expanded (HFMSE) were designed for SMA and represent the gold standard for assessing motor function, but other measures of clinical status, like fatigue, can help provide a fuller picture because they align with the stated treatment goals of people with SMA and their caregivers.45
New therapies are clearly needed to build upon and extend the success of SMN-targeted treatments
Indeed, people living with SMA and their caregivers have called for new treatments that help improve muscle strength and endurance. Advocacy groups and the broader community believe that a combination of treatments may provide benefit for those with SMA. For some, this could mean combining SMN-targeted and non–SMN-targeted treatments.3,10
The Life Takes Muscle Podcast
Join leading SMA expert Dr Diana Castro and her guests as they explore topics like the unmet need of addressing progressive muscle weakness, the untapped potential of people living with SMA, and the role of myostatin as an inhibitor of muscle growth.
A FUTURE BEYOND SURVIVAL
See what challenges have been faced in the past and what opportunities could lie in the future with potential new strategies to directly address progressive muscle weakness.