<p>The clinical trajectory of spinal muscular atrophy (SMA) remains highly variable, even among patients with similar SMN2 copy numbers and early access to disease-modifying therapies (DMTs). As the treatment landscape evolves, so does the need for more nuanced strategies to monitor progression over time. In this discussion, our experts explore current monitoring approaches and address unique considerations for adolescents and adults navigating long-term SMA care.</p>

We do have variable outcomes for our patients with SMA, even for those whose disease is identified through newborn screening and treated early. Moreover, even when we think that we are treating someone presymptomatically, they may already have some ongoing motor neuron loss that we are not detecting clinically. It is not clear how many cells actually get transduced with gene therapy when we give these treatments, so we can see variable outcomes. For example, some patients who have 2 copies of SMN2 may have a more severe phenotype when they receive gene therapy vs those who are asymptomatic at the time of treatment. Then, as we monitor them over time, even though there is clear benefit, we may see that there are still these residual deficits of varying degrees. I think that there are other genetic modifiers that we do not yet fully understand or know about for SMA. We have identified some of those, but beyond SMN2 copy number, we just do not fully understand all the factors that contribute to a more severe phenotype.

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In terms of trying to monitor SMA progression, I think that our standard has been to use the traditional motor function scales, such as the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), the Hammersmith Infant Neurological Examination (HINE), and the Hammersmith Functional Motor Scale (HFMS). We are starting to try to incorporate some biomarkers, such as compound muscle action potential amplitude, neuromuscular ultrasound muscle thickness, and neurofilament levels, to see if there is a trend that helps us identify patients with SMA who might be progressing more rapidly or have more significant involvement already, which can help guide us in choosing when to start a second therapy.

I love the idea of having biomarkers to look at and use to follow patients, but following patients clinically over time is important as well. A huge issue, especially for teenagers and adults with SMA, is fatigue. Getting through a school day, college classes, or a workday can be challenging because of fatigue. We typically look at motor outcomes, but we have not been great at incorporating patient-reported outcomes. We need to do a better job of really understanding what makes a difference for patients.

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There are certain times in the lives of patients with SMA when they tend to have more difficulties. For example, puberty can be a challenging time. Patients will have more difficulty when they have rapid growth, with increased weakness and fatigue. Pregnancy is another time when there are challenges. So, I think that we need to look at isolated and focused times as well when considering the trajectory of SMA, the impact of SMA on a patient’s life, and what we can do at that particular time of their life to help.

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I have heard from my colleagues that, after 5 to 7 years of treatment with DMTs, their adult patients with SMA may report that they feel like they are not doing quite as well. These DMTs have not been around long enough to follow patients for 15, 20, 30, or 40 years to understand what that trajectory looks like. We are still in the process of learning about the effects of long-term treatment with DMT and about how best to respond (eg, maybe with other therapies or support) when patients with SMA are experiencing those particularly vulnerable times.

It is important to reflect on the fact that this disease becomes relatively stable over time for many people who are living with it. Even in the most severe phenotype that presents early (ie, in infantile-onset SMA), there is kind of a bottoming out or a plateau that happens. In the milder forms of SMA, progression can be so subtle that oftentimes patients or families do not perceive any change over 1 year; it takes longer to see changes in these patients. So, unless interventions are transformative, it takes time to assess whether there is an impact. We cannot lose sight of that when we are trying to determine whether what we are doing is making a difference for our patients.

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I think that it is exciting that sometimes we are now needing to use normal developmental scales, such as the Bayley Scales of Infant and Toddler Development (BSID) or the Peabody Developmental Motor Scales (PDMS), to actually capture a patient’s level of function. In terms of stressful times for people with SMA, I think that there is a resilience that comes from being on SMN repletion that has been really nice to see. Previously, it was often quite catastrophic for our patients to have a fracture or an acute respiratory illness because they would come out of that with a very different baseline. I think that this can still happen to an extent, but it is less severe than it used to be due to the benefits of being on SMN-enhancing therapy.

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The last thing I would say is that I am curious about how senescence will affect patients with SMA who have been treated their whole lives. Post-polio syndrome showed how aging impacts motor neuron loss. In SMA, motor neurons that have been impacted by SMN-repleting therapy are doing the work of many motor neurons by themselves. So, when they are lost in the aging process, there will likely be an aspect of aging in treated SMA that will be important to explore.