Commentary
Video
Beyond the Guidelines: Monitoring and Defining SMA Progression
Author(s):
Spinal muscular atrophy (SMA) linked to chromosome 5q is an autosomal recessive disorder caused primarily by biallelic variants in the survival motor neuron 1 (SMN1) gene affecting approximately 1 in 15,000 live births. The first publication on SMA standards of care was developed in 2007 and later updated in 2018 by convening an International Conference of SMA experts. Through that, 2 publications were produced and globally distributed.
Years later, the field has significantly changed, with 3 new SMN-enhancing treatments—nusinersen (Spinraza®, Biogen), onasemnogene abeparvovec-xioi (Zolgensma®, Novartis), and risdiplam (Evrysdi®, Genentech)—at clinicians’ disposal. Ultimately, the approval of nusinersen and successful SMA newborn screening pilot programs helped facilitate implementation of SMA newborn screening, which resulted in dramatic change in SMA natural history.
The availability of disease-modifying therapies for 5q SMA and implementation of SMA newborn screening led the urgency to update the SMA best practice recommendations for diagnosis, which were published a few short months ago. These recommendations, led by an SMA working group of American and European health care providers, stress that SMA newborn screening is essential to towards getting an accurate diagnosis for patients. In the paper, the group provided recommendations for characterizing newborn screening-identified infants before treatment; minimum recommendations for starting or offering SMA newborn in a state or country; recommendations for activities and services to be provided by an SMA specialty care center accepting SMA newborn screening referrals; and recommendations for partnership with individuals with SMA and caregivers to support newborn screening-identified infants and their caregivers.
To better understand how these updates may impact SMA diagnosis and clinical care, NeurologyLive® convened a panel of experts who served as study authors on the recommendations. These included Mary Schroth, MD, FAAN, chief medical officer at Cure SMA and a pediatric pulmonologist; Kapil Arya, MD, a pediatric neurologist from Little Rock, Arkansas; Juan Francisco Vazquez Costa, MD, PhD, an adult neurologist who treats motor neuron diseases in Valencia, Spain.
In the final episode, the panel provided commentary on some of the critical gaps in the understanding and management of SMA, including long-term effects of disease-modifying therapies and diagnostic limitations. In the discussion, panelists provided insight on the uncertainties about the durability of current treatments, optimal therapy sequencing, and comparing available treatment options. In addition, they discussed the need for better biomarkers for diagnosis presymptomatic SMA and the increasing importance of building care capacity for adults with SMA.
Timeline of Discussion:
0:00 - 0:35 - Marco Meglio: Introduces the topic, asking about the unknowns and gaps in SMA management.
0:35 - 1:45 - Kapil Arya, MD: Discusses the unknown long-term effects of SMA treatments, treatment sequencing challenges, and the lack of comparative studies on current therapies.
1:45 - 6:20 - Juan Francisco Vazquez Costa, MD, PhD: Addresses the challenges in diagnosing SMA due to inconsistent SMN2 copy number results between centers, the treatment of presymptomatic patients with four SMN2 copies, and the need for more research on prodromal SMA.
6:20 - 10:00 - Mary Schroth, MD, FAAN: Highlights the need for better biomarkers in presymptomatic SMA diagnosis, the role of genetic modifiers in SMA presentation, and the challenges of providing care to the growing population of adults with SMA. The group reflects on the future of SMA treatments, the potential for new combination therapies, and the ongoing need to refine diagnostic and care approaches.
Transcript edited for clarity.
Marco Meglio: What are some areas we still don’t have a great grasp on that weren't fully included in the recommendations or updates? Just talk a little about some of the unknowns and things we need to improve on over the next few years, even though we've made a lot of progress over the last five to 10 years.
Kapil Arya, MD: I'd say some of the biggest unknowns for me are the long-term effects of disease-modifying therapies, looking ahead 5, 10, or 15 years—whether there are any adverse effects and if these treatments remain as effective as they are at the outset. Number two, whether there’s any additional benefit to using both SMN1 and SMN2-enhancing therapy, or what the treatment sequence should be. And number three, of the three treatment options we currently have, especially for a child diagnosed via newborn screening, scientifically speaking, head-to-head, which one is the best choice? Those are the three big unknowns for me that still need a lot of research.
Juan Francisco Vazquez Costa, MD, PhD: For me, there are also several unknowns. One important thing regarding diagnosis, and we touched on this briefly, is the limitations of genetic testing. We know that when two centers perform the same genetic diagnosis, we may see discordance in the number of SMN2 copies. This could be important, for instance, when treating presymptomatic patients. In Spain, we only have approval to treat presymptomatic patients with two or three SMN2 copies. So, in our center, we use two techniques to validate the SMN2 copy number results, and we’ve found some discordance when using two different techniques. So, I think it’s crucial for each center to validate results using multiple methods. Another important question is whether presymptomatic patients with four SMN2 copies should be treated, and if so, when. In the US, most of these patients are treated, but that's not the case in Europe due to the lack of evidence for efficacy. Another interesting topic is the concept of prodromal SMA—when does SMA actually begin? Is it when we detect symptoms, neurogenic changes on an EMG, or increased neurofilaments? Finally, I think we need to define the natural history of SMA based on SMN2 copy numbers rather than SMA type, which could help us measure the real-world impact of treatments.
Mary Schroth, MD, FAAN: I echo what Dr. Arya and Dr. Vazquez Costa said. In our working group, we had an interesting discussion about defining presymptomatic versus symptomatic SMA in infants. One thing we learned is that we don’t have a perfect biomarker yet to help us identify when motor neuron loss begins, but we need this urgently. Some evidence suggests this loss may start prenatally, at least in the most severe types. Additionally, Dr. Vazquez Costa raised an interesting point about the natural history of SMA and SMN2 copy numbers. There are likely other genetic modifiers at play, because the correlation between SMN2 copies and SMA type isn't always straightforward. Another major challenge in the US is that we need to build capacity to provide care for adults with SMA. More than half of those living with SMA are now adults, but we’re struggling to meet their care needs. Lastly, the pipeline for SMA treatment remains robust, with new disease-modifying drugs and combination therapies that look promising, though we still don’t have a cure.
