Commentary
Video
Evolving Best Practices: Data Behind the New SMA Guidelines
Author(s):
In this episode, experts discuss groundbreaking updates in spinal muscular atrophy diagnosis, emphasizing the importance of early intervention and newborn screening.
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 episode 2, the panel discusses the recent advances in SMA diagnosis and treatment that led up to the newly published recommendations. In particular, they touch upon the success of the nusinersen trials and the expansion of newborn screening across the U.S. In addition, the group discuss real-life case studies comparing the outcomes of patients diagnosed and treated early versus later, reinforcing the need for early intervention. Furthermore, the panel covers the limitations of newborn screening, including missed diagnoses, and stresses the importance of maintaining clinical awareness for rare cases of SMA.
Timeline of Discussion
0:00 – 0:30 – Marco Meglio: Introduction of the clinical evidence and data supporting new SMA practices.
0:30 – 2:30 – Juan Francisco Vazquez Costa: Discussion of major milestones in SMA diagnosis, emphasizing early motor neuron loss in presymptomatic patients and the cost-effectiveness of newborn screening.
2:30 – 3:30 –Mary Schroth: Overview of Spinraza trials and newborn screening success in the U.S., culminating in universal screening implementation by January 2024.
3:30 – 5:30 – Kapil Arya: Case study comparisons of two patients—one diagnosed early, one diagnosed after symptom onset—highlighting vastly different outcomes based on the timing of treatment.
5:30 – 6:45 – Mary Schroth: Caveat regarding newborn screening's 95% accuracy and the importance of recognizing SMA symptoms in patients with point mutations.
6:45 – 8:00 – Kapil Arya: Further discussion on potential gaps in newborn screening accuracy and the need for vigilance in diagnosing SMA in certain cases.
Transcript edited for clarity.
Marco Meglio: Talk a little bit about some of the clinical evidence and data that led to these new practices. Could you describe some of the updates in the literature and research that you’ve seen, and how it may have helped formulate these updates?
Juan Francisco Vazquez Costa, MD, PhD: Well, if I may, I think there are two main milestones in recent years that have given us the opportunity to recommend newborn screening as a universal test for all children. One is what I mentioned earlier—we know that in the presymptomatic period, there is considerable motor neuron loss, so we shouldn’t wait until patients show symptoms. We also know from trials that the earlier we start treatment, the better the results. This is a very important factor.
The second milestone is that studies have shown that newborn screening is not only feasible but also cost-effective. This paves the way for newborn screening to become routine. In this paper, 100% of us agree that newborn screening should be performed for all children. This is a major milestone because, five years ago, it wasn’t a universal recommendation, and in many countries, it’s still not a reality. But there’s now a lot of evidence that implementing newborn screening as soon as possible benefits both the patients and the healthcare system because it’s cost-effective.
Mary Schroth, MD, FAAN: In the US, two pivotal things occurred. First was the success of the Spinraza trial in symptomatic infants under six months of age, which demonstrated improved survival and outcomes, leading to the approval of the first treatment for SMA. The second was the success of newborn screening. A pilot study in New York identified an infant before symptom onset, which led to the federal recommendation for SMA newborn screening across the US in 2018. I’m happy to report that as of January 2024, SMA newborn screening has been implemented in every US state and Washington, DC. This is a tremendous achievement and will rapidly change the course of the disease.
Kapil Arya, MD: I’ll illustrate the excellent points made by Juan and Mary by sharing examples of two of my patients. One was diagnosed after symptom onset at four months of age with two SMN2 copies and no SMN1 copies. The other was diagnosed at two days old through newborn screening with the same genetic makeup. Both received gene therapy—one at five months and the other just a few days old. The difference in their development trajectories is striking. The child treated within days of birth, now two years old, is practically a normal child. You wouldn’t know they have a neuromuscular disease unless you were aware of their genetic makeup.
Unfortunately, the child treated later still isn’t sitting up, is dependent on a G-tube for feeding, and is chronically ventilated. The difference between these cases highlights what Juan and Mary mentioned—the earlier you diagnose and treat, the better the outcome. Newborn screening now makes early diagnosis possible, which is both life-changing for the child and cost-effective for society.
Mary Schroth, MD, FAAN: There is one caveat with newborn screening and SMA genetic testing. These tests identify 95% of individuals with SMA, but the remaining 5% may have one SMN1 copy with a point mutation, which makes the SMN1 gene nonfunctional and unable to produce the SMN protein. These individuals will present with SMA symptoms and come to clinical attention. So, it's still important to recognize the symptoms of SMA and consider genetic testing. If genetic testing shows only one SMN1 copy, further sequencing may be needed to identify a point mutation.
We’ve made tremendous progress with newborn screening, but there’s still a need to be clinically aware of those 5% who may present with symptoms despite normal or incomplete genetic results.
Kapil Arya, MD: Thank you for that important point, Mary. I’ll also add that newborn screening is just a lab test at the end of the day, and mistakes can happen. It's estimated that up to 4-5% of children with SMA might be missed by newborn screening, although I personally haven’t seen such high numbers. But, theoretically, it’s possible. So Mary’s point about maintaining clinical vigilance and having a high suspicion in children presenting with symptoms like low muscle tone or tongue fasciculations is critical and should be kept in mind.
