Commentary
Video
Adult-Onset SMA: Diagnosis and Best Practices for Clinicians
Author(s):
In this segment, the panel discussed adult-onset 5q spinal muscular atrophy (SMA), highlighting its frequent underdiagnosis and subtle symptoms such as cramps, fasciculations, and sports intolerance.
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.
Episode 5 primarily focused on adult-onset 5q SMA, shedding light on its often-underdiagnosed presence in adults. The panel provided clinical insight on the subtle and variable symptoms that can appear in late adolescence or adulthood, such as cramps, fasciculations, and sports intolerance. In addition, they emphasized the importance of considering SMA in patients with a long history of unexplained symptoms, highlighting the diagnostic role of EMG and the need for genetic testing in patients with neurogenic patterns.
Timeline of Discussion:
0:00 - 0:30 – Marco Meglio: Introduction of the topic, specifically addressing adult-onset 5q SMA and its underdiagnosis.
0:30 - 3:30 – Juan Francisco Vazquez Costa, MD, PhD: Discussion on the frequency and delayed diagnosis of adult-onset SMA, including common symptoms and the diagnostic process.
3:30 - 4:30 – Mary Schroth, MD, FAAN: Emphasizes the importance of CK levels and the sports intolerance symptom often seen in adult patients.
4:30 - 5:45 – Juan Francisco Vazquez Costa, MD, PhD: Explains the gradual progression of symptoms in adult-onset patients and how many are misinterpreted as "lazy" for years before diagnosis.
5:45 - 6:00 – Mary Schroth, MD, FAAN: Recommends genetic testing for adults with a history of these symptoms.
6:00 - 6:25 – Kapil Arya, MD: Reinforces the importance of taking functional symptoms seriously and pursuing genetic testing.
6:25 - 7:20 – Juan Francisco Vazquez Costa, MD, PhD: Concludes with insights into the diagnostic use of EMG for detecting motor neuron loss in adult-onset SMA patients.
Transcript edited for clarity.
Marco Meglio: One of the aspects in the paper, which we've kind of talked about a little bit, is adult-onset 5q SMA diagnosis. For our clinical community, what should they know about these recommendations in regard to adult-onset 5q SMA? Could you explain what you discussed in the paper and how it may relate specifically to this patient group?
Juan Francisco Vazquez Costa, MD, PhD: Well, I think the first important thing to acknowledge is that adult-onset SMA exists. Although it's rare, it is probably more frequent than we thought because many patients may be underdiagnosed. When we diagnose adult patients, they've usually had symptoms for 10 or 20 years before they were diagnosed, which gives us an idea of how many patients might be without a diagnosis. Some adult patients are diagnosed because they have a sibling who is more severely affected, and then they realize that the problems they've had—whether in sports or other activities—might be related to what their sibling has. So, the first thing is to acknowledge that SMA symptoms can start in adulthood or late adolescence, and it's important to be aware of the symptoms they most frequently report. This is pretty well-characterized in the paper. Some patients may present with proximal weakness or falls, but many may only have subtle symptoms like cramps, fasciculations, or sports intolerance. Some may even come to our clinic because they were found to have increased hyperCKemia in a blood test, which starts the diagnostic process. So, the range of symptoms in adulthood is very variable, and it’s important to know that.
Mary Schroth, MD, FAAN: I want to emphasize that CK levels don't always guide you in diagnosing adult-onset SMA. In pediatrics, CK levels are usually normal, whereas in Muscular Dystrophy, they’re extremely elevated. In adult-onset SMA, CK levels might be elevated or they might not, which was new and interesting knowledge for me. Additionally, the history of sports intolerance or not being able to keep up with peers is common in many individuals. At conferences, many people report that they didn't think much of it until later when more symptoms like weakness or difficulty developed. It’s a fascinating subtype of SMA that we need to learn more about.
Juan Francisco Vazquez Costa, MD, PhD: Yeah, and it's important to note that some adult-onset patients report very mild symptoms from adolescence or even late childhood. Often, as they reach adolescence or adulthood, they may become overweight because they weren’t good at sports. I had a patient whose parents told him for years that he was lazy, and it wasn’t until he reached adulthood, around age 30, that his weakness was apparent, and he was finally diagnosed. For many years, he was just seen as lazy. The disease in those patients progresses very slowly, and it may change gradually over time.
Mary Schroth, MD, FAAN: Our point here is that if you have an adult patient with this kind of history, consider doing genetic testing for SMA.
Kapil Arya, MD: For my older adolescent and young adult patients, I echo exactly what Juan said. Many of them tell me, "I just thought I wasn't the sporty type." But if they have any functionally limiting symptoms, it needs to be taken seriously, and genetic testing should be done.
Juan Francisco Vazquez Costa, MD, PhD: In these patients, we universally find a neurogenic pattern on EMG. Even if they don’t have visible weakness, the EMG will clearly show neurogenic changes, meaning they’ve lost many motor neurons over time. Compensation has prevented obvious weakness, but the motor neuron loss is there, and you can detect it with an EMG. If you have an adult patient with hyperCKemia or sports intolerance, but their EMG is normal, you don’t need to pursue genetic testing for SMA, because it likely won’t be SMA.
