Nancy L. Kuntz, MD: At this point in time, we have to have suspicion of the disease or the disorder in order to do the testing. What signs or symptoms would you use to key you in toward the need to proceed with testing for spinal muscular atrophy [SMA]?
Claudia A. Chiriboga, MD, MPH: Well, it depends on the age of presentation. Because in infant onset, the babies will be very floppy and typically will have, in addition to hypotonia, weakness and difficulty with breathing and ultimately with swallowing. Babies who are intermediate might just have some motor delays and then develop more severe weakness. And then children with the type 3 who oftentimes are late in diagnosis may have clumsiness of gait and frequent falls and not be identified until later. So those are some of the aspects that you look for early on in terms of trying to make a diagnosis.
Elizabeth Kichula, MD, PhD: Looking at those earliest-onset patients, I really think of areflexia and tongue fasciculations as being the red flags to look for. And I think it’s important to think about in the type 2s and type 3s or the later onset—that they may still have some reflexes, but they can be significantly decreased because sometimes people are looking for the pure absence of reflexes, and the presence of them can sometimes lead them astray in the diagnostic evaluation.
Claudia A. Chiriboga, MD, MPH: Quite true, but tongue fasciculations and dysphagia are somewhat late findings, but the areflexia is a very early finding, especially with the floppy frog legs. I think those are some of the early presentations that we’ve identified in our presymptomatic children infants when they start to develop symptoms.
Elizabeth Kichula, MD, PhD: And a lot of SMA has what we see in other neurodegenerative diseases that strike early on in development, where there can kind of be an overall normal developmental trajectory for a period of time, often with some delays early on. But it’s that plateau in the regression that really presents to red flags. Although as we talk about the new treatment options, I think we’ll also have to talk about how we have to have a higher index of suspicion to think about these diagnoses earlier.
Nancy L. Kuntz, MD: Do you have any other thoughts that we should throw in about key findings that you’ve experienced over the years that help you with picking the children with SMA out of the broader differential?
Basil Darras, MD: Quite often you have an infant or somewhat older child in whom you see weakness and hypotonia. And the question is, does the child have SMA or let’s say a myopathy? And looking at the face is very, very important because most of our patients with SMA, at least early on, they have a very expressive face. And the reason is that there is preservation of the innervation of the facial muscles. So that’s something that I usually discuss with the residents. They don’t have the myopathic face we see with say congenital myopathies.
Nancy L. Kuntz, MD: Right.
Claudia A. Chiriboga, MD, MPH: For older-onset, later-onset SMA, the neurogenic tremor—the mini polymyoclonus—is oftentimes overlooked and not attributed to SMA. And I think that’s an early sign that sometimes is overlooked.
Elizabeth Kichula, MD, PhD: The other thing I try to remind people of is particularly in the type 3s, they may have a slight elevation of CK [creatine kinase], and we should not be completely led astray with that. It would be very unusual to have a CK higher than 1000 U/L, but certainly a slight elevation can be common in those patients who are still ambulatory.
Nancy L. Kuntz, MD: Any other thoughts about differential diagnosis?
Elizabeth Kichula, MD, PhD: I think it’s a little bit challenging to talk about differential diagnosis in a disease that has so many phenotypes, looking at the broad severity. The differential is very different if you’re talking about an infant who’s coming in at 3 to 4 months with severe hypotonia than if you are talking about a 6-year-old who’s coming in with an increase in falls and problems getting up the stairs.
So the differential really can be quite broad. I think it frequently boils down to really trying to elicit the actual weakness very early on, particularly when you’re evaluating children whose primary concern is low tone, and really trying to evaluate how you’re going to look at the weakness in these young, often noncompliant patients that we’re seeing. And so try to get a grasp of their antigravity movements at their functional movements by having them climb stairs and get up off the floor, I think, are really important clues in looking at things.
As you go down the diagnostic pathway, particularly with SMA type 1 patients who are presenting symptomatically, they often can have such a classic phenotype. If they do have, they’re more likely to have the tongue fasciculations at present and to have areflexia, and jumping directly to genetic testing is often indicated. In a lot of the older children it can be a little bit more difficult and they may go through a little bit more of a diagnostic journey.
Claudia A. Chiriboga, MD, MPH: That’s a good point, if you’re not sure of an infant with hypotonia, it’s best to test them for SMA because you need to identify that early, and then you can address the broader differential diagnosis if it turns out that it’s not SMA.
Basil Darras, MD: It can get confusing when you have a child with proximal weakness, or it happens that they also have some degree of CK elevation, as you said earlier. And sometimes patients who have type 3 SMA, they can even have a little bit of capsular hypertrophy, so the possibility of muscle disease comes up. In some of those cases, particularly when there is some urgency, perhaps doing electromyography [EMG] might be useful because the EMG findings in SMA are very, very typical. But I have to say that we’re not doing a lot of electromyography these days outside the ICU [intensive care unit] setting. It’s unusual to do electromyography, and most of the time, as you said, we just send the DNA test and try to make the diagnosis excluded.