Nancy L. Kuntz, MD: We’ve all encountered a wide spectrum of severity with spinal muscular atrophy, everything from early infantile onset through onset in adult years. Can you provide any perspective on that, Claudia? Do we have any clues about what creates the variability in severity?
Claudia A. Chiriboga, MD, MPH: Absolutely. Well, the traditional classification of types, which probably is going to fall in disuse because of the changing landscape of SMA [spinal muscular atrophy] with treatment, is based on ultimate functional outcome. And as you noted at the beginning of this conversation, the earlier the presentation, the more severe the phenotype. So infants presenting with signs and symptoms under 6 months of age are the most affected. We’re not talking about the type 0s or the embryonal lethal cases, as Basil was talking about. But those are the most common. And the incidence is about 60%. Their survival is diminished, so the prevalence is less than that. And those are babies who are classified as never sitting independently. So now we would say the nonsitters, rather than saying type 1. And then there is the intermediate type—which is the SMA type 2, or the sitters—which are children who do sit and who present also in infancy but usually after 6 months of age and up to 18 months of age. And those children have a milder phenotype.
The type 3s are classified because of the ability at some point in time of walking, and they may lose that ability depending on how early they present. And that we would call them now ambulating patients. And then the adults who present after age 30 or so would be the least affected phenotype that we have. And what modulates that severity, even though it is the same gene mutation that all of them have, is that backup gene that Basil was talking about, the SMN2, which has that alternative splicing: instead of producing that delta 7 nonfunctional protein, it produces the 10%, 15% of a full-length SMN protein, which is the 1 that children with SMA are missing.
And then if you have different number of SMN2 copy numbers, that will modulate the severity of the phenotype. So typically, even if you look at those bar graphs in which there’s a wide base, the median number of SMN2 copy numbers is 2 for babies with severe phenotype: all type 1s. And that increases the milder the phenotype, so there’s an inverse relationship between SMN2 copy number and severity. So type 1s will typically have 2 copies. The sitters, or type 2s, will have 3 immediate copy numbers; the type 3s, or the ambulating patients, will have between 3 and 4 copy numbers.
Nancy L. Kuntz, MD: Because they have more SMN protein.
Claudia A. Chiriboga, MD, MPH: Because each of those are producing a little bit more, and at some point, you may have so many copy numbers that you may not have any evidence of the disease even though you have the deletion, depending on how much functional protein is being made by those copy numbers.
Elizabeth Kichula, MD, PhD: I think there are a couple of important comments about the SMN2 copy number, which I think you started to talk about, Claudia. While we can talk about averages, there are exceptions to every rule, and there certainly can be type 1s who have more than 2 copies of SMN2. And also, I think we run into more problems with getting an accurate SMN2 copy number when we have higher copy numbers, which are also some of the limitations that may come up again later in our conversation when we talk about decisions regarding treatment.
Claudia A. Chiriboga, MD, MPH: Quite true. Some laboratories don’t even measure beyond 3 copy numbers. Absolutely. And that base can be very broad. So it’s more a prediction of what you expect based on probability rather than an absolute.