Phenotypes of Spinal Muscular Atrophy

Crystal Proud, MD: Historically, spinal muscular atrophy [SMA] was categorized into 3 main phenotypes: type I, type II, and type III. While we are moving away from utilizing these phenotypes in an era of treatment, they may be relevant for us to review as we refer to them with regard to clinical trial data. Nancy, could you please briefly describe these 3 main categories and what they might mean?

Nancy L. Kuntz, MD: It's very important to mention that we recognize that the phenotypes or these categories were developed before the gene was identified and before people were even very certain that this was a spectrum of 1 disorder. Now that we realize that the same gene is involved in all of the forms of 5q SMA, we are less independent on the individual types: type I, II, and III. This is important not only because now these are going to be changing as we begin to treat the children, but also because there truly is a spectrum of disorder from the very rare neonatal onset that most of us have only seen once or twice in our entire careers, where there is only 1 backup copy of the SMN2 gene that we'll talk about in a moment, to all way into a spectrum where there's a type with adult onset.

It isn’t clearly delineated between these groups. This relates even to the presentation to primary care physicians and neurologists. There is a spectrum of severity, with the most frequent presentation being one during infancy, where during the first 6 months of life but not during the newborn period, there's an onset of the symptoms. This is what has been called Werdnig-Hoffmann or type I.

As John so eloquently put it, the infants start with making little motor progress, so that the incomplete head control that is normal in the newborn period persists and begins to look like a head lag or head instability in slightly older infants. It's very common for these children to use a lot of common sense and slow down their feeding when they begin to have bulbar weakness and problems swallowing, so that the way it presents to parents and to pediatricians frequently is with very slow feeding, children who seem to never feed or finish 1 feeding before it's time for the next.

Sometimes this even presents with slow weight gain because they just can't get in enough calories. At around the time these symptoms develop, one of the phenotypic things that can be seen during infancy to separate it from other disorders is the presence of tongue fasciculation. Once you've seen these, it's very easy to recognize them again. The important thing to remember is that these are involuntary tremulous or twitch-like movements within the muscle of the tongue.

It's not a repetitive sucking or tongue thrusting like you would see in infants, but more of if the tongue is still and the outline of the tongue is stable, you'd see a little dimpling within the tongue. That would be tongue fasciculation, something that along with the very difficult, if not absent, muscle stretch reflexes are relatively characteristic and should make one think of infantile onset or type I spinal muscular atrophy.

All the other types of spinal muscular atrophy in childhood are really just smaller degrees of some of the same symptoms. So, what had been called type II, or some people characterized by spinal muscular atrophy where the children can attain the ability to sit independently but not to progress to weight bearing or standing, is a slightly milder form. These children, in addition to having, again, marked decrease if not absence of muscle stretch reflexes, have a tremulousness, a tremor that appears during reach and activities, particularly in the upper extremity.

This can, for some children, be so dramatic that it can be one of the first things that therapists or parents or pediatricians might notice, a very high frequency, low amplitude, even tremor that is characteristic of the milder form or intermediate form of spinal muscular atrophy. The final form is type III that people talk about, and is very similar at presentation to a limb-girdle muscular dystrophy with proximal weakness, more prominent in the lower extremities than the upper extremity, and usually presents either with falls or with a change in gait, or difficulty getting up from the ground or the floor.

I had a patient who had difficulty getting out of his crouch as a baseball catcher at his presentation with type III spinal muscular atrophy. These children occasionally also have some of that same tremor, though it's not always as marked as in the more severe younger children. We are in an era where spinal muscular atrophy is treatable, and therefore, we're working very hard. We'll hear in a moment about newborn screening.

When primary care physicians and clinicians encounter many of the children in the future, we will be seeing them as a result of a newborn screen, where the concept of type I, II, and III is less important to the children, who would all benefit from treatment and treatment early on in the course. But it still gets brought up by the insurance companies, who want to know what type. But that's what they're referring to, the historical type I, II, and III of spinal muscular atrophy.

Crystal Proud, MD: Thank you for sharing that categorization with us, especially as it's one that we really refer to more in the historical sense now to provide some reference and some landscape for us.