Spinal Muscular Atrophy Diagnostic Workup


Philippa Cheetham, MBChB, MRCS, MD, FRCS: So if you were picking up the phone to talk to a community neurologist to have a patient in their office and they said to you, “You know, I’m concerned that this patient may have this diagnosis,” what would be the questions that you would ask of a community neurologist to say, “Have you done this, have you done this, have you done this?” to get the preliminary work up to know that they’re on the right road to making that diagnosis, before they even get to you?

Crystal Proud, MD: I think that first and foremost is listening to the patient. What Sebastian said to us was that it had become something that had been affecting his life. He was setting them apart from his peers. It was not only setting him apart, but it was getting worse over time. He was having more trouble. Once again, there is that feature of regression or loss of previously gained skills. At that point, when you have someone who was telling you that they have weakness in your visualizing a degree of weakness in front of you, 1 of the first tests to do is a muscle enzyme test looking at CPK [creatine phosphokinase]. If it is elevated into the multiple thousands, 15,000 to 20,000, that indicates constant muscle breakdown from a process like muscular dystrophy.

Philippa Cheetham, MBChB, MRCS, MD, FRCS: That was my next question. So, we’re going to be talking shortly about some of the specific treatments for spinal muscular atrophy. Now, for somebody who is not specializing in this area, we know that there are other neurological issues like muscular dystrophy. And yet, these treatments that were going to be talking about a very specific to spinal muscular atrophy and yet with other issues like Duchenne muscular dystrophy, I’m sure is a very similar presentation of these kinds of symptoms that patients present with, yes?

Crystal Proud, MD: There are, and so it’s important to make sure that we’re kind of going down the right path. Are we dealing with muscles with dystrophy or nerve damage, and neurogenic abnormalities, which is SMA [spinal muscular atrophy]. So the CPK can be mildly elevated in our patients that have SMA but not to the degree that it would be for a dystrophy. So 1 test at least add to the list. And then these days, it’s actually incredibly easy to test for spinal muscular atrophy with no cost to the patient because all funding and support through various organizations, whereby that SMA testing can be done at no cost and returned within a week.

Philippa Cheetham, MBChB, MRCS, MD, FRCS: And we’ve heard also about how Sebastian initially was getting physical therapy for tightness in his lower limbs. Is that a common presentation, that patients are going off down these other avenues and coming to you through not just through positions but through patients who have been taken care of by other support systems like physical therapy?

Crystal Proud, MD: Absolutely. I really enjoy talking with my physical therapy and occupational therapy colleagues because they may actually see these patients before they see me. You know, it’s I think pretty typical for many doctors that, if you have weakness or if you have discomfort or tightness, I’m going to send you to PT [physical therapy] to see if I can make that better. And I think we need a little bit of a mind shift here where we can continue to try to make it better. But we also need to figure out the why. And I am where the “why”, hopefully, comes from.

Philippa Cheetham, MBChB, MRCS, MD, FRCS: Right.

Crystal Proud, MD: So doing both at the same time is really what would urge these neurologists and primary care people.

Philippa Cheetham, MBChB, MRCS, MD, FRCS: One of the things that I remember very clearly from medical student days doing pediatrics, is that you guys love to draw a family tree—brothers, sisters, mom, dad, cousins. You take value in asking questions about family tree to identify who may be the carrier where the other children in the family may be affected? How important is it to look at siblings like Sebastian and know whether there is other people in the family that may have an undiagnosed spinal muscular atrophy as well?

Crystal Proud, MD: It is autosomal recessive and so it’s a little bit more difficult than if it were autosomal dominant. So, there are many, many families who have no other family member diagnosed with spinal muscular atrophy. And so the family tree, while in pediatrics, you’re right. We do consider that very important. So in the event that there’s no one else in the family with a muscle or nerve condition, it does not mean that this is not SMA.

Philippa Cheetham, MBChB, MRCS, MD, FRCS: And you talked about the inheritance, the autosomal recessive vs. autosomal dominant. Can you drill down on what that means for the layperson when you’re explaining to mom and dad about the inheritance of this disorder, particularly for parents for thinking about the children? Can you explain what that means, autosomal recessive?

Crystal Proud, MD: So, for Sebastian, it means that most likely his mom was a carrier. And as a carrier, you are not typically symptomatic so, mom would have no way of knowing that she was a carrier. She have no muscle weakness and otherwise would be a healthy individual. Dad was also likely a carrier and once again, asymptomatic, no way of identifying that he was a carrier. And those 2 individuals have a child who then has a 25% likelihood of having spinal muscular atrophy.

Dr. Proud, it always makes me smile when patients have a diagnosis without understanding treatment categories or disease categories. They always seem to want to know am I stage 1? Am I type III, type I mark? And yet often is not a clear understanding of what these different disease categories actually mean. As far as SMA is concerned, we’ve heard about type I, type II type III. How do you break it down and categorize the disease?

Crystal Proud, MD: So these days, I actually do not categorize any longer. And the reason for that is because we’re in an era of treatment, where someone who used to be a type I is now defying that category. But I can refer to it in a historical sense. So we refer to someone as being a type I patient if they never reach the ability to sit. So, that’s going to be our infants with spinal muscular atrophy. Usually, they present with profound weakness in the first 6 months of life.

A type II patient reaches the ability to sit but never stands and walks. And then, our type III patients reached the ability to walk though many of them actually without treatment would lose that ability. And so Sebastian would be characterized, if I was characterizing him, as a type III patient who has the ability to walk.

Philippa Cheetham, MBChB, MRCS, MD, FRCS: And you mentioned type III as the ability to walk. But it’s not like might walk or not walk. You find that patients and that type III category, some are walking but it’s delayed walking or they’re walking at the time they’re expected to but their posture may be different. Their balance may be different.

Crystal Proud, MD: Absolutely. So Sebastian walked, in talking with his parents, at the time that one should, so he walked before the age of 1. But his parents noticed at about the age of 3 or by the age of 3 that there was a difference in the quality of his walk. And that is pretty characteristic of many of my patients, that even if no one else recognizes it visually, they feel different. They’re not the most athletic kid. They’ll have more tripping and falling, things like that.

As some of my patients who are categorized or would’ve been categorized as a type III patient, they actually lose the ability to walk and may need a wheelchair, even a power wheelchair to be able to move in the environment. And as we think about types, it’s critical to recognize that it’s a phenotype, that the DNA is the same across all of these phenotypes. All these patients have a missing or mutated SMN1 gene. They may have a different number of copies of that backup gene, which may help facilitate what that phenotype looks like.

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