Early Referral to Neurologists for SMA Diagnosis


Expert pediatric neurologists review the importance of early recognition and referral to neurologists for the diagnosis of spinal muscular atrophy and when it’s appropriate to approach treatment.

John Brandsema, MD: We talked about the incidence of about 1 in 10,000. Carrier frequency is much higher. We have about a 1 in 50 carrier frequency, and sometimes it is even higher for people of certain ethnicities. What I have found, in our clinic [Children’s Hospital of Philadelphia] at least, is that when we have parents identified as carriers, and they choose to test their fetus for whether they are affected with SMA [spinal muscular atrophy], that referral is still urgent, of course. But it is in a very different mind space than what you alluded to earlier, Julie, with the postpartum: “I have this beautiful healthy baby, and now someone is telling me I have to make a decision between all these treatment options.” It is so overwhelming. You have some time to talk through what SMA is as a disease, what kind of things we could plan for when the baby is to be born, and for some families, still, they might make decisions about the pregnancy knowing this about the fetus. This is important information to understand. Then, the last question I would have for you, Julie, is let’s say somebody comes to you, either through prenatal diagnosis or through newborn screening, and they have a very high SMN2 copy number. Let’s say it is greater than 4, which is what most of the reports will say. This has been an area that is a little more nuanced in terms of what exactly to do in that circumstance, and I am wondering what your opinions are.

Julie Parsons, MD: Yes; there is a little controversy in terms of what to do. To me, the most important thing is the history and the examination with the patient. If a patient is completely strong and has reflexes—and it is a little harder to get the exact copy count as the patients have more than 4 copies, so you can go back and get a copy count. It becomes a little less accurate, but we do have a couple of patients who have 5 copy numbers. To diagnose a patient with 5 copy numbers—a typical, normal, healthy baby whom I cannot tell has SMA—we are doing electricals [electrophysiology]. We are doing nerve conduction studies for these patients to continue to follow them along, and I am following up with them every 4 months with an exam history and with electricals to look and see what that patient looks like. I struggle with if this is the right thing to do or not, and certainly, there are some pediatric neurologists who say, “Well, if you have SMA, you should be treating them immediately,” but as we will discuss some of the therapies, they are not all benign; they are not all easily tolerated. Is it reasonable to treat a newborn with therapies, either with repeated spinal taps or with gene transfer therapy that carries some risk with it, when we are not necessarily sure about durability? Is it reasonable to treat them when they may not present with symptoms until they’re 30 or 40 years old? That is really challenging. I have to say that, with the prenatal testing we have had, we have had a couple of women in their 30s who have SMA and have copy numbers of 5, 6, 7, and they had no idea they had SMA. Do we treat a patient based on their genetics? Does that make sense in terms of the risk-benefit ratio? I know there are other people who are aggressive and will say, “If they have it, I’m treating them, and I’m treating them early.” What has your tack been, John?

John Brandsema, MD: I think it is really nuanced, and I do not know that there is a black or white answer now. I think what I am trying to balance in my mind, too, is we do have a consensus statement from experts in the field that was very clear that anybody with fewer than 4 copies of SMN2 should be treated with the first iteration. Then they published a revised version where those with 4 copies also would be treated. But it is when treating those who have more than 4 copies of SMN2 that I think it gets really challenging because you mentioned, of course, the examples of the very mild phenotype or no phenotype that are out there, where people do not even realize they have SMA and yet have both copies of SMN1 deleted. The other part to that thinking is what we know about motor neuron disease in general, which is that we cannot detect it very well. In people who have genetic ALS [amyotrophic lateral sclerosis], and we watch them like hawks with motor unit number estimation and electrophysiology, which you alluded to, physical exams, and everything else we can think of, it can be up to 50% of your motor neurons that are gone before there is any manifestation we can detect. How can you conceptualize not getting ahead of that with the targeted treatment and losing 50% of your available pool of motor neurons? Is that not going to be an implication for that person at some point in their life? That is the argument, I think, for treating earlier. I certainly do not think you would get the same answer if you had 10 neurologists who specialize in treating SMA in a room right now. I do not know that that is going to change soon, but we are all trying to learn about it together.

Julie Parsons, MD: If we do get a sensitive biomarker, that would be so helpful to us when making those decisions.

John Brandsema, MD: Absolutely.

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Transcript Edited for Clarity

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