Peter L. Salgo, MD: Now we’re going to look at something called spinal muscular atrophy [SMA]. I must tell you that before researching it for this broadcast, it was not a disease that was on my radar. But it’s out there. So what is it exactly?
John Brandsema, MD: Spinal muscular atrophy is actually the most common genetic cause of infant death. It’s not the most common genetic disease, but it’s the most infant lethal genetic disease.
Peter L. Salgo, MD: Well, I’m not a pediatrician. That probably accounts for my ignorance.
John Brandsema, MD: Pediatricians probably will run across this at some point in their career. It’s a neurodegenerative disorder, and it’s a motor neuron issue primarily. Because of a genetic predisposition, this disease is autosomal recessive, and affected patients tend to have a presentation with weakness of their limbs and in more severe forms their bulbar musculature and respiratory function as well. After the time of diagnosis, there may be a little bit more gain but eventually a plateau and then a relentless decline in function in the people affected.
Peter L. Salgo, MD: Editorial here. This is in little kids. This is dreadful; it’s awful.
John Brandsema, MD: It is a spectrum disorder, so it can present in infants—that’s the most common group. The incidence is about 60% to present with the most severe form, which presents before 6 months of age, in what we call in the natural history type 1 SMA. But there are milder forms that could present at later times of life as well. There are children who start to walk but then eventually start to become weaker after they are walking. There’s even an adult-onset form that presents after age 18 and can resemble ALS [amyotrophic lateral sclerosis] and other neurodegenerative disorders in adulthood.
Peter L. Salgo, MD: If we were to give it nomenclature, type 1 is infant onset?
John Brandsema, MD: Um-hum.
Peter L. Salgo, MD: Type 2 is intermediate, as you described.
John Brandsema, MD: Um-hum.
Peter L. Salgo, MD: Then there’s types 3 and 4, and they even have names, right?
John Brandsema, MD: Yes.
Peter L. Salgo, MD: I did look this up. Kugelberg Welander disease?
John Brandsema, MD: Yeah. Werdnig-Hoffman would be the most severe, presenting before 6 months of age. Then type 2 is defined by being able to sit but never achieving walking. Type 3 would be achieving walking and maybe losing that ability over life, or perhaps retaining it; that’s Kugelberg Welander disease. Then there’s the very rare type 4 adult-onset form.
Peter L. Salgo, MD: We come back to a question. Because it’s young children mostly, it’s not the child who’s going to walk into your office and say, “Look at me. I’ve got a problem.” It’s parents, right? Do parents recognize this early? Do parents, do you think, come to you and say, “My kid’s got a rare disease. What do I do?”
Sika Dunyoh: Yes. I think seeing progression in such a young age and then start to see a decline, parents are usually the very first to recognize that there’s a problem and then immediately reach out to their physician.
Peter L. Salgo, MD: The horror of that recognition. I didn’t get it until I was a parent. Now that I am, I can’t even imagine what parents are going through. Do you see parents with this?
John Brandsema, MD: Yes. One of the challenges is as the pediatrician taking care of this disease, because it again is rare—1 in 10,000 incidents approximately in the population—some of the symptoms that patients start presenting with are relatively diffuse and more common. The most common thing would be in an infant, hypotonia and a little bit of floppiness, which can be part of normal spectrum of development in some kids. Most primary specialists might think of something like instituting some physical therapy for a couple of months and seeing whether that helps the patient. But in SMA type 1, that is an eternity because they’re going to get worse during that time and start to show problems with their breathing and their feeding. It’s really important to recognize this disorder early on, but there are many other diseases similar to SMA that could present with very similar symptoms in that same age group.
Peter L. Salgo, MD: And again, you said this is genetic. Is there a name for this gene? Do we know where it is on the genome?
John Brandsema, MD: Yeah. This is a unique genetic situation in this disorder. The problem is with the survival motor neuron, or SMN gene. And there are 2 copies of that genome on chromosome 5: SMN1 and SMN2. They’re quite similar to each other. They differ only in a few nucleotides. But there’s 1 critical nucleotide for function that’s different between the 2 of them. People with genetic SMA most often have a deletion of that SMN1 gene, both copies. They are missing their SMN1 gene or part of it for function, both alleles.
Sometimes, 1 is deleted and the other is mutated in some way to make it nonfunctional. But because of that missing SMN1 gene, they’re reliant on the SMN2 gene to make the survival motor neuron protein—SMN protein. In contrast to Huntington disease, in which the problem is toxic gain-of-function, in SMA it’s missing something. That’s the issue. They’re missing that SMN protein, and because they’re deficient in SMN, they develop these symptoms of motor neuron loss and weakness.