Overview of Spinal Muscular Atrophy

James Wymer, MD, FAAN: SMA, or spinal muscular atrophy, is a gradually progressive motor neuron disease. It’s a genetic motor neuron disease. The classical model of motor neuron disease that we know about is Lou Gehrig disease, or ALS [amyotrophic lateral sclerosis]. Spinal muscular atrophy is very different from that. It’s not the same disease. But it does involve the gradual loss of motor neuron function. The other functions—sensory, as well as cognitive function—are very well preserved. SMA is a genetic disease that begins at birth. Patients gradually lose motor function abilities. This includes walking. In some kids, it can involve their speech. It can involve breathing and swallowing, but mostly the arms and the legs are involved.

Spinal muscular atrophy is a genetic disease. The primary cause is a genetic mutation in the survival motor neuron—SMN. The mechanism typically involves a deletion of SMN1, which is the primary survival motor neuron. There is a little second side copy of it, SMN2, which is 99% identical to SMN1. But, that 1% difference means it minimally functions as an SMN protein.

So you’ve got a copy of gene that’s barely functional, and you’ve got the major copy. If that copy is deleted, patients will go on and develop spinal muscular atrophy. Some patients have multiple copies of this SMN2. If you get 3, 4, or 5 copies, that little bit of function of SMN2 all of a sudden becomes enough so the nerves can function and survive. That’s why we have different types of SMA. We’ll talk about type 1, type 2, type 3, and type 4. The type of SMA depends how much SMN2 there is to cover for the loss of SMN1.

SMA is present in about 1 in every 11,000 births. What’s interesting is about 1 in 50 people are carriers for the disease. The actual genetic mutation that I’m talking about is present in about 1 in 50 people, but because it’s what we call recessive, you have to get a mutation from mom and from dad to get the disease. So that’s why it’s only present in about 1 in every 11,000 people. The people in the other group—the other 1 in 50—are perfectly normal. They may have 1 mutated gene, but they’re got 1 perfectly normal SMN1, and that’s enough to provide normal function so they can live life fully and do well.

SMA is a progressive motor neuron disease, that is gradual loss of the motor function. The way it can typically present is with weakness in the bigger muscles, or the more proximal muscles—the hip girdle, the shoulder girdle. You could see a gradual loss in function of some of these muscles. The way SMA will present depends on how old you are. Some of the pediatric patients, or some of the infant cases, the type 1 SMAs, will present with weakness very early in life. They won’t be able to sit up. They’ll have difficulty rolling. If the disease is severe enough, and if it involves their mouth and their ability to swallow, they may have difficulty suckling. They may start presenting with normal milestones, and then they start losing those.

Now, if we look at the type 2 and type 3 patients who present at 6 months, 1 year, or 2 years, again, they start making more of those milestones, but then they start losing milestones. When we get into the later onset and some of the type 3 and type 4 cases, or when they present with the disease after age 18, some of these patients will have normal lifespans. They may not be the best athletes. They may be slow and clumsy. They may have some mild proximal weakness that may present later in life and become a problem. Some patients present with tremors. They can present in many different ways, but they all have the same pattern of this gradually progressive weakness. It just depends on the type—how early and how severe is it going to present?