Using Genetic Testing to Help Diagnose Spinal Muscular Atrophy

Nancy L. Kuntz, MD: What is your experience, all of you on the panel, in terms of the genetic testing? So many of the genetic tests that can be offered are offered in broad panels with many, many different genes tested and a variable cost, but sometimes a significant cost. Do you find that the SMA [spinal muscular atrophy] or SMN gene testing is readily available, reliable when done in a targeted fashion rather than as part of a panel? Do you have any sense of the cost?

Elizabeth Kichula, MD, PhD: I think it’s really important, especially since the high majority of these are deletions, that this is not something that would be picked up on whole exome sequencing. And I think as more and more people rush to do whole exome sometimes as the first test, I think it’s important to remember the disorders that you’re missing, and SMA would be included there.

Claudia A. Chiriboga, MD, MPH: And also, it’s an issue of timing, because if you just do the SMN1 gene, it can be done quickly. In some centers we can do it in 3 days, and time is of the essence because time is motor neuron. Whereas the whole exome sequencing can take 3 months or so, and that’s time that you lose looking for things that you might not even identify, as you pointed out.

Elizabeth Kichula, MD, PhD: And I think the other important piece is to really pay attention to what test you are sending. So different laboratories may just test for the double deletion that is responsible for 95% of cases and may not identify carriers. Others may do only deletion testing, and others may do deletion testing and then reflex to sequencing if the deletion testing is negative. So it’s very important to be aware of exactly what the test is doing before you send it.

Nancy L. Kuntz, MD: Exactly what steps would you take, Basil, if you had a patient in whom you had a high suspicion—say an older child, a school-age child with some proximal weakness, limb girdle weakness, and relatively decreased reflexes—but for whom the initial deletion testing comes back negative and you still have that suspicion? What are the best steps to take?

Basil Darras, MD: If the testing is totally normal, it does not even show 1 copy of the SMN1 gene—and I’m saying that because if the result comes back as the child being a carrier, it’s discussed earlier actually to pursue sequencing of the second allele, the second chromosome, trying to find a small-scale mutation, a microdeletion, microduplication, or any type of mutation that could give us SMA in a compound heterozygous state. If it comes back as the child having two SMN1 copies, there’s always the possibility of having a small mutation that’s in a homozygous state. But that’s so rare that if you don’t have consanguinity, for example, it’s something that most colleagues will not actually pursue any further. But I think there’s been a rare exception but something that I don’t think that is seen in clinical practice on a routine basis.

So the child seems to have a normal test, and particularly the CPK [creatine phosphokinase level] is somewhat elevated. I don’t think it’s a bad idea to think about doing electromyography to see whether you have any neurogenic changes or whether you have myopathic findings, where the EMG could be normal. So the EMG is an extension of the physical exam, and it could be something that could be pursued in a case like this to give you some guidance as to how to proceed in that case. Now, whether you’re dealing with a patient who has a neuropathy or a patient who has an EMG that looks like SMA, the possibility of nonchromosome 5q SMA comes up. But these are very, very rare diseases. In my clinic I have only a couple of patients who have nonchromosome 5q SMA. The EMG will help us discern myopathic findings, and then we may end up doing a muscle biopsy, for example.