The Importance of Early Screening of Spinal Muscular Atrophy

Introduction:

Welcome to the Contemporary OB/GYN podcast series brought to you by Quest Advanced Women's Health. And now here's your host for this podcast, Scott Kober.

Scott Kober:

Thank you and welcome to this podcast. My name is Scott Kober, [inaudible] OB/GYN, and today we'll be talking about the importance of early screening for spinal muscular atrophy. I'm happy to be joined by Lisa Blazejewski, a genomic science specialist at Quest Diagnostics, to talk about some of the key issues for practicing OB/GYNs to be mindful of.

Scott Kober:

Welcome, Lisa, and thank you so much for joining me today.

Lisa Blazejewski:

Thanks for having me.

Scott Kober:

So, Lisa, what is spinal muscular atrophy, and why is it a condition that should be on the radar screen of today's practicing OB/GYNs?

Lisa Blazejewski:

Spinal muscular atrophy, or SMA, is a severe progressive motor neuron disease that occurs in approximately one in 10,000 live births. It is the most common genetic cause of death in children. There's currently no cure for SMA, although in recent years, treatments have been approved that slow disease progression and may prevent disease development. However, these treatments are ideally started prior to symptom onset, which makes recognition of couples at risk of passing the disease along to their child before or during pregnancy especially important. Because of its severity and relative frequency, as well as the fact that screening to detect carrier couples is now available, SMA is something that should be on every OB/GYN's radar.

Scott Kober:

Now, why has there been a new spark of interest regarding SMA in recent years?

Lisa Blazejewski:

Until a few years ago, there was nothing that could be done about a diagnosis of SMA. The most severe form of the condition was universally lethal. The news about emerging treatments for SMA has certainly brought some new attention to the condition, but companies offering carrier screening have been interested in SMA for a long time because of its severity and relative frequency.

Scott Kober:

So what causes SMA, and how is it transmitted from parents to a child?

Lisa Blazejewski:

SMA occurs when an individual is born without any working copies of a gene called SMN1. Without working SMN1 genes, little to no functional SMN1 protein, which is required for the survival of motor neurons, is produced. Motor neurons eventually die in the absence of the SMN1 protein.

Lisa Blazejewski:

SMA is a recessive disease. About 98% of affected individuals inherit one non-working copy of SMN1 from each parent. In rare instances, one parent passes on a non-working copy of the gene, and the second copies acquires a new mutation during the production of the egg or sperm prior to conception. This is known as a spontaneous or de novo mutation. De novo mutations are involved in less than 2% of all cases of SMA.

Scott Kober:

Oh. So what are the various types of SMA, and how are they different?

Lisa Blazejewski:

The separation of SMA into numbered subtypes dates back to the time before the genetic basis of the disease was well understood. Consequently, the subtype definitions were based on age at disease onset and the maximum level expected motor function. Initially, the thought was that these were distinct conditions with unique clinical courses, but it's now understood that SMA is a single disease with phenotype and severity that lie along a continuum. The terminology of subtypes is now primarily used as a point of reference for prognosis and management with the understanding that there is not a clear cut delineation between each subtype.

Lisa Blazejewski:

With that background, traditionally type zero disease denotes a prenatal onset of symptoms; type one has symptom onset before six months of age; type two presents between six and 18 months of age; type three has an onset beyond 18 months; and type four is adult onset disease. Adult onset SMA is quite rare, so when you hear people talk about SMA, they are generally talking about type zero, one, and two, which are seen in young children. You will particularly hear about children with type zero and one. These are children who most likely will never reach any motor milestones, and they often die at a young age.

Scott Kober:

So what exactly is a silent carrier of SMA, and why is that important?

Lisa Blazejewski:

In order to discuss silent carriers, we first have to discuss carriers in general. On average, the carrier frequency of SMA in the United States is about one in 50, or about 2% of the general population. The frequency of carriers varies by ethnicity, but generally falls in the one to 2% range, so from one in a hundred to one in 50 individuals. In most instances, someone who is defined as an SMA carrier has a working copy of SMN1 on one of their chromosomes and a non-working copy on the other, but in approximately 4% of carriers, so 4% of the 2%, or about one in a thousand people, two working copies of SMN1 sit on one chromosome while there is zero working copies on the other. That's known as a two-plus-zero arrangement, or silent carrier status, and it's important to recognize they're silent carriers, because the most common screening methodology for SMA carrier status does not distinguish between individuals who have two copies of SMA have one arranged in the typical one-plus-one or more rare two-plus-zero pattern.

Scott Kober:

Are there any specific signs or symptoms that clinicians can use to detect a possible silent carrier of SMA, or is it something that's clinically indistinguishable?

Lisa Blazejewski:

Because all carriers of SMA have enough SMN1 protein, there are no clinical signs or symptoms to identify a silent carrier. Even a carrier with one copy of SMN1 has enough working protein that their motor neurons remain healthy. A silent carrier actually has two copies of the gene just as a non-carrier does. So from a physical standpoint, again, they are completely indistinguishable. Further, on typical carrier screening, their silent status manifests as if they are non-carriers of SMA.

Scott Kober:

So then how is SMA carrier status typically detected today?

Lisa Blazejewski:

The most common current methodology is what is called a dosage analysis of the SMN1 gene. It measures the total number of intact copies of the gene that are present. So if you have one copy identified as being present, you're called a carrier. But for silent carriers who, again, have two copies of the gene present, but in the two-plus-zero formation, even though they are at risk to pass on a chromosome without working SMN1 onto their children, they will appear as non-carriers because they have two copies of SMN1 detected.

Lisa Blazejewski:

Dosage analysis is literally what it sounds like. How many doses of SMN1 can we see? It can't, however, tell us how they are arranged on an individual's chromosomes, and that is where the concept of two-plus-zero testing comes in, which is an enhancement that has just been incorporated into Quest's SMA carrier screening. The enhancement centers on something called a single nucleotide polymorphism, or SNP, which is a variation that doesn't cause disease but is just a known variation in a known location along a chromosome. In specific populations, there is a SNP in SMN1 that is known to be strongly associated with the risk of having that two-plus-zero configuration that we have discussed. In other populations, the SNP makes it less likely that one carries their SMN1 genes in that configuration. And so by screening for that SNP in addition to the traditional dosage testing, a better risk assessment may be made of who is more or less likely to pass on that genetic abnormality to their children.

Scott Kober:

So what do current consensus expert guidelines say about SMA screening protocols?

Lisa Blazejewski:

The American College of Obstetricians and Gynecologists and the American College of Medical Genetics and Genomics both recommend that carrier screening for SMA be offered to all women who are pregnant or considering pregnancy. It's a blood test just like any other screen, so there is nothing more complex about SMA screening from the provider side than tests for cystic fibrosis, or sickle cell anemia, or any other well known carrier screens.

Scott Kober:

What is the recommended next step for individual who receives a result showing either one copy carrier or two copies with increased risk from the SNP?

Lisa Blazejewski:

In either of those cases, the recommendation would be the same. The individual's partner should be screened if they have not already been screened. Because SMA is a recessive disease, in order for a baby to be at risk, both parents have to carry the risk of passing it on.

Lisa Blazejewski:

Now, if both parents share a risk of passing on the disease, they should be referred for genetic counseling. If the carrier screening is run during pregnancy, there can be consideration of fetal diagnostic testing. If this information is obtained prior to conception, there can be discussions of alternate reproduction options, such as egg donors, sperm donors, adoption, and so on.

Scott Kober:

So, Lisa, as we're wrapping up this conversation, what are the two or three key points that you would want our audience to take away from this discussion?

Lisa Blazejewski:

First of all, SMA is relatively common among genetic conditions with prevalence of approximately one in 10,000 births, and it is severe, the most common genetic cause of death in children. Secondly, carrier screening for SMA is available and is recommended by major OB/GYN and genetics societies. And, third, carrier screening is made more challenging by the complexity of the SMM1 gene and its potential arrangements. The SMA carrier screening platform that many labs are using and most OB/GYNs are ordering may not fully address the complexity of the SMN1 gene, but screening is available that can refine the risk for patients to be so-called silent carriers of SMA, and allow more patients to know if they have the risk of being carriers for SMA and potentially having babies that will inherit this devastating disease. Quest Diagnostics now offers this comprehensive testing.

Scott Kober:

Well, great. I think this has really been a terrific discussion about some of the core issues surrounding current screening protocols for [inaudible]. So thank you so much for joining me today, Lisa.

Lisa Blazejewski:

Thank you so much for having me.

Introduction:

Thank you for joining us today. You've been listening to the Contemporary OB/GYN podcast series. This podcast is brought to you by Quest Advanced Women's Health.