Podcast transcript
Dr. Malik, I'd like to begin the conversation with you today. Could you start by giving an overview of the role genetic testing plays in the diagnosis and management of neuromuscular illnesses?
Malik: Genetic testing plays a crucial role in the diagnosis and management of neuromuscular illnesses. It can help provide a definitive diagnosis in cases where clinical symptoms alone may not be conclusive. Neuromuscular disorders often share overlapping symptoms, making it difficult to distinguish between them based solely on clinical presentation.
Let me give you an example of a patient that we saw yesterday in our MDA clinic. This was a 29-year-old man who presented with progressive weakness. His exam was significant for high arches, hammer toes, and decreased vibration in the distal lower extremities, which would typically suggest the presence of a hereditary sensory motor neuropathy. However, he was also noted to have fasciculations over the hands, quads, and peri oral region which is typically seen in motor neuron disease. Finally, he was noted to have winged scapula, which is most commonly seen in muscle diseases. We performed genetic testing and he was found to have a mutation in the TRPV4 gene, which has been identified in patients with scapuloperoneal SMA and CMT2C. Genetic testing in this case was critical in coming to a diagnosis.
Aside from the use of genetic testing for diagnostic purposes, increased accessibility to genetic testing has helped significantly in providing early diagnosis in affected individuals and families, helping to reduce the need for additional, sometimes invasive, testing. Genetic testing can help families understand the risk of passing on the condition to their children. This information is vital for making informed decisions about family planning and reproductive options.
Finally, in this era of gene therapy, genetic information gained from testing can inform the development of targeted therapies and aid in selecting candidates for clinical trials testing new treatments.
One of the things I was curious about in preparing for our conversation today was the ways genetic testing has evolved over the last few years. Could you talk about that as well as some of the latest techniques used to identify genetic mutations?
Malik: We've come a long way. The early years of genetic testing involved techniques like karyotyping, which involved examining the number and structure of chromosomes. This was especially useful for diagnosing large chromosomal abnormalities, the kind that you see in Down syndrome.
In the 1980s and the 1990s, with the advent of PCR, it allowed for amplification of specific DNA sequences. This enabled the identification of single gene mutations. About a decade or so later, the development of automated DNA sequencing technologies such as Sanger sequencing revolutionized genetic testing. It now became possible to sequence entire genes and identify mutations underlying various genetic conditions.
About 10 years ago, next generation sequencing, or NGS, technologies emerge, allowing for simultaneous sequencing of multiple genes or even entire genomes. This led to the rise of panels for specific disorders, whole exome sequencing and whole genome sequencing, which enabled more comprehensive genetic testing. Advances in next generation sequences have led to increase speed, accuracy, and cost effectiveness of testing.
Rich, I was wondering if you could touch on the main benefits that early genetic testing can provide for individuals who are suspected of having a neuromuscular illness.
Dineen: Sure, and this always takes an opportunity for me to remind people that with a lot of the conditions, an individual may not have a family history. So although they're genetic, they may not necessarily be hereditary in terms of having a prior family history. Given that information, there have been essentially two approaches to try to identify at-risk individuals in the general population. First that I can think of is newborn screening, that test that's done on every infant shortly after birth. The state of Illinois has been testing for Pompe disease for many years now. With regard to recent developments, the state of Illinois began screening for spinal muscular atrophy in the year 2020. As treatment is now available for that condition in a short amount of time, virtually all of the states in the United States are now screening for that condition so that infants can have the benefit of early identification and treatment.
As the landscape is also changing for conditions like Duchenne muscular dystrophy, there have also been discussions about whether that particular condition should be added to the newborn screening panel.
A second area that I can think of that is used for screening, the general population pertains to individuals who are either planning a family or individuals who are currently pregnant where they may be offered a carrier screening of some type. And that has also completely changed in the last several years where we used to do carrier screening based upon somebody's background and possibly family history. So for example, if somebody was of European background, we might offer cystic fibrosis testing. If someone was African American, Sickle cell testing. That's all changed today where we're really offering carrier screening for conditions regardless of background and family history.
A concept which is called expanded carrier screening actually can screen an individual for close to a couple hundred different conditions with a single test. And again, a lot of the focus on that is to identify couples who may be at risk to have a child with one of these conditions, and again, going back to the newborn screening examples where spinal muscular atrophy and Duchenne muscular dystrophy are parts of those expanded carrier screening tests.
Are there any challenges or limitations for using genetic testing with patients who have neuromuscular illnesses?
Dineen: One of the challenges is really keeping current on the genetic testing landscape. The number of testing options continues to change and different testing laboratories continue to update their genetic technology and other types of testing methods.
For some of the neuromuscular conditions that we work with in clinic, there may be many, many laboratories available that can do testing. But then there are some conditions such as FSHD muscular dystrophy where there may only be sort of a few genetic testing options for the entire country. But part of our job is really to be knowledgeable about that information and be able to offer it to our patients.
In regard to limitations, there are a number reasons for which genetic testing can be limiting. Sometimes it can be based on a specific condition. So if I think about the general category of type 2 CMT for example, a very large percentage of those patients still don't get informative genetic testing. And that's not because that the testing isn't doing its job. It's just pointing out that we still have a lot to learn of potentially specific genes or other genetic mechanisms that might cause that particular condition.
Another area, and even with genetic tests that we consider to be very comprehensive, tests like whole exome sequencing or WES, or whole genome sequencing or WGS, there are still patients who have negative test results, even in those instances when we strongly suspect that there may be a genetic cause to their symptoms. And so genetic testing has come a long, long way, but there's still ways for us to go.
What about the level of accessibility and affordability for genetic testing?
Dineen: Just like Dr. Malik, I'll use an example from yesterday's clinic, a woman who came in with a new diagnosis of CMT 1A. Her father had had genetic testing back in 2006. His testing for a single gene cost thousands of dollars back then. Whereas today, she was able to participate in a program and really not have any cost associated with her test. And even if there was an instance where her healthcare coverage did not provide coverage for testing, there are many laboratories that would've done that testing for about $250. So it shows how testing has dramatically decreased in cost as Dr. Malik had said earlier. And I think probably one of the biggest misconceptions that people have is that all genetic testing is expensive.
That being said, there are certain groups where there can be challenges, and I think particularly the Medicare population, where Medicare recognizes very few genetic tests still at this time where they may recognize genetic tests for the area of cancer, but for very few other areas. That being said, again, our job as a clinic is to know the options available to patients, and those continue to increase. So some of those other options continue to be things like pharmaceutical industry sponsor tests where genetic testing can be offered to somebody at no cost as long as somebody is sort of comfortable with some of the parameters of participating in that type of testing. And again, there are also cash options for some genetic tests, generally in the area of a few hundred dollars. So, I'd say in most situations, we're able to find an option that works for a patient where everybody feels comfortable proceeding.
I've got a follow-up question about accessibility that maybe is for both of you. It's a two-part question, one on just how unique is it for RUSH to have this level of genetic testing available to patients? And the second part of that is for referring providers listening in, can you talk about the challenges in referring providers maybe not knowing of all the level of genetic testing that's available for their patients? And is there a bridge that you have to cross to help providers in the community and the region know about the offerings that are available here at RUSH?
Malik: I think the first thing is having the right clinical question, right? And so that's definitely the most challenging piece of neuromuscular illnesses. So you do need a little bit of an expertise and experience in recognizing what particular neuromuscular disorder you may be dealing with, because then that would subsequently help with targeted genetic testing.
As Rich mentioned, there are now options available for sponsored genetic testing, which are really large panels. So those types of genetic testing and diagnostic studies may be routinely available at most centers, but if those first battery of tests start coming back negative, that's really where the diagnosis sometimes comes into question. And sometimes you need an experienced genetic counselor, especially one who has experience in neuromuscular disorders to direct future diagnostic testing for these patients.
Dineen: I think what I'll add to that is I'm only as good at my job based on the neuromuscular specialists. I feel that the neuromuscular specialists absolutely guide me and instruct me in terms of what type of tests that we're looking for. And my job is to really try to see if I can find a laboratory and a testing option that will work for that patient.
Is there any differentiator with this genetic testing that RUSH can offer that's different from, say, other non-academic medical centers or even peer institutions within the city? What are some of the differentiators of the offerings that RUSH has?
Dineen: First is just a general observation. For many of the patients that have come to our clinic, many of them have been on a long diagnostic journey, and some of them have even gone through some genetic testing before they've come to see us. But a lot of times where there have been gaps or sometimes where their genetic testing was many years ago where genetic testing has changed and is now more comprehensive.
Another area that ends up being important for patients who are candidates for more comprehensive genetic testing, I'd say that there's an additional area of having to work with that person's insurance or healthcare coverage to actually get approval for genetic testing. And that sometimes takes some time and some challenges and some know-how basically to work with the system and make sure that that testing's approved and that the patient understands the steps that would be involved in getting the testing accomplished.
Dr. Malik, the extension of the question that I have is thinking about how the advancements in genetic testing have led to the development of precision medicine for neuromuscular disorders. Could you talk about that evolution in the shift in care?
Malik: That's really the next step, and that's what we are most excited about. So the genetic testing historically has helped us provide accurate diagnosis, and that was great. But now in this day and age, it's helping identify therapeutic targets that informed development of new drugs, specifically designed to address underlying genetic mutations.
The poster child for that, of course, are the treatment options that are now available for spinal muscular atrophy, SMA. The FDA approved a medication called SPINRAZA or nusinersen in December of 2016. Patients with SMA typically do not have a functional SMN1 gene, so they rely on the SMN2 gene for production of this important protein that's helpful for nerve health. SPINRAZA is an antisense oligonucleotide that targets the SMN2 gene and produces its effects by inclusion of Exon 7 and subsequent production of full length SMN2 protein. So in the landmark trial, which was the ENDEAR clinical trial that led to the approval in infants who were on SPINRAZA, these kids were more likely to be ventilation-free at 24 months. It resulted in better milestones in SMA infants with two copies of SMN2 and improvement in motor function, which was fantastic.
But in 2019, we saw the FDA approval of ZOLGENSMA. Now this drug is a little bit different. It's an adeno-associated virus, AAV virus, vector-based gene therapy. In the phase 1 trial, which was the AVXS-101 study, participants who were SMA children under the age of two received just a one-time intravenous dose of AveXis then. All of these children achieved ventilation-free survival up to 24 months of age and even further. Eleven out of those 12 infants who were treated maintained the ability to sit unassisted. Two were even able to stand and walk independently, which was phenomenal. This drug completely changed the historical trajectory of the disease because if you look at SMA kids, only 8 percent of these patients will typically survive without permanent ventilation at the age of 20 months. And here we were seeing kids who were not only off of invasive ventilation, but they were achieving motor milestones like sitting up, taking steps, etc., which was very, very exciting for us.
Rich, is there anything that you would like to add for this?
Dineen: Just the fact that I think, a lot of times for the patients that we're seeing in clinics, they often have had their symptoms for many, many years, and sometimes we'll question, "What is the need for getting a more specific diagnosis?" It's not uncommon that we'll hear the phrase, "Well, it is what it is, or I have what I have." And it's really trying to educate them of how things have changed a lot. And sometimes knowing your exact diagnosis and specifically if there's a gene that's involved can really make a dramatic difference in terms of treatment options either now or certainly in the near future. So we're definitely in a hopeful time and I think trying to send that message to the patients as well, that we're in sort of a hopeful time period and there can be definite advantages to having a genetic diagnosis.
Dr. Malik, with this focus on genetic testing and the precision treatments for neuromuscular diseases, I'm wondering if the push or the interest and the excitement around these gene-based interventions and diagnostics is coming from a particular place within the field. I'm thinking of another example outside of neuromuscular care, for example, Parkinson's disease. There's been a really strong focus over the last five years on finding the genetic drivers for Parkinson's disease. What was the origin or what has been the driving for genetics within neuromuscular care?
Malik: I think what we are also excited about and hopeful about is extending genetic diagnosis and possibly gene therapy for what we think about as neurodegenerative disorders. The more common neurodegenerative neuromuscular disorder that we see is of course ALS or amyotrophic lateral sclerosis or Lou Gehrig's disease. So we initially thought that ALS was, perhaps, maybe 90 percent of the cases that we were seeing were sporadic and only about 11 to 13 percent were thought to have a genetic predisposition towards it. But we are understanding definitely that there may be a greater genetic component behind ALS. And I'm very happy to report and very excited to report that this year, the FDA approved a gene-based therapy for ALS, which is phenomenal, right? So I think genetic testing is helping us understand other diseases that were perhaps not recognized as a clear genetic illness a little bit better, and providing us with some optimism that perhaps there might be some new treatment options available for these devastating illnesses.
I'd like to wrap up our conversation by talking with you both about ongoing research that's happening at RUSH. Rich, I'd like to start with you first. Could you give us an overview on the scope of research that's going on around neuromuscular illnesses?
Dineen: Some of the areas or roles that I'll have in the clinic within the area of research is for someone who receives a genetic diagnosis, some of the things that we attempt to do, as Dr. Malik alluded to earlier, is number one, are there any currently available clinical trials? But let's say for example there are not, there are other things that the patient can do almost to describe as an area of advocacy. In terms of one of the things that we'll discuss is signing up with a disease registry, where, if there are advances in regard to therapy or if there are additional research options, there's a way for that patient to be notified of those advances. Also, I think that as our patient population continues to grow, having improved databases of our patient population so that we can also reach out to patient groups when there's been advances in treatment or new options as well.
What about from your perspective, Dr. Malik?
Malik: The neuromuscular section at RUSH has participated in a number of clinical and observational trials. So we were engaged in drug trials involved in myasthenia gravis as well as observational trials there. We've also participated in clinical trials for patients with neuropathy. And currently there's an ongoing trial, which is more of a natural course and a biomarker trial for ALS.
I would also like to mention that our center was one of the first to provide access to FDA-approved medications for Pompe disease and the new medications that are now available for ALS and some of the gene therapies that I mentioned for SMA, etc. So we were very quickly able to set up a workflow and put that in place working with other departments, including interventional radiology in certain cases to help patients get access to these medications at our center.
