Duchenne Muscular Dystrophy

Podcast Transcript

Neuro Pathways Podcast Series

Release Date: September 1, 2025
Expiration Date: August 31, 2026

Estimated Time of Completion: 15 minutes

Duchenne Muscular Dystrophy
Alexandra Bonner, MD

Description
Each podcast in the Neurological Institute series provides a brief, review of management strategies related to the topic.

Learning Objectives

• Review up to date and clinically pertinent topics related to neurological disease
• Discuss advances in the field of neurological diseases
• Describe options for the treatment and care of various neurological disease

Target Audience
Physicians and Advanced Practice providers in Family Practice, Internal Medicine & Subspecialties, Neurology, Nursing, Pediatrics, Psychology/Psychiatry, Radiology as well as Professors, Researchers, and Students.

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• American Medical Association (AMA)
  Cleveland Clinic Center for Continuing Education designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
  
  Participants claiming CME credit from this activity may submit the credit hours to the American Osteopathic Association for Category 2 credit.

• American Nurses Credentialing Center (ANCC)
  Cleveland Clinic Center for Continuing Education designates this enduring material for a maximum of 0.25 ANCC contact hours.

• Certificate of Participation
  A certificate of participation will be provided to other health care professionals for requesting credits in accordance with their professional boards and/or associations.

• American Board of Surgery (ABS)
  Successful completion of this CME activity enables the learner to earn credit toward the CME requirements of the American Board of Surgery’s Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit.

Credit will be reported within 30 days of claiming credit.

Podcast Series Director
Andreas Alexopoulos, MD, MPH
Epilepsy Center

Additional Planner/Reviewer
Cindy Willis, DNP

Faculty
Alexandra Bonner, MD
Center for General Neurology

Host
Glen Stevens, DO, PhD
Cleveland Clinic Brain Tumor and Neuro-Oncology Center

Agenda

Duchenne Muscular Dystrophy
Alexandra Bonner, MD

Disclosures

In accordance with the Standards for Integrity and Independence issued by the Accreditation Council for Continuing Medical Education (ACCME), The Cleveland Clinic Center for Continuing Education mitigates all relevant conflicts of interest to ensure CME activities are free of commercial bias.

The following faculty have indicated that they may have a relationship, which in the context of their presentation(s), could be perceived as a potential conflict of interest:

Glen H Stevens, DO

DynaMed Consulting

All other individuals have indicated no relationship which, in the context of their involvement, could be perceived as a potential conflict of interest.

CME Disclaimer

The information in this educational activity is provided for general medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options of a specific patient's medical condition. The viewpoints expressed in this CME activity are those of the authors/faculty. They do not represent an endorsement by The Cleveland Clinic Foundation. In no event will The Cleveland Clinic Foundation be liable for any decision made or action taken in reliance upon the information provided through this CME activity.

HOW TO OBTAIN AMA PRA Category 1 Credits™, ANCC Contact Hours, OR CERTIFICATE OF PARTICIPATION:

Go to: Neuro Pathways Podcast September 1 , 2025 to log into myCME and begin the activity evaluation and print your certificate If you need assistance, contact the CME office at myCME@ccf.org

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Introduction: Neuro Pathways, a Cleveland Clinic podcast exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neurorehab, and psychiatry.

Glen Stevens, DO, PhD: Duchenne muscular dystrophy is one of the most common and severe forms of muscular dystrophy, typically diagnosed in early childhood, but beyond the progressive muscle weakness lies a rapidly evolving treatment landscape, one that now includes gene therapy and collaborative research efforts aimed at transforming outcomes. In this episode, we'll unpack the basics of Duchenne's muscular dystrophy, explore the promise and challenges of gene therapy, and discuss what the future holds for patients and clinicians. I'm your host, Glenn Stevens, neurologist, neuro-oncologist in Cleveland Clinic's Neurological Institute, and joining me for today's conversation is Dr. Alex Bonner. Dr. Bonner is a Cleveland Clinic pediatric neurologist, fellowship-trained in neuromuscular medicine. Alex, welcome to Neuro Pathways.

Alex Bonner, MD: Thank you.

Glen Stevens, DO, PhD: Alex, why don't we start by having you introduce yourself? Tell us where you trained, what you do on a regular basis here.

Alex Bonner, MD: I completed my training here at Cleveland Clinic. I completed my pediatric neurology residency, as well as my neuromuscular fellowship here, and have stayed on as staff to be the neuromuscular expert for our group.

Glen Stevens, DO, PhD: So, Duchenne muscular dystrophy, I know a lot of people get anxious when they hear the terms, but for our audience, tell us what Duchenne muscular dystrophy is and how it typically proceeds.

Alex Bonner, MD: Duchenne muscular dystrophy is a progressive disorder of muscle breakdown, so it affects skeletal muscle, cardiac muscle, respiratory muscle. And it is progressive, so it worsens over time and ultimately shortens the lifespan.

Glen Stevens, DO, PhD: What age does it typically present?

Alex Bonner, MD: Often, these kids present around three to four years of age. In hindsight, there might be some reports of a little bit of motor delay in developing motor milestones, but often, these kids come to attention around three to four years of age, maybe with some difficulty keeping up with peers, maybe just seeming to have some difficulty with climbing stairs, that sort of thing is the picture you might hear from parents. I think it's interesting to note that, here in Ohio, we are actually the first state to add Duchenne to the newborn screen. So, we have added a CK level to the newborn screen so that we can try to pick up any of these cases early on and start monitoring them at an earlier age, but that has not been rolled out in most other places, so it's unique to where we're practicing here.

Glen Stevens, DO, PhD: Yeah, I'm glad you mentioned that because I was going to ask you if it's part of the newborn screen, but the tests that they're doing is just the creatine kinase?

Alex Bonner, MD: It is. It's a CK level, which can be a little bit wonky in newborns for a number of reasons. So labor and delivery is stressful if kids are in the neonatal ICU for some reason. There are different factors, weight, age, that can affect that CK level. So, it has required some interpretation on my part and some follow-up testing, but it's been an interesting transition to navigate.

Glen Stevens, DO, PhD: How many days after birth they do it? Is it done immediately? Is it done day 2?

Alex Bonner, MD: Typically, the newborn screen is sent very quickly. So, we have noted, especially in the neonatal ICU, a lot of inconclusive CK levels where they're not glaringly high but not quite normal, that have required some follow-up CK levels to ensure that they come back down to normal.

Glen Stevens, DO, PhD: And I know you have no way of really being able to answer this, but the delay for other states initiating this?

Alex Bonner, MD: It's a relatively new discussion. So, I think that a lot of the work in Duchenne research has come out of Columbus, Ohio, so it makes sense that Ohio was at the forefront. But when you're thinking about newborn screening, what you really want to know is, "If we can identify a disorder early, can we intervene?" And that's one of the criteria for a condition being included on the newborn screen. And it's really more recently that that's true for Duchenne muscular dystrophy that we have some therapies and we can change the way that we care for these kids, but other states are on a state-by-state basis having to assess the risk-benefit.

Glen Stevens, DO, PhD: Let's talk about the genetics of Duchenne muscular dystrophy. What is it?

Alex Bonner, MD: Duchenne is an X-linked recessive disorder. So females tend to be carriers. They tend not to manifest symptoms, although a small percentage of females can manifest some cardiac symptoms later in life, and so it's good to have that on your radar and know that women can get screened, but it's really males who manifest the symptoms. So I'll predominantly be talking about boys and young gentlemen.

Glen Stevens, DO, PhD: And what percent would get it from a parent versus a spontaneous mutation?

Alex Bonner, MD: About a third, about 33% of mutations can be de novo, so new to the child, while the other two-thirds will be inherited from a parent.

Glen Stevens, DO, PhD: So, if a child did have an increased CK level, and in follow-up, it's elevated, it's staying elevated, your suspicion is very high, do you do genetic testing at that point, or no?

Alex Bonner, MD: I do. Right now, depending on the level, I would consider sending a screen of the dystrophin protein first, there's sponsored available here, but which testing you choose to send might depend on where you're practicing. But if the level is frankly high, I would consider sending that dystrophin screen first. But of course, an elevated CK level is not specific to Duchenne, it's just a marker of muscle breakdown. So there are a lot of other disorders that are being captured or potentially being captured with this newborn screen.

Glen Stevens, DO, PhD: Do patients have to be sent to medical genetics, or the neurologist can order the testing?

Alex Bonner, MD: Actually, a changing landscape right now. So, for targeted testing, I'm still able to send that testing myself. For more broad testing, if that's needed, sometimes, things like a whole exome sequencing or whole genome sequencing, insurance providers are not always covering that testing unless there's involvement of a specific genetic counselor and some other hoops to jump through. So, from a targeted testing standpoint, I can and do initiate that testing. And if we have to expand further, I'll pull in our medical genetics team.

Glen Stevens, DO, PhD: So, we'll get into gene therapy in a minute, but let's just say, prior to gene therapy, I have Duchenne's. As a child, I come to see you. What types of treatments do you offer?

Alex Bonner, MD: The standard of care prior to gene therapy has historically been steroids, so this is chronic steroid use. There's different regimens that can be utilized daily steroids, high-dose weekend, but it is chronic steroids, and the benefits of that have been demonstrated. There were some improvements in scoliosis and pulmonary function, and different markers in patients with Duchenne, but of course, we are all familiar with the consequences of chronic steroid use, and so it comes with a host of problems as well and was certainly not an ideal solution for this population.

Glen Stevens, DO, PhD: So, what percentage of kids today would get steroids?

Alex Bonner, MD: A number. So, the gene therapy has emerged relatively recently. There are other therapies available that we can talk about, but many, if not, most kids are still receiving steroids either prior to receiving gene therapy or they've already been receiving steroids through much of their life. And then we often give steroids after gene therapy, at least for a period of time, and then the question of if further steroids are needed after gene therapy remains open.

Glen Stevens, DO, PhD: So, let's go through some of the other drugs.

Alex Bonner, MD: Prednisone is our usual, it's our tried-and-true steroid, but there are two other glucocorticoid and glucocorticoid-adjacent therapies that are available. Deflazacort is approved for the treatment of Duchenne muscular dystrophy. The goal with that medication is to see if it can reduce some of the weight gain that you see with prednisone, and it does seem to do that, but it also increases the risk of cataracts. There is vamorolone, which is another glucocorticoid receptor modulator, that is supposed to reduce the amount of height restriction that these patients might experience, but it has some complications with its use in terms of it can also cause adrenal suppression but cannot be used in terms of treating an adrenal crisis. So, it's not always the most easy medication to navigate. Givinostat is an oral histone deacetylase inhibitor, so it really works downstream. It's not treating the underlying cause of Duchenne muscular dystrophy, but it manages some of the downstream effects of inflammation, muscle regeneration, that sort of thing, and that's a relatively new medication. So, outcomes on givinostat are still emerging, but it is available.

And there's a class of medications of which there are four called exon skipping therapies. The goal of an exon skipping therapy is to essentially restore the reading frame of the DMD gene. So, in the DMD gene, if there is a mutation that disrupts that reading frame so that the gene is not coding for the dystrophin protein, the goal of exon skipping is to say, "Well, if we can skip this exon, would that allow portions of that reading frame to be restored, allowing for a shortened, maybe slightly dysfunctional dystrophin protein to form and still be present?" So there are four of those that are available, but only about 30% of patients with Duchenne are exon skipping amenable, so even potentially eligible for an exon skipping therapy. And of course, patients have different mutations, they might respond differently to an exon skipping therapy, so outcomes with those can also require some interpretation.

Glen Stevens, DO, PhD: Role of calcium channel blockers?

Alex Bonner, MD: So, we use ACE inhibitors and ARBs to try to manage the heart failure that we see in Duchenne muscular dystrophy. So, we can often start that early to try to support the function of the left ventricle.

Glen Stevens, DO, PhD: It's interesting, the histone deacetylase inhibitors, we've used in the neuro-oncology field, and the most classic drug is valproic acid. Was that ever used in Duchenne's that you know of?

Alex Bonner, MD: I'm not sure, actually. That's a good question.

Glen Stevens, DO, PhD: I'm sure the purified drug that you're using works better for it, but I just wonder if old school-wise it was ever used.

Alex Bonner, MD: Yeah. I know that valproate has been looked at in certain other muscular and motor neuron conditions without much effect, but I'm not sure about the Duchenne population specifically.

Glen Stevens, DO, PhD: And the scoliosis, do many kids end up having to have surgery for that?

Alex Bonner, MD: Some do, some do not. Oftentimes, we try to stay ahead of it with bracing and physical therapy, but it's certainly something to pay attention to because we already know that respiratory muscles are affected, and scoliosis can make that even more of a challenge for these kids.

Glen Stevens, DO, PhD: And average age that a child would require respiratory assistance, a trach or BiPAP at night, or some?

Alex Bonner, MD: I think at this juncture, probably late teens, early 20s. It depends. So, overnight respiratory support is something we certainly begin using a little bit earlier. Some support with BiPAP, CPAP overnight.

Glen Stevens, DO, PhD: Right. They usually talk about that to have them rest, right?

Alex Bonner, MD: Yeah, yeah, and just to support that breathing when you're lying supine, when you don't have gravity supporting your diaphragm. But in terms of higher levels of respiratory intervention, that can be a ways down the road.

Glen Stevens, DO, PhD: The average age of death?

Alex Bonner, MD: Now is late 20s, early 30s, actually, which is different than natural history studies from the '70s or earlier, but a lot of that has really been driven by improvements in cardiorespiratory support and clinical management guidelines, monitoring, respiratory support, early intervention, that sort of thing. So, those have been major drivers in prolonging lifespan, in addition to some of the therapies that we have available. We do not yet know the role that gene therapy will have in lifespan or respiratory function.

Glen Stevens, DO, PhD: So, let's go to gene therapy. Tell us what gene therapy is, why it's being looked at in this disorder, and what the potential benefits are.

Alex Bonner, MD: That's a simple question, yeah.

Glen Stevens, DO, PhD: Yeah. Simple, simple.

Alex Bonner, MD: Very straightforward. So, gene therapy is a interesting, exploding arena across medicine, but really, we're seeing a lot in neuromuscular medicine for a couple of reasons that I can discuss. But the idea is that, if you have a single gene mutation, and we know that that mutation causes symptoms, can we deliver that gene directly to the cells that need it, allow the cells to code that gene and create the protein, and basically cure the disorder? So, for Duchenne muscular dystrophy specifically, the DMD gene encodes the dystrophin protein. And when there are mutations in the DMD gene that prevent that dystrophin protein from forming, that causes Duchenne muscular dystrophy. I will pause briefly to say that, when there is a mutation that causes a shortened or truncated form of dystrophin, that is when you get the more mild, more slowly progressive Becker muscular dystrophy phenotype.

But today, we're really talking about when there's an absence of that dystrophin, the Duchenne muscular dystrophy phenotype. So, can we deliver the full length dystrophin gene to the muscle cells and allow those muscle cells to encode it? And the answer right now is not yet, actually, and there's an interesting reason for that because the DMD gene that encodes for dystrophin is massive. So a lot of early work was done to identify what are the critical components of the DMD gene that we need to make the most functional protein. So they looked at all these critical components, packaged them together into a microdystrophin, trying to leave out the parts that seem to be less critical, and this microdystrophin is a size that can be incorporated into our known viral vectors.

There are so many questions that this therapy has revealed. We have a lot of information and a lot of motivated people looking to answer those questions. So, I think there's room to think that we can learn more about how to use this gene therapy safely, and hopefully, a lot of that information can translate to gene therapies for other disorders because it's coming down the pipeline.

Glen Stevens, DO, PhD: Well, it's difficult because we're asking a lot for a clinical trial, and we have very small in. Cardiology trial is looking at 10,000, 50,000, 100,000 people, and we go, "Well, we got 20," or we got 50 at the most, and half of them don't get the drug. So, it comes very complicated. We're starting to get up against the clock. Are we doing anything here gene-wise, trying to develop anything?

Alex Bonner, MD: We are. So, here at Cleveland Clinic, we are developing a comprehensive gene therapy program. So there's a group of expert clinicians under the leadership of Rabi Hanna who are developing this program to bring our clinical expertise together across disciplines and specialties. For example, in rolling out delandistrogene moxeparvovec, I had begun working with a number of these clinicians because I don't want to be giving a gene therapy to a patient if I don't have support from a hepatologist to help manage their liver, from an immunologist, from a hematologist who can help me take care of this group of patients. And so we have really come together to say, "Can we work together, learn from each other, and provide this comprehensive support for any patients receiving a gene therapy across disciplines, including ophthalmologic or ENT?" Our goal is also to make Cleveland Clinic a place where we can bring in clinical trials and have the framework to support those trials and those patients by optimizing safety, and collaborating, and sharing resources. So that is coming down the pipeline here at Cleveland Clinic Children's.

Glen Stevens, DO, PhD: Well, it's exciting. Obviously, intuitively, it all makes a lot of sense. It gets complicated by the scope of what you need to do and just the scope of the genes that you're working with, so never simple, but it makes sense, right? And I think that the answers will come, it's just when. And I'm sure you have a lot of anxious families and parents looking for things, and I think we just have to be open and honest about what's going on and what is realistic and what's not realistic. And I-

Alex Bonner, MD: And what we know and what we don't know.

Glen Stevens, DO, PhD: Yeah. And I think our motto in the tumor area is that our goal is to try to have a clinical trial for almost every patient. Most of what we look after is non-curative. And I think that we can't cure something, we need to be looking for good rational trials so that we can one day cure them, and I think that's what you're doing.

Alex Bonner, MD: And to optimize function. If we can't find a cure, can we help with breathing? Can we help with upper extremity function that allows for more independence longer term? There's all these different ways to find meaning in change over time, and those are the things I try to think about and talk through with families as well.

Glen Stevens, DO, PhD: Final takeaways?

Alex Bonner, MD: It is a privilege to practice medicine.

Glen Stevens, DO, PhD: Good. Well, listen, Alex, it's been a pleasure visiting with you and getting to understand a little bit more about disorder and the things that are going on here. If somebody wants to come for a consultation, what do they need to do?

Alex Bonner, MD: Give the office a call.

Glen Stevens, DO, PhD: We'll get them in.

Alex Bonner, MD: All right.

Glen Stevens, DO, PhD: All right. Thank you.

Alex Bonner, MD: Thank you.

Closing: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast, or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And for further learning, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website, that's consultqd.clevelandclinic.org/neuro, or follow the Cleveland Clinic Neurological Institute on LinkedIn. And thank you for listening.