Continuum Audio Limb-Girdle Muscular Dystrophies With Dr. Teerin Liewluck
Limb-girdle muscular dystrophies (LGMDs) encompass a group of genetically heterogeneous skeletal muscle disorders. There has been an explosion of newly identified LGMD subtypes in the past decade, and results from preclinical studies and early-stage clinical trials of genetic therapies are promising for future disease-specific treatments.
In this episode, Gordon Smith, MD, FAAN, speaks with Teerin Liewluck, MD, FAAN, FANA, author of the article "Limb-Girdle Muscular Dystrophies" in the Continuum® October 2025 Muscle and Neuromuscular Junction Disorders issue.
Dr. Smith is a Continuum® Audio interviewer and a professor and chair of neurology at Kenneth and Dianne Wright Distinguished Chair in Clinical and Translational Research at Virginia Commonwealth University in Richmond, Virginia.
Dr. Liewluck is a professor of neurology at the Division of Neuromuscular Medicine and Muscle Pathology Laboratory at Mayo Clinic College of Medicine in Rochester, Minnesota.
Additional Resources
Read the article: Limb-Girdle Muscular Dystrophies
Subscribe to Continuum®: shop.lww.com/Continuum
Earn CME (available only to AAN members): continpub.com/AudioCME
Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud
More about the American Academy of Neurology: aan.com
Social Media
Host: @gordonsmithMD
Guest: @TLiewluck
Full episode transcript available here
Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast.
Dr Smith: This is Dr Gordon Smith with Continuum Audio. Today I'm interviewing Dr Teerin Liewluck, a good friend of mine at the Mayo Clinic, about his article on the limb girdle muscular dystrophies. This article appears in the October 2025 Continuum issue on muscle and neuromuscular junction disorders, a topic that is near and dear to my heart. Teerin, welcome to the podcast, and maybe you can introduce yourself to our listeners.
Dr Liewluck: Thank you very much, Gordon, and I want to say hi to all the Continuum fans. So, I'm Dr Teerin Liewluck, I'm the professor of neurology at Mayo Clinic in Rochester, Minnesota. So, my practice focus on all aspects of muscle diseases, both acquired and genetic myopathies. Glad to be here.
Dr Smith: I just had the great pleasure of seeing you at a seminar in Houston where you talked about this topic. And so, I'm really primed for this conversation, which I'm very excited about. I find this topic a little hard, and I'm hoping I can learn more from you. And I wonder if, as we get started, recognizing many of our listeners are not in practices focused purely on muscle disease, maybe you can provide some context about why this is important for folks doing general neurology or even general neuromuscular medicine? Why do they need to know about this?
Dr Liewluck: Yes, certainly. So, I would say limb girdle muscular dystrophy probably the most complex category of subgroup of muscle diseases because, by itself, it includes thirty-four different subtypes, and the number's still expanding. So, each subtype is very rare. But if you group together, it really have significant number of patients, and these patients present with proximal weakness, very high CK, and these are common patients that can show up in the neurology clinic. So, I think it's very important even for general neurologists to pick up what subtle clues that may lead to the diagnosis because if we are able to provide correct diagnosis for the patients, that's very important for patient management.
Dr Smith: So, I wonder if maybe we can talk a little bit about the phenotype, Terran. I mean, your article does a great job of going over the great diversity. And you know, I think many of us here, you know, limb girdle muscular dystrophy and we think of limb girdle weakness, but the phenotypic spectrum is bananas, right? Rhabdomyolysis, limb girdle distal myopathy. I mean, when should our listeners suspect LGMD?
Dr Liewluck: Yes, I think by the definition to all the LGMD patients will have limb girdle of proximal weakness and very high CK. So, these are common phenotypes among thirty-four different subtypes. But if it did take into details, they have some subtle differences. In the article, what I try to simplify all these different subtypes that we can categorize at least half of them into three main group that each group the underlying defect sharing among those subtypes and also translate into similar muscles and extra muscular manifestations. You will learn that some of the limb girdle muscular dystrophy may present with rhabdomyolysis. And we typically think of this as metabolic myopathies. But if you have a rhabdomyolysis patient, the CK remain elevated even after the acute episode, that's the key that we need to think this could be LGMD. That's for an example.
Dr Smith: So, I wonder if maybe we can start there. I was going to go in a different direction, but this is a good transition. It's easy to see the opportunity to get confused between LGMD or, in that case, a metabolic myopathy or other acquired myopathies. And I think particularly adult neurologists are more accustomed to seeing acquired muscle disease. Are there particular clues that, or pearls that adult neurologists seeing patients with muscle disease can use to recognize when they should be thinking about LGMD given the diverse phenotype?
Dr Liewluck: Yes. What I always tell the patient is that there are more than a hundred different types of muscle diseases, but we can easily divide into groups: acquired and genetic or hereditary. So, the acquired disease is when you encounter the patients who present with acute or subacute cause of the weakness, relatively rapidly progressive. But on the opposite, if you encounter the patient who present with a much more slowly progressive cause of weakness over several months or years, you may need to think about genetic disease of the muscle with also including limb-girdle muscular dystrophy. The detailed exam to be able to distinguish between each type of muscular dystrophy. For example, if proximal weakness, certainly limb girdle muscular dystrophy. If a patient has facial weakness, scapular winking, so you would think about facial scapular hematoma dystrophy. So, the slowly progressive cause of weakness, proximal pattern of weakness, CK elevation, should be the point when you think about LGMD.
Dr Smith: So, I have a question about diagnostic evaluation. I had a meeting with one of my colleagues, Qihua Fan, who's a great peripheral nerve expert, who also does neuromuscular pathology. And we were talking about how the pathology field has changed so much over the last ten years, and we're doing obviously fewer muscle biopsies. Our way of diagnosing them has changed a lot with the evolution of genetic testing. What's your diagnostic approach? Do you go right to genetic testing? Do you do targeted testing based on phenotype? What words of wisdom do you have there?
Dr Liewluck: Yes, so, I mean, being a muscle pathologist myself, it is fair to say that the utility of muscle biopsies when you encounter a patient with suspects that limb girdle muscular dystrophy have reduced over the year. For example, we used to have like fifteen, seventeen hundred muscle biopsies a year; now we do only thirteen hundred biopsies a year. Yes, as you pointed out, the first step in my practice if I suspect LGMD is to go with genetic testing. And I would prefer the last gene panel that not only include the LGMD, but also include all other genetic muscle disease as well as the conjunctive myopic syndrome, because the phenotype can be somehow difficult to distinguish in certain patients.
Dr Smith: So, do you ever get a muscle biopsy, Teerin? I mean you obviously do; only thirteen hundred. Holy cow, that's a lot. So, let me reframe my question. When do you get a muscle biopsy in these patients?
Dr Liewluck: Muscle biopsy still is present in LGMD patients, it's just we don't use it at the first-tier diagnostic test anymore. So, we typically do it in selected cases after the genetic testing in those that came back inconclusive. As you know, you may run into the variant of unknown significance. You may use the muscle biopsy to see, is there any histopathology or abnormal protein Western blot that may further support the heterogenicity of the VUS. So, we still do it, but it typically comes after genetic testing and only in the selected cases that have inconclusive results or negative genetic testing.
Dr Smith: I'd like to ask a question regarding serologic testing for autoantibodies. I refer to a really great case in your article. There are several of them, but this is a patient, a FKRP patient, who was originally thought to have dermatomyositis based on a low-titer ME2 antibody. You guys figured out the correct diagnosis. We send a lot of antibody panels out. Wonder if you have any wisdom, pearls, pitfalls, for how to interpret antibody tests in patients with chronic myopathies? We send a lot of them. And that's the sort of population where we need to be thinking about limb-girdle muscular dystrophies. It's a great case for those, which I hope is everyone who read your article in detail. What do you have to say about that?
Dr Liewluck: Yes, so myositis antibodies, we already revolutionized a few of muscle diseases. I recall when I finished my fellowship thirteen years ago, so we don't really have much muscle myositis antibodies to check. But now the panel is expanded. But again, the antibodies alone cannot lead to diagnosis. You need to go back to your clinical. You need to make sure the clinical antibodies findings are matched. For example, if the key that- if the myocytes specific antibodies present only at the low positive title, it's more often to be false positive. So, you need to look carefully back in the patient, the group of phenotypes, and when in doubt we need to do muscle biopsies. Now on the opposite end, the other group of the antibody is the one for necrotizing autoimmune myopathy; or, the other name, immune-mediated necrotizing myopathy. This is the new group that we have learned only just recently that some patients may present as a typical presentation. I mean, when even thinking about the whole testing autoimmune myopathy, we think about those that present with some acute rapidly progressive weakness, maybe has history of sudden exposures. But we have some patients that present with very slowly progressive weakness like muscular dystrophies. So now in my practice, if I encounter a patient I suspect LGMD, in addition to doing genetic testing for LGMD, I also test for necrotizing doing with myopathy antibodies at the same time. And we typically get antibody back within what, a week or two, but projected testing would take a few months.
Dr Smith: Yeah. And I guess maybe you could talk a little bit about pitfalls and interpretation of genetic tests, right? I think you have another case in your article, and I've certainly seen this, where a patient is misdiagnosed as having a genetic myopathy, LGMD, based on, let's say, just a misinterpretation of the genetic testing, right? So, I think we need to think of it on both sides. And I like the fact that the clinical aspects of diagnosis really are first and foremost most important. But maybe you can talk about wisdom in terms of interpretation of the genetic panel?
Dr Liewluck:Yes. So genetic testing, I think, is a complex issue, particularly for interpretation. And if you're not familiar with this, it's probably best to have your colleagues in genetics that help looking at this together. So, I think the common scenario we encounter is that in those dystrophies that are autosomal recessive, so we expect that the patient needs to have two abnormal copies of the genes to cause the disease. And if patients have only one abnormal copy, they are just a carrier. And commonly we see patients refer to us as much as dystrophy is by having only one abnormal copy. If they are a carrier, they should not have the weakness from that gene abnormality. So, this would be the principle that we really need to adhere. And if you run into those cases, then maybe you need to broaden your differential diagnosis.
Dr Smith: I want to go back to the clinical phenomenology, and I've got a admission to make to you, Teerin. And I find it really hard to keep track of these disorders at, you know, thirty-four and climbing a lot of overlap, and it's hard to remember them. And I'm glad that I'm now going to have a Continuum article I can go to and look at the really great tables to sort things out. I'm curious whether you have all these top of mind? Do you have to look at the table too? And how should people who are seeing these patients organize their thoughts about it? I mean, is it important that you memorize all thirty-four plus disorders? How can you group them? What's your overall approach to that?
Dr Liewluck: I need to admit that I've not memorize all twenty-four different subtypes, but I think what I triy to do even in my real-life practice is group it all together if you can. For example, I think that the biggest group of these LGMD is what we call alpha-dystroglycanopathies. So, this include already ten different subtypes of recessive LGMD. So alpha-dystroglycan is the core of the dystrophin-associated glycoprotein complex. And it's heavy glycosylated protein. So, the effect in ten different genes can affect the glycosylation or the process of adding sugar chain to this alpha-dystroglycan. And they have similar features in terms of the phenotype. They present with proximal weakness, calf pseudohypertrophy, very high CK, some may have recurrent rhabdomyolysis, and cardiac and rhythmic involvement are very common. This is one major group. Now the second group is the limb-girdle muscular dystrophy due to defective membrane repair, which includes two subtypes is the different and on dopamine five. The common feature in this group is that the weakness can be asymmetric and despite proximal weakness, they can have calf atrophy. On muscle biopsy sometimes you can see a myeloid on the muscle tissues. And the third group is the sarcoglycanopathy, which includes four different subtypes, and the presentation can look like we share. For the rest, sometimes go back to the table.
Dr Smith: Thank you for that. And it prompts another question that I always wonder about. Do you have any theories about why such variability in the muscle groups that are involved? I mean, you just brought up dystroglycanopathy, for instance, as something that can cause a very distal predominant myopathy; others do not. Do we at this point now have an understanding given the better genetics that we have on this and work going on in therapeutic development, which I want to get to in a minute, that provides any insight why certain muscle groups are more affected?
Dr Liewluck: Very good question, Gordon. And I would say the first question that led me interested in muscle disease---and this happened probably back in 2000 when I just finished medical school---is why, why, why? Why does muscle disease tend to affect proximal muscles? I thought by now, twenty-five years later, we'd have the answer. I don't. I think this, you don't know clearly why muscle diseases, some affect proximal, some affect distal. But the hypothesis is, and probably my personal hypothesis is, that maybe certain proteins may express more in certain muscles and that may affect different phenotypes. But, I mean, dysferlin has very good examples that can confuse us because some patients present with distal weakness, some patients present with proximal weakness, that's by the same gene defect. And in this patient, when we look at the MRI in detail, actually the patterns of fatty replacements in muscle are the same. Even patient who present clinically as a proximal or distal weakness, the imaging studies show the same finding. Bottom line, we don't know.
Dr Smith: Yeah, who knew it could be so complex? Teerin, you brought up a really great point that I wanted to ask about, which is muscle MRI scan, right? We're now seeing studies that are doing very broad MR imaging. Do you use some muscle MRI very frequently in your clinical evaluation of these patients? And if so, how?
Dr Liewluck: Maybe I don't use it as much as I could, but the most common scenario I use in this setting is when I have the genetic testing come back with the VUS. So, we look at each VUS, each gene in detail. And if anything is suspicious, what I do typically go back to the literature to see if that gene defect in particular has any common pattern of muscle involvement on the MRI. And if there is, I use MRI as one of the two to try to see if I can escalate the pathogenicity of that VUS.
Dr Smith: And a VUS is a "Variant of Unknown Significance," for our listeners. I'm proud that I remember that as a geneticist. These are exciting times in neurology in general, but particularly in an inherited muscle disease. And we're seeing a lot of therapeutic development, a lot going on in Duchenne now. What's the latest in terms of disease-modifying therapeutics and gene therapies in LGMD?
Dr Liewluck: Yes. So, there are several precritical and early-phase critical trials for gene therapy for the common lymphoma of muscular dystrophies. For example, the sarcoglycanopathies, and they also have some biochemical therapy that arepossible for the LGMD to FKRP. But there are many things that I expect probably will come into the picture broader or later phase of critical tryouts, and hopefully we have something to offer for the patients similar to patients with Duchenne muscular dystrophy.
Dr Smith: What haven't we talked about, I mean, holy cow? There's so much in your article. What's one thing we haven't talked about that our listeners need to hear?
Dr Liewluck: Good questions. So, I think we covered all, but often we get patients with proximal weakness and high CK, and they all got labeled as having limb-girdlemuscular dystrophy. What I want to stress is that proximal weakness and high CK is a common feature for muscle diseases, so they need to think broad, need to think about all possibilities. Particularly don't want to miss something treatable. Chronic, slowly progressive cause, as I mentioned earlier, we think more about muscle dystrophy, but at the cranial range, we know that rare patients with necrotic autonomyopathy and present with limb good of weakness at a slowly progressive cost. So, make sure you think about these two when suspecting that LGMD patient diabetic testing has come back inconclusive.
Dr Smith: Well, that's very helpful. And fortunately, there's several other articles in this issue of Continuum that help people think through this issue more broadly. Teerin, you certainly don't disappoint. I enjoyed listening to you about a month ago, and I enjoyed reading your article a great deal and enjoy talking to you even more. Thank you very much.
Dr Liewluck: Thank you very much, Gordon.
Dr Smith: Again, today I've been interviewing Dr Teerin Liewluck about his article on limb-girdle muscular dystrophy, which appears in the October 2025 Continuum issue on muscle and neuromuscular junction disorders. Please be sure to check out Continuum Audio episodes for this and other issues. And thanks to our listeners for joining today.
Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.