LGMD Awareness Day: A Researcher’s Perspective on Rare Disease Progress and Gaps

Limb-Girdle Muscular Dystrophy (LGMD) Awareness Day is observed each year on September 30^th, as part of broader LGMD Awareness Month, to highlight the challenges faced by individuals and families living with this rare neuromuscular disorder. LGMD refers to a group of genetic conditions, currently divided into more than 30 subtypes, that causes progressive weakness and wasting of the voluntary muscles, particularly those around the hips and shoulders.

There is currently no cure for LGMD, and treatment is focused on supportive care, physical therapy, and management of complications. As part of efforts to raise awareness for LGMD, NeurologyLive® sat down with Melissa Spencer, PhD, director of the neuromuscular division at UCLA. Spencer, who also serves as co-director for the Center of Duchenne Muscular Dystrophy at UCLA, studies the pathways responsible for muscle health and has a passion in uncovering the pathogenic mechanisms that occur in various genetically inherited neuromuscular diseases like LGMD and Duchenne muscular dystrophy (DMD).

In this conversation, Spencer outlined the unique hurdles facing LGMD research, including its rarity, heterogeneity, and the need for deeper understanding of fundamental biology before effective therapies can be realized. She also discussed how lessons from DMD are shaping LGMD research, while also stressing the importance of collaboration and data-sharing to improve safety in gene therapy. Furthermore, Spencer talked about the next steps in advancing this community, emphasizing more natural history studies, predictive biomarkers, and refined gene-editing and replacement strategies.

NeurologyLive: What are the most critical aspects of LGMD the clinical community should be aware of?

Well, I should say upfront that I’m a basic scientist, even though I direct a clinical division, so I try not to go too deep into the clinical side. But one of the most important things to recognize about LGMD is its rarity. Duchenne is already considered a rare disease, but compared with LGMD, it is actually more prevalent. Within the LGMDs, there are many different subtypes, each defined by distinct genetic mutations. That diversity makes it difficult to study, fund, and advocate for, because each subtype essentially needs its own research agenda and therapeutic development pipeline.

What unites them clinically is that they typically begin with weakness in the proximal muscles—the shoulder girdle, hip girdle, upper arms, and thighs. Over time, many of these subtypes progress to affect the entire body. Some also have unique patterns of muscle involvement; for example, ocular pharyngeal muscular dystrophy begins with eye muscles and then progresses. In LGMD2A, which I study, the back of the leg is more affected than the front. So while there are broad similarities, each subtype has its own distinct clinical fingerprint, and that complexity is one of the challenges in both diagnosis and therapy development.

What are some of the reasons we’ve had so much difficulty developing drugs for LGMD, both mechanistically and pathologically?

I think it largely comes down to numbers and biology. In Duchenne, research accelerated because an animal model was identified unexpectedly through inbred mouse breeding. Once the gene mutation was identified in the late 1980s, researchers had both a model and a relatively large patient population, which attracted advocacy and funding. The biology was also easier to grasp—mutations in a structural protein make it clearer why the muscle cell would be fragile and degenerate.

For many LGMD subtypes, the biology is much less obvious. In LGMD2A, for example, the mutation isn’t in a structural protein, so it’s harder to connect the dots. Before you can develop a therapy, you need to know the fundamental biology: where the protein is expressed, what cell types are involved, where it shouldn’t be expressed, and what functional readouts to measure when you replace the gene. That kind of groundwork takes time, resources, and a dedicated workforce, which rare diseases often lack. And because the patient numbers are so small, advocacy groups have to carry much of the funding burden. Without that, progress is very slow.

How can the LGMD community take successes from Duchenne and translate them into actionable steps?

We are learning from Duchenne, especially from the nonprofit and advocacy side. Many small foundations are now driving LGMD research by funding science, building patient registries, and pushing for education and advocacy. That said, there’s always a tension between wanting to get treatments to patients quickly and taking the time to ensure those therapies are safe and effective.

One major issue is the immune response to AAV vectors used in gene therapy. For most LGMD subtypes, we know the genetic cause, which makes gene replacement an attractive option. But without enough understanding of immune responses, the cost–benefit balance shifts. Recent safety issues have highlighted the risks, and that makes regulators and companies more cautious. I believe we need stronger collaboration—sharing rare patient samples, building databases, and distributing data across labs—to understand these immune mechanisms and to develop predictive biomarkers for safety. Leaders in the field like Barry Byrne, Kirsten Bonnemann, and Francesco Muntoni have pushed for greater transparency from companies, and that’s the kind of collaborative culture we need to make progress.

On a more general note, what kinds of research efforts are still needed to move the LGMD field forward?

The first is natural history. Without understanding how a disease progresses over time, you can’t design a meaningful clinical trial. Even in Duchenne, where natural history is fairly well documented, there’s variability. With LGMD’s diversity, you need large-scale studies to understand the baseline trajectory of progression. That way, if an intervention slows or stabilizes the disease, you can distinguish it from the natural course.

Second, biomarkers are critical. Measuring muscle strength is difficult, especially in degenerative conditions. If we could measure a blood protein that correlates with disease progression or therapeutic effect, that would be transformative.

Third, we need to improve AAV vectors and dosing. Many adverse events occur at high doses, so developing safer vectors that work at lower doses is essential. But even then, we need to understand why these adverse events occur and how to predict them.

Finally, for some LGMD subtypes, we simply don’t know enough about the basic biology. We know the gene and the protein, but not what that protein does in detail, how it’s processed, or how it interacts with other muscle proteins. Without that, therapies will remain blunt instruments. So in many ways, we are still in the foundational science stage. The field has momentum, but compared with areas like cancer research, we are decades behind in terms of resources, infrastructure, and dedicated study sections at NIH. LGMD needs that kind of investment to move toward true precision therapies.

Transcript edited for clarity.