Limb girdle muscular dystrophy (LGMD) encompasses more than 30 ultra-rare genetic subtypes that share a core pattern of progressive weakness in the hip and shoulder girdles, often spreading to other muscle groups and affecting cardiopulmonary function over time. Because each subtype is exceedingly uncommon, families frequently face delayed diagnosis, limited clinical expertise, and scarce trial opportunities.<\/p>\n
The CureLGMD2i Foundation was born from that reality: after her daughter\u2019s diagnosis with LGMD2i\/R9 (FKRP-related LGMD), Kelly Brazzo created a patient-led organization to build registries, support natural-history studies, seed biomarker and imaging projects, and de-risk early therapeutic programs\u2014including small molecules and gene therapy\u2014by uniting patients, clinicians, and industry around concrete, data-driven goals.<\/p>\n
As part of our coverage of LGMD Awareness Day, Brazzo sat down to discuss several LGMD-related questions, including the importance and origins of the day, and the hallmark features of this neuromuscular disease. She spoke on platform gene-therapy approaches, robust genetic testing, and subtype-specific advocacy as levers to accelerate development. In addition, Brazzo commented on cardiopulmonary surveillance, contracture management, access to neuromuscular specialists, and the need to build natural history studies so patients are \u201ctrial-ready\u201d when opportunities arise.<\/p>\n
NeurologyLive: What is the significance and origin of LGMD Awareness Day?<\/p>\n
Kelly Brazzo: LGMD Awareness Day was founded by a dear friend of mine, Carol Abraham, who is also living with limb-girdle muscular dystrophy. And you know, it\u2019s been such an amazing opportunity for us to spread awareness of an otherwise ultra-rare disease that most people have never heard of. In fact, I never did until I had a child diagnosed with it.<\/p>\n
So it\u2019s something that we can all do together\u2014whether you\u2019re a patient, a family member, a loved one, or just someone interested in learning more about the condition\u2014we all work together to help spread awareness and understanding of how and what an impact this condition can make.<\/p>\n
There are actually 30 different subtypes of limb-girdle muscular dystrophy. Each of them is individually ultra-rare, but when we\u2019re combined as a larger group, we can create more impact, and we\u2019re not quite so \u201crare\u201d when we combine together. Altogether, LGMD consistently presents with muscle weakness and wasting starting in the hip and shoulder girdles, and it expands beyond that. It\u2019s progressive in nature. And right now, at this point, there are zero approved therapies for any of the 30 subtypes.<\/p>\n
What are some of the key clinical features that should raise suspicion of LGMD diagnosis?<\/p>\n
I\u2019ll leave some of that to the clinical experts, but as a \u201cparent expert,\u201d some of the most common features are the waddling gait. In fact, when my daughter was little\u2014before we knew anything was wrong\u2014we thought maybe she had a limb-length discrepancy, like one leg was longer than the other. And then part of me thought it was just a sassy little girl walk. She would sway her hips, and, you know, she had a little bit of a \u201cdrama girl\u201d attitude. So we kind of thought that was her personality.<\/p>\n
But as time went on, we noticed other things, which we now know was the Gowers\u2019 sign. When she would fall\u2014which happened more than typical for a two-year-old\u2014she would grunt when she got up off the ground and have to use her hands to walk up her legs. When we took her to the doctor, he said, \u201cIf it was a boy, I\u2019d swear it was Duchenne muscular dystrophy.\u201d And I said, \u201cOkay, great, I guess we ruled out any sort of muscular dystrophy,\u201d because I didn\u2019t know there were other types. Little did I know there were\u2014and that there\u2019s limb-girdle, which, as I said, has 30 subtypes.<\/p>\n
Other common features might be difficulty getting out of a chair, struggling to get up steps, and reduced shoulder strength\u2014a lot of people say they have trouble raising their hands above their head or even brushing or washing their hair. There\u2019s also scapular winging, when the shoulder blades stick out more. Those are some of the most common features my daughter has experienced, and from talking to other parents and family members, those are things they notice at the beginning. And really, I\u2019d say the most troublesome is instability and falling. Eventually you can get to the point where you can\u2019t get back up off the ground independently, and that becomes quite a challenge being out in public that way.<\/p>\n
Where do we stand on promising investigational therapies, including gene therapy?<\/p>\n
Thankfully, my daughter has LGMD2i\/R9\u2014FKRP-related, and for our condition, we do have a small-molecule treatment in phase 3, which we\u2019re really excited about. There are also two gene therapy programs\u2014one actively in phase 1\/2, and another one unfortunately on hold right now. We are really advocating for the Pediatric Rare Disease Priority Review Voucher (PRV) to get reauthorized. As you know, funding has become difficult for a lot of smaller biotechs looking to invest in this space. With an ultra-rare disease, it\u2019s hard to create that investment if you don\u2019t have a clear return. The PRV has been a big push to help get more investment into the field.<\/p>\n
In the meantime, across other subtypes, we\u2019ve had a tough couple of months. Unfortunately, several gene therapy programs were lost from the pipeline due to some unfortunate circumstances. A lot of families are heartbroken and devastated. We\u2019re really hoping to find other investors or companies willing to help pick up those pieces, or that we see new companies enter the space and pick up what\u2019s been lost. Many patients devoted their time to natural history studies or early-phase trials\u2014we\u2019re really hoping that information gets shared so it can be used more broadly, and that patients have access to that data to keep momentum in the LGMD community. We\u2019re pushing and advocating for that as well.<\/p>\n
Are there any promising biomarkers that have emerged for LGMD?<\/p>\n
Taking a step back, we\u2019ve learned so much from the Duchenne community\u2014bigger numbers, powerhouse advocacy. We\u2019ve been able to piggyback on their work rather than redoing it all. And as many people know, LGMD subtypes were among the first to have any type of gene therapy explored, thanks to contributors like Donovan Decker. In light of that, the fact that we still don\u2019t have an approved gene therapy shows how long this takes.<\/p>\n
Clinicians and scientists will tell you LGMD looks like an ideal candidate for gene therapy: all 30 subtypes have known genetic causes, and most of the genes are small enough to fit into viral vectors\u2014unlike Duchenne, where you need micro-dystrophin because the gene is too large. Even so, because our numbers are smaller, there\u2019s less investment\u2014purely a financial reality. So we\u2019re pushing to accelerate via platform approaches, where you hold the vector constant and swap the gene cargo to save cost and time. Hopefully we\u2019ll see momentum return to that area.<\/p>\n
On biomarkers, for FKRP-related (LGMD2i\/R9), we do have some in development. We\u2019re working on MRI-based biomarkers for some subtypes, and for FKRP specifically, we\u2019re working on a biomarker of \u03b1-dystroglycan glycosylation, which could serve as a surrogate endpoint for treatments in development.<\/p>\n
Sadly, among 30 subtypes, only a handful have dedicated advocacy groups. Most don\u2019t. Umbrella organizations like the Speak Foundation help speak for all the limb-girdles, but it really makes a difference when each subtype has its own advocacy org to build awareness and structure\u2014this truly speeds up progress. Some groups were just founded. We\u2019ve even run out of letters and had to change the nomenclature. For those of us who were \u201c2i\u201d moving to R9, it\u2019s been a labor of love\u2014hard to make the transition, but we\u2019re slowly adopting it. And we keep finding new genes.<\/p>\n
Have there been conversations about testing gene therapies in multiple different LGMD subtypes?<\/p>\n
Yes. In a platform approach, once you determine a specific vector that seems safe and effective, and all you\u2019re doing is changing out the gene cargo, you can, in theory, move more quickly from one subtype to another. In theory, 30 different genes could go into the same vector. Of course, not all are the same\u2014some LGMD genes are bigger or more complicated\u2014so it isn\u2019t as simple as it sounds.<\/p>\n
But there are definitely ways to cut back on manufacturing and toxicology costs versus doing everything separately for 30 subtypes. Patients don\u2019t have time to wait to go through the alphabet one letter at a time. We\u2019re advocating with bigger companies to ask: what can we do to more rapidly develop treatments while patients are waiting? Once muscle is wasted, it\u2019s harder to fix. We\u2019re often trying to conserve what\u2019s left and hope for functional gains. Each year waiting can mean strength that may not be regained. So anything we can do to responsibly accelerate matters.<\/p>\n
Back to biomarkers: again, FKRP-related LGMD (2i\/R9) has some in development\u2014MRI work and the \u03b1-dystroglycan glycosylation biomarker as a potential surrogate. But across the 30 subtypes, we need more groups doing this. Advocacy matters for speed.<\/p>\n
What are some of the most common non-motor symptoms clinicians should expect with LGMD, and how do we treat these?<\/p>\n
I have to start by saying: it\u2019s crucial that patients get complete genetic testing to know their subtype. We still meet patients who say, \u201cI have LGMD,\u201d and when you ask for the subtype, they don\u2019t know. Some have a variant of unknown significance and need clarification; others were diagnosed years ago before all subtypes were identified. If they go back for updated genetic testing, they might finally know\u2014and that\u2019s essential.<\/p>\n
Why? If there\u2019s a clinical trial, you want to be counted so you can be called to enroll. If you don\u2019t know your subtype, you won\u2019t be identified. We can\u2019t count you in a registry, can\u2019t include you in natural history, and certainly not in a subtype-specific trial.<\/p>\n
Some subtypes affect cardiovascular and respiratory function. A lot of patients say, “I have sleep apnea,” but it might actually be respiratory insufficiency due to diaphragmatic weakness. Not all subtypes have this, but for example, in LGMD2i\/R9, that can happen. Patients may be tired because they\u2019re not breathing well at night; when they get colds, they can have a weak cough and need a cough assist to clear secretions.<\/p>\n
For the heart, patients should be having echos and EKGs, and sometimes cardiac MRI, which is the gold standard depending on progression. You don\u2019t want to find out you\u2019re in heart failure and only then learn your subtype has cardiac implications. You can\u2019t \u201csee\u201d this coming, so prophylactic medications may help prevent cardiac damage\u2014but only if you know to monitor and treat early. One of our biggest advocacy pushes is: know your subtype, get clear genetic testing, and keep pushing until you have an answer. It\u2019s not always simple, but it\u2019s important.<\/p>\n
How much of a concern are cardiac issues in LGMD, and what tips would you offer to families and clinicians to get ahead of them?<\/p>\n
The number one thing is: get to a clinic with a neuromuscular specialist who truly understands LGMD. If you don\u2019t have one locally, you might have to travel, and yes, there\u2019s a burden\u2014especially with physical disability\u2014but it\u2019s really important. If you\u2019re in an MDA clinic, you can get involved in their MOVR\/Data Hub. You want a specialist who understands your condition and can refer you to cardiology, pulmonology, PM&R\/physiatry, and orthopedics, if needed.<\/p>\n
In our case, contracture management has been important. My daughter has had two surgeries\u2014a heel-cord lengthening and, later, a spinal fusion for severe scoliosis. Not everyone will need that, but if you\u2019re not monitored, you can miss things. A specialist clinic can track complications and support you proactively.<\/p>\n
Beyond that, people ask about staying healthy: are there supplements that may help prevent heart failure down the road? What types of exercise are appropriate staying as active as possible without overdoing it? Also, quality-of-life adaptations: OT can help with home modifications to maintain independence.<\/p>\n
And please make sure you\u2019re in natural history studies and a registry once you know your subtype, so we can collect data and you\u2019re clinical-trial ready. You might not have a trial today, but if you\u2019re counted\u2014through efforts like the LGMD GRASP consortium\u2014you\u2019ll be easier to find when trials open. It also makes your subtype more interesting to investors and biotech, which can influence which rare disease gets studied next.<\/p>\n
There\u2019s so much more to this than just a doctor\u2019s visit. People often ask, \u201cHow can we have a clinical trial for my subtype?\u201d You can be the difference. In an ultra-rare disease like LGMD, every patient counted matters. Being in the system is imperative.<\/p>\n
Transcript was edited for clarity.<\/p>\n","protected":false},"excerpt":{"rendered":"Limb girdle muscular dystrophy (LGMD) encompasses more than 30 ultra-rare genetic subtypes that share a core pattern of…\n","protected":false},"author":2,"featured_media":170412,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[25],"tags":[916,90,56,54,55],"class_list":["post-170411","post","type-post","status-publish","format-standard","has-post-thumbnail","category-genetics","tag-genetics","tag-science","tag-uk","tag-united-kingdom","tag-unitedkingdom"],"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/posts\/170411","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/comments?post=170411"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/posts\/170411\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/media\/170412"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/media?parent=170411"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/categories?post=170411"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/tags?post=170411"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}