Authors: Sawyer Hyde, Cristina Nuila Hernandez, Shilten Kenzhegazy, and Greta Beall
Editors: Keon Deng
March 3, 2026 at 11:00 AM
Limb-girdle muscular dystrophy (LGMD) is a disorder that results in muscle weakness and wasting, which is the steady breakdown and thinning of muscles in the area. The name limb-girdle refers to the shoulder and pelvic girdles, which attach the upper limbs to the torso. LGMD symptoms start at the hips and shoulders and go down into the limbs, and can also affect the skeletal, respiratory, and circulatory systems. Essentially, mutations in genes responsible for proteins involved in muscle function lead to muscle weakness as the disease progresses. This paper delves into the physiology behind LGMD, diagnosis processes for genetic testing, treatments, advocacy groups, and calls for changes within cost and diagnostic barriers.
There are over 30 different subtypes of LGMD that vary in severity and age of onset. LGMD is autosomal recessive, requiring two mutant versions of the gene to inherit the disease. Mutations in the CAPN3 gene lead to LGMD2A (25), and mutations in the DYSF gene lead to LGMD2B (24). The most prevalent forms have an earlier age of onset, faster progression, and significant CK elevation. Around 10% are forms with a later age of onset, slower progression, and minimal to no elevation in creatine kinase (CK), a protein that catalyzes energy production in muscle cells. CK is released into the blood with muscle damage. While elevated CK is indicative of muscle damage in the majority of LGMD subtypes, chronic or slow-progressing muscle diseases can still result in LGMD with a normal CK concentration.
Different LGMD subtypes have distinct gene mutations, which are associated with variations in age of onset, disease progression, and the body systems involved (muscular, circulatory, and respiratory systems) (13). The problems arise within genes and proteins involved in muscle tissue. This includes effects on physical cohesion and muscle contraction, cell signaling, membrane maintenance, and the removal of toxic metabolites from muscle cells (13).
The wide range of LGMD symptoms makes diagnosis more difficult. Muscle biopsy is primarily used for LGMD by examining muscle fiber size and observing muscle tissue degeneration and regeneration (1). However, inflammation is often present in these samples, distracting from the key features required for rapid diagnosis. This inflammation is frequently confused with polymyositis, another rare inflammatory muscle disease. Genetic testing through this approach yields a diagnostic rate of 30-40%.
A significant improvement in diagnosis is Next-Generation Sequencing (NGS), allowing sequencing of many LGMD-relevant genes at once, yielding 34-45% diagnostic accuracy (6). Additionally, it reduces the need for an invasive biopsy procedure and greatly improves the speed of official diagnosis. Whole-exome sequencing, which uses NGS but focuses only on protein-coding regions of DNA, is especially relevant for LGMD as the condition is dependent on protein irregularities. The cost of Whole-exome sequencing ($200) is similar to biopsy ($140), but further testing to confirm results can range between $3,500 to $22,000 (9).
Thus, a significant barrier for any LGMD patient is the cost of diagnosis. Payment denial and high out-of-pocket costs slow the already complex diagnosis process. For example, prior insurance authorization must be obtained before even ordering tests to mitigate this risk. Even then, whether insurance will cover the necessary screenings varies on a case-by-case basis. Therefore, patients and families must find their own resources to meet the costs. Some methods may include participation in research trials or connections with philanthropic organizations, namely, disease-specific LGMD advocacy groups.
As with most rare diseases, the lack of available research, limited knowledge among healthcare providers, and inaccessibility to the required testing are common barriers to an efficient and accurate diagnosis. However, significant progress in diagnosis has been made. In the US, the diagnosis time for dysferlinopathy (LGMD2B) has decreased from 20.5 years from symptom onset in the 1970s to 3.1 years in the 2000s (26).
In response to these issues in LGMD diagnosis, researchers are developing tailored modalities to ease patient care. Skeletal muscle MRIs have the ability to pinpoint LGMD-affected muscles in a minimally invasive way for ease of diagnosis and patient comfort (11). Another promising method is derived from a 2024 study by the University of Siena, which found the presence of full-length CAPN3 in urine and skin samples from LGMD patients (12). This opens up the possibility of a simple skin biopsy or urine samples in place of the typical muscle biopsy as significantly less invasive methods to diagnose LGMD. The progress towards less invasive diagnostic methods has promise to decrease risks and increase the efficiency of diagnosis for LGMD patients.
Across the United States, there are a plethora of online resources available from the following advocacy groups, which can help navigate the difficult diagnostic process. The Limb-Girdle organization, in partnership with Sarepta Therapeutics, shares stories and helps visitors stay connected to community resources, news, and research (27). The advocacy group websites provide potential treatment options, including individual symptom management, quality of life improvement, and having healthcare providers to address and monitor effects on the body. The organization offers information on genetic testing, offered with no charge from programs like Detect MD and the Lantern Project. They can also enroll in research studies through The Rare Genomes Project, a program at MIT and Harvard with a team of scientists performing genomic sequencing for families with rare conditions within the United States to investigate the genetic links of the rare disease within families.
Treatments for LGMD currently aim to alleviate specific symptoms, which vary by subtype. For example, night ventilation is used to help patients with subtypes involving respiratory impairment, helping them breathe (18). Monitored moderate and low intensity strength training with specialists is used to focus on muscle strength maintenance for those with atrophied and weak muscles. It has been reported to be well tolerated, aiding in bicep strength and endurance. High-intensity training may also be beneficial, but may potentially cause elevated CK levels (muscle damage), pain, and overload symptoms (18). Aerobic training is also used for rehabilitation. Body weight-supported physiotherapy is used to help those unable to perform traditional types of exercise maintain muscle strength by using assistance such as a harness to reduce weight. Another method is a specialized treadmill surrounded by a pressure chamber to help patients perform exercises. Combined, these rehabilitation methods increase aerobic capacity and muscle strength in patients.
Future LGMD research may focus on molecular and gene therapy to slow the progression of the disease. Preliminary studies in cell transplantation have shown to potentially have beneficial effects, but the research for cell therapies is still in the early stages (28). No successful research has been completed for gene therapies, but potential treatments for future studies include stem cell transplantations and exon skipping, bypassing a protein-producing gene to make damaged gene sections more functional, which may be potential treatments in the future (23). Other potential gene editing techniques include CRISPR and RNA gene editing.
The LGMD community today faces the absence of FDA-approved treatments (16). As discussed, all “treatment” options for LGMD are only forms of supportive care for the patient. While attempts are being made towards a badge of approval, the community has recently faced a major setback. Sustained research funding will improve the diagnosis rate and potentially create an official FDA-approved treatment, which will lead to viable treatment options.
The impacts of LGMD spread beyond those diagnosed with the disease; the families of patients are also affected. In a 2017 study, researchers surveyed 19 parents of young adults aged 20 to 30 living with LGMD (22). The study found that many of them were caregivers to their children, which can cause significant emotional and financial stress. A significant impact mentioned by many of those surveyed is the unpredictability of LGMD progression, which varies significantly for each person affected. Many parents of LGMD patients are uncertain of how the disease will progress and worry about the future. Despite facing challenges, those living with LGMD and their families can live a fulfilling life. Many have created blogs or communities to share their own stories living with LGMD, empowering others around them to freely express themselves (29). Those surveyed emphasized the importance of support systems. Surveys that showed a high level of happiness emphasized strong social networks and a sense of community they can rely on (22).
While LGMD’s many subtypes come with high diagnostic costs, long diagnostic times, and a lack of disease treatment, research has taken strong strides in discovering better diagnosis and treatment options for those with LGMD. Research has yielded identifications of new biomarkers, less invasive testing, and improved imaging. While treatment is still primarily supportive in treating symptoms, researchers are continuously discovering treatments that drastically improve quality of life. Advocacy is absolutely crucial in this process; organizations and communities help provide resources and visibility to families with LGMD. They serve as the link to hear from the experiences of those with LGMD and reach policy makers that can enact real change. With continued support from advocates, researchers, and policymakers, LGMD will see massive improvements in diagnosis, treatment, and care. To get there, each voice we raise to understand and speak out on how impactful LGMD is as a rare disease gets us closer to our goals in better supporting those living with it.
References
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