From Diagnosis to Treatment: Managing Limb-Girdle Muscular Dystrophy

This blog is dedicated to people living with Limb-Girdle Muscular Dystrophy. It explains what it is, the symptoms, how it is diagnosed and current and investigational treatments.

What is Limb-Girdle Muscular Dystrophy?

Limb-girdle muscular dystrophy (LGMD) refers to a group of diseases that cause weakness and wasting of the muscles, mainly proximal muscles, specifically muscles of the shoulders, upper arms, pelvic area, and thighs.¹  The severity, age of onset, and specific symptoms can vary widely among its many subtypes, and even among family members suffering with Limb-Girdle muscular dystrophy. ^{1, 2}

Understanding how many cases of Limb-Girdle muscular dystrophy there are can be challenging due to its diverse symptoms and similarity to other muscle conditions. However, estimates suggest that it affects around 0.8 to 6 people per 100,000 individuals worldwide.³

What causes Limb-Girdle Muscular Dystrophy? 

Limb-Girdle muscular dystrophy is a hereditary disease. The different forms of Limb-Girdle muscular dystrophy are caused by mutations in many different genes.^1,4 These genes are responsible for the formation of proteins that play vital roles in muscle function, regulation, and repair. When one of these genes contains a mutation, cells cannot produce the proteins needed for healthy muscles.²

There are two major groups of Limb-Girdle muscular dystrophies: LGMD1 and LGMD2. These groups are based on how the disease is inherited. LGMD1 is autosomal dominant, meaning only one copy of the mutated gene is necessary to cause the disease. In contrast, LGMD2 is autosomal recessive, meaning two copies of the mutated gene are necessary to cause the disease.^{2, 4} Mutations in many different genes can cause specific types of LGMD1 and LGMD2 (see a list of the different LGMD1 and 2 subtypes and the causing mutations here). In addition to these subtypes, there are many cases of LGMD for which the causative gene is not yet known. ²

What are the symptoms?

Symptom onset can be in both childhood and adulthood. In the early stages of Limb-Girdle muscular dystrophy, individuals may start to walk with a “waddling” gait because of weakness of the hip and leg muscles. They may have trouble getting out of chairs, rising from a toilet seat, climbing stairs or running. Weakness in the shoulder area can make tasks like reaching overhead, holding arms outstretched, or carrying heavy objects challenging. ^{1, 2}

Muscle wasting can lead to changes in posture or appearance, particularly in the shoulders, back, and arms. Weak shoulder muscles often cause the shoulder blades to “stick out” from the back, known as scapular winging. Some people may develop an abnormally curved lower back or a spine that curves to the side (scoliosis). Joint stiffness (contractures) can also occur, restricting movement in the hips, knees, ankles, or elbows. Overgrowth (hypertrophy) of the calf muscles occurs in some people with Limb-Girdle muscular dystrophy. ¹

Weakening of the heart muscle (cardiomyopathy) occurs in some forms of Limb-Girdle muscular dystrophy. Some affected individuals also experience mild to severe breathing problems related to the weakness of muscles needed for breathing. Additionally, some individuals may experience difficulty swallowing (dysphagia). ^{1, 2}

Diagnosis of Limb-Girdle Muscular Dystrophy

Inquiring about family history, and a physical examination are key in the process of diagnosis of LGMD. Family history can help determine the inheritance pattern of the disorder, while the physical examination helps to determine which muscles are affected and how they are affected.⁴

Physicians often also request to check a person’s blood to test for creatine kinase (CK), an enzyme that leaks out of damaged muscle. A high CK level suggests that the muscles are being harmed. However, the test does not show exactly what type of disorder may be causing the muscle destruction. Sometimes, other tests, such as an electromyography may be performed. In this kind of test, the electrical activity of the muscles is measured, and nerves are stimulated to see where the problem lies.⁵

Genetic testing can be performed to pinpoint specific gene mutations associated with various subtypes of LGMD. If needed, a muscle biopsy (removal of a small muscle sample) can also distinguish between different types of muscular dystrophy and other conditions if genetic testing do not provide a clear diagnosis. ^5,6

Treatment of Limb-Girdle Muscular Dystrophy

The treatment of Limb-Girdle muscular dystrophy focuses on supportive care to maintain mobility and functional independence, manage associated complications and maximize quality of life for those affected by the disease, as there are currently no treatments that can alter the course of the disease.⁷ Treatment plans are tailored to each person’s specific symptoms and may include:

• Therapy and exercise. Physical and occupational therapy programs are usually part of the treatment for Limb-Girdle Muscular Dystrophy. Occupational therapy focuses on daily activities, especially those involving hand use, to make tasks such as using a computer less tiring. Physical therapy emphasizes mobility and (where possible) strengthening of large muscle groups to allow greater motion in the joints and to prevent contractures.  Some experts recommend swimming and water exercises as a good way to keep muscles as toned as possible ^{7, 8}
• Assistive devices. Simple devices like a cane or a long-handled reacher can make walking and accomplishing tasks easier as weakness progresses. A power wheelchair or scooter becomes convenient when weakness in the pelvic girdle and upper legs causes frequent falls. ^{7, 8}
• Speech therapy can help individuals who experience slurred speech.⁸
• Heart monitoring. The heart can be affected in several types of Limb-Girdle Muscular Dystrophy, including LGMD1B and LGMD2A-I. Regular check-ups involving electrocardiograms, echocardiography or cardiac magnetic resonance imaging can help monitor heart issues. Treatments may include medications, pacemakers, or even heart transplants in severe cases. ^{7, 8}
• Respiratory care. Breathing difficulties can develop over time for some people with Limb-Girdle Muscular Dystrophy. Regular monitoring and non-invasive ventilation devices can support breathing if respiratory function declines. ⁷
• Techniques to improve swallowing. Difficulty swallowing, and arm weakness can lead to malnutrition in some patients. Such patients may benefit from techniques to improve swallowing, such as altering food consistency, using a chin tuck maneuver, or placing a feeding tube.⁷

New Treatments for Limb-Girdle Muscular Dystrophy

Several new therapies are being investigated in the laboratory. These approaches are not yet available for use in people as their safety and efficacy are still being tested.⁴

Stem-Cell Transplantation. Stem cells are early-stageflexible cells that can give rise to mature muscle fibers. They are found in muscle tissue and other places in the body.⁹ For people with Limb-Girdle muscular dystrophy, there are two stem-cell transfers that may be possible: autologous or allogenic. Autologous stem-cell transfer uses the patient’s own cells, which are treated in a lab to fix the genetic issue and then re-implanted. Allogenic stem-cell transfer involves injecting healthy donor stem cells into the patient. In both methods, the goal is to inject stem cells that can turn into healthy muscle cells and help repair the damaged muscles.⁴  In a small study involving 65 individuals with Limb-Girdle Muscular Dystrophy, this approach appeared to slow the progression of muscle deterioration. However, further clinical trials are needed to thoroughly evaluate the safety and effectiveness of this method..¹⁰

Exon skipping.  Proteins are essential molecules in our bodies that perform various functions, such as building and repairing muscles. Exons are parts of our DNA that contain the instructions for making specific parts of a protein. When these exons come together, they help produce a complete protein, with each exon contributing a piece. ^4,11 In some forms of Limb-Girdle muscular dystrophy, there are changes (mutations) in certain exons. These mutations cause the body to make faulty proteins that don’t work correctly. Exon skipping involves using small DNA pieces to cover up the mutated exon. By doing this, the cell ignores the faulty part when making the protein. This helps the body produce a protein that works properly, even though there is a mutation. ^{4 , 11} This technique is being tested in mice.¹² However, no human studies have been performed yet.

Gene delivery. Gene delivery involves inserting a healthy gene into cells to replace a faulty one. This is done using a vector, such as the Adeno-Associated Virus (AAV), a small, harmless virus that can carry genes into cells.⁴  Clinical trials at early stages are investigating if this technique will help restore the production of several muscle proteins in patients with different forms of Limb-Girdle Muscular Dystrophy, which could potentially lead to an improvement of the disease.¹³  There are several clinical trials testing the efficacy and safety of this therapy at the moment.

RNA interference. In the process of making proteins, our DNA first creates a temporary copy called messenger RNA (mRNA). This mRNA acts like a recipe that our cells use to make proteins. In this technique, researchers inject small RNA pieces produced in the lab that match the mRNA of the gene they want to silence. When these small RNA pieces bind to the mRNA, they signal the cell to break down the mRNA, preventing the cell from making the protein. ^{4, 14} Researchers are currently testing this method in mice. For example, researchers used RNAi to target a mutation in the myotilin (MYOT) gene in mice, which causes LGMDA1A. As a result, mice experienced increased strength and muscle mass. ^4,15 However, no human studies have been performed yet.

Gene editing. Gene editing involves recognizing a specific DNA or RNA sequence and modifying it. Although there are different methods of gene editing, the CRISPR-Cas system has gained a lot of popularity in recent years. ⁴ CRISPR is a system originally found in bacteria that helps them fight viruses. The CRISPR-Cas system uses a “template” to find a specific piece of DNA in a cell and then removes, replaces or inserts a piece of DNA at this location.¹⁶ Using this system, scientists were able to correct mutations in the CAPN3 gene causing Limb-Girdle Muscular Dystrophy in human muscle cells in the laboratory.^17,18

Conclusions

Limb-girdle muscular dystrophy (LGMD) is an ‘umbrella’ term that includes a group of hereditary diseases that cause weakness and wasting of the muscles in the arms and legs. Currently, treatment for limb-girdle muscular dystrophy is supportive. The treatment plan is tailored to each person’s specific symptoms and may include the use of assistive devices and adaptive equipment, speech therapy, heart monitoring, respiratory care or swallowing techniques. In the last decade, different techniques have been investigated to treat Limb-Girdle Muscular Dystrophy, such as stem-cell transplantation, exon skipping, gene delivery, RNAi, and gene editing. However, more investigation in clinical trials is needed to confirm their efficacy and safety.

Are you affected by Limb-Girdle Muscular Dystrophy and want to explore your possible treatment options?

At myTomorrows, we have a team of Patient Navigators who are medically trained, multi-lingual professionals, who help you to explore your treatment options and support you through your journey.

You can book a call with a Patient Navigator to discuss your options and learn more about participating in clinical trials .

Dominant Limb-Girlde Muscular Dystrophy subtypes 

Recessive Limb-Girlde Muscular Dystrophy subtypes 

Source: Bouchard C and Tremblay JP. 2023.