From Diagnosis to Treatment: Managing Limb-Girdle Muscular Dystrophy

Wondering how Limb-Girdle Muscular Dystrophy (LGMD) may affect everyday movements? Curious about what symptoms may develop over time, the therapies currently available, and what treatments are being investigated?

These are common questions for people living with LGMD, their families, and caregivers.

This blog aims to answer those questions. It offers a clear overview of LGMD and provides reliable, easy-to-understand information. The goal is to support greater understanding of LGMD, whether for individuals living with the condition, those involved in their care, or anyone seeking to learn more.

What is Limb-Girdle Muscular Dystrophy (LGMD)?

Limb-Girdle Muscular Dystrophy (LGMD) refers to a group of rare diseases that cause muscles to get weak and shrink over time. It mostly affects muscles near the center of the body, such as the shoulders, upper arms, hips, and thighs. ^{1, 2, 3}

It is difficult to estimate how many people have Limb-Girdle Muscular Dystrophy. This is because this condition has very diverse symptoms that can look like other muscle diseases. However, research estimates that it affects around 0.8 to 6 people per 100,000 individuals worldwide. ⁴

What Causes Limb-Girdle Muscular Dystrophy?

Limb-Girdle Muscular Dystrophy (LGMD) is a hereditary disease, which means it can be passed down in families through changes in genes.

Different types of LGMD are caused by mutations (changes in the DNA) in specific genes. ^{1, 5} These genes are responsible for the formation of proteins that muscles need to function, repair, and stay healthy. When one of these genes has a mutation, the cells may not produce the protein correctly – or at all – which is necessary for healthy muscles. ^{1, 2, 3}

Most genes come in pairs, with one copy inherited from each parent. Whether a person develops LGMD depends on how the mutated gene is inherited. There are two major groups of LGMD:

• LGMD1 is autosomal dominant. This means only one copy of the mutated gene is necessary to cause the disease.
• LGMD2 is autosomal recessive. This means two copies of the mutated gene are necessary to cause the disease. ^{3, 5}

Each group includes many subtypes, depending on the specific gene affected. You can view a list of LGMD1 and LGMD2 subtypes and their associated gene mutations here.⁵  In addition to these subtypes, there are many cases of LGMD where the gene responsible has not yet been identified. ³

What are the Symptoms of LGMD?

Limb-Girdle Muscular Dystrophy (LGMD) can affect people in different ways.

Symptom onset in LGMD may occur in childhood or adulthood, and both the type of symptoms and severity can vary. These differences often depend on the specific LGMD subtype. However, even people with the same subtype, including members of the same family, can experience different symptoms. ^{1, 3}

Early LGMD signs may include walking with a waddling step. This happens when the hip and leg muscles become weak. Everyday tasks like climbing stairs, getting out of a chair, or running can become difficult. ^{1, 2, 3}

Shoulder weakness can make it hard to:

• Reach overhead.
• Hold arms outstretched.
• Lift or carry heavy objects. ^{1, 2, 3}

As the disease progresses, it may change how the body looks or moves. This can include:

• Shoulder blades sticking out from the back (called scapular winging).
• A curved spine (lordosis or scoliosis).
• Stiff joints in the hips, knees, or elbows (called contractures) that limit movements.
• Large-looking calf muscles in some people due to overgrowth (hypertrophy). ^{1, 2, 3}

Other problems may appear, such as:

• Heart weakness (cardiomyopathy) in some types of LGMD.
• Breathing trouble, due to weak chest muscles.
• Difficulty swallowing (dysphagia). ^{1, 2, 3}

Diagnosis of LGMD

Diagnosing Limb-Girdle Muscular Dystrophy (LGMD) usually starts with a review of the family history and a physical exam. Doctors may ask if other family members have had muscle problems. This can help show how the condition might be passed down. A physical exam helps to determine which muscles are affected and how they are affected. ³

Several tests may be used to confirm an LGMD diagnosis:

• Blood test for creatine kinase (CK): CK is a special type of protein found in muscles. When muscles are damaged, CK leaks into the blood. A high CK level shows that the muscles are being harmed. However, this test can’t tell exactly what type of disorder may be causing the muscle destruction. ³

• Electromyography: This test checks how the muscles respond to electrical signals. It can help show whether the problem is in the muscle itself or in the nerves that control it. ^{2, 3}

• Genetic testing: This test looks for specific gene mutations linked to different LGMD subtypes. It is one of the most accurate ways to diagnose LGMD. ^{2, 3}

• Muscle biopsy: If genetic testing doesn’t give clear answers, doctors may take a small sample of muscle tissue to examine under a microscope. This can help rule out other muscle conditions and support an LGMD diagnosis. ^{2, 3}

Treatment of LGMD

There is no cure for Limb-Girdle Muscular Dystrophy (LGMD) yet. However, LGMD treatment can help people stay active for a longer time, manage symptoms, and feel better. ³

Treatment plans are personalized to each person’s needs and may include:

Physical therapy

Physical therapy can help people with Limb-Girdle Muscular Dystrophy improve or maintain movement, strengthen certain muscles, and keep their joints flexible. It may also help slow muscle loss and prevent contractures, that happen when the tissues around  a joint tighten and shorten, which make the joint stiff and hard to move.

Therapy may include:

• Strength exercises like step-ups or bending and straightening the knees.
• Low-impact activities such as walking, swimming, or water exercises. ^{3, 6, 7}

Occupational therapy

Occupational therapy focuses on helping people improve their ability to perform daily tasks, including:

• Bathing, dressing, and eating
• Using tools or devices (e.g., computers, utensils).
• Planning routines to reduce fatigue. ^{3, 6, 8}

Assistive devices

Assistive devices can help people with LGMD stay independent as their muscles get weaker.

• Simple tools like a cane or long-handled reacher can make walking and reaching easier.
• If the legs or hips become too weak for safe walking, a power wheelchair or scooter can help prevent falls and support daily movement. ^{7, 8}

Read our blog on physical therapy, mobility aids, and home modifications for people with Limb-Girdle Muscular Dystrophy.

Speech therapy

Speech therapy can help people with LGMD who have slurred or unclear speech.

A speech therapist may suggest:

• Exercises to strengthen the lips, tongue, and throat muscles, which can help make speech clearer.
• Voice training, such as practicing slower, clearer speech.
• Breathing exercises to help speak for longer without needing to stop for air.

These techniques can make speech easier to understand during everyday conversations. ⁹

Techniques to improve swallowing

Some people with Limb-Girdle Muscular Dystrophy may have trouble swallowing. Weakness in the arms can also make eating harder. Together, these issues may lead to poor nutrition.

To help with swallowing, doctors or therapists may recommend:

• Changing the texture of food, such as using softer or pureed options.
• Using a chin tuck technique to help prevent choking.
• Using a feeding tube, if needed, to help the person get enough nutrition. ³

Heart monitoring

The heart can be affected in some types of Limb-Girdle Muscular Dystrophy (LGMD), such as LGMD1B and LGMD2A–I. ^{7, 8}

Regular check-ups can help find heart problems early. Doctors may use tests that check the heart’s rhythm, structure, and function to monitor for any changes over time.

Treatment may include medications, a pacemaker, or, in serious cases, a heart transplant. ^{3, 6}

Respiratory care

Some people with Limb-Girdle Muscular Dystrophy may develop breathing problems over time. This happens when the muscles that control breathing become weaker.

Doctors may monitor lung function regularly. If breathing becomes harder, they may recommend non-invasive support, such as a BiPAP machine. This device helps push air into the lungs during sleep or rest, making it easier to breathe. ³ 

Investigational Treatments for Limb-Girdle Muscular Dystrophy

Researchers are studying several investigational treatments for Limb-Girdle Muscular Dystrophy (LGMD). These are being tested in LGMD clinical trials and early lab studies to see if they can slow down or stop the disease. These treatments are not yet available for use in people, because their safety and effectiveness are still being evaluated. ⁵

Stem-Cell Transplantation

Stem cells are special cells found in the body that grow into many different types of cells, including muscle cells. Scientists are exploring ways to use these cells to repair or replace muscle that has been damaged by LGMD.

There are two main types of stem cell treatments being studied:

• Autologous stem cell transplant: This uses the person’s own stem cells. These cells are collected and treated in a lab to fix the genetic issue.
• Allogenic stem cell transplant: This uses stem cells from a healthy donor.

These stem cells are injected into the person’s body, with the aim that they will turn into healthy muscle cells and help repair the damaged muscles.⁵

This technique is currently being tested in the laboratory. Clinical trials will be needed to evaluate the safety and effectiveness. ^{3, 5}

Exon skipping

Proteins help muscles grow, repair, and work properly. Exons are small sections of DNA that act like puzzle pieces, each carrying instructions for part of a protein. When put together, they help form a complete, working protein.

In some forms of Limb-Girdle Muscular Dystrophy, there are mutations in certain exons. This prevents the pieces from fitting together properly, resulting in a faulty protein that doesn’t work correctly.

Exon skipping uses small pieces of synthetic molecules to “skip over” the mutated exon when the body is making the protein. It works in this way:

• The small pieces of synthetic DNA hide the mutated exons.
• The body then ignores these pieces and connects the remaining exons.
• As a result, the cell can make a shorter, but still working, version of the protein. ^{3, 5, 10}

This technique is being tested in the laboratory. However, no human studies have been performed yet. ^{3, 5}

Gene delivery

Gene delivery works by placing a healthy gene into muscle cells to replace the faulty one that causes the disease.

Scientists use delivery systems called vectors to carry the gene. The most common type is a lab-modified virus called Adeno-Associated Virus (AAV). In the lab, this virus is altered so it can carry the healthy gene and deliver it to muscle cells. It is also modified to reduce the chance of causing illness.

Once inside the muscle, the gene may help the body make the protein that was missing or not working properly. ⁵

This method is being tested in early clinical trials. ^{11, 12, 13, 14}

Gene editing

Gene editing for Limb-Girdle Muscular Dystrophy (LGMD) works by finding a specific DNA sequence and modifying it. The most studied method is the CRISPR-Cas system. CRISPR is a system originally found in bacteria that helps them fight viruses.

This gene editing system works in some basic steps:

• A guide molecule directs the system to the exact spot in the DNA that needs to be modified.
• A special protein acts like scissors and cuts the DNA at that spot.
• The cell then tries to fix the cut using its natural repair system.
• During this repair, the faulty DNA may be removed, fixed or replaced with a working copy. ^{5, 15}

This technique is being tested in labs.[16] However, no human studies have been performed yet.

RNA interference

Some types of Limb-Girdle Muscular Dystrophy (LGMD) are caused by harmful proteins that damage muscle cells. RNA interference (RNAi) is an experimental technique designed to stop these proteins from being made.

DNA contains instructions for making proteins. Before a protein is built, the body makes a temporary copy of these instructions called messenger RNA (mRNA). The mRNA acts like a recipe that tells the cell how to make the protein.

RNA interference works like this:

• Scientists create small synthetic RNA pieces in the lab that match the faulty mRNA.
• These pieces attach to the faulty mRNA.
• This causes the cell to break down the faulty mRNA before it can make the harmful protein.

By stopping harmful proteins early, RNA interference may help slow or prevent muscle damage. ^{5, 17}

This method is still being tested in the lab. No human studies have been done yet. ^{5, 17}

All these investigational treatments are being studied for safety and effectiveness, and may not offer direct benefit to participants. Participation in clinical trials is voluntary and subject to eligibility criteria

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. It mostly affects muscles near the body’s center, like the shoulders, upper arms, hips, and thighs.

Currently, treatment for LGMD is supportive. The treatment plan is tailored to each person’s specific symptoms and may include the use of assistive devices, speech therapy, heart monitoring, respiratory care or swallowing techniques.

In the last decade, different techniques have been investigated to treat LGMD, 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.

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

References

Dominant Limb-Girdle Muscular Dystrophy subtypes

Recessive Limb-Girlde Muscular Dystrophy subtypes

Source: Bouchard C and Tremblay JP. 2023.