Causes of limb-girdle muscular dystrophy

Limb-girdle muscular dystrophy (LGMD) is a progressive disorder that causes weakness and wasting (atrophy) of the muscles in the shoulder and hip regions, known as the limb-girdle area.

Even though the symptoms of LGMD vary from patient to patient, common symptoms include muscle and joint soreness, difficulty standing from a seated position, and difficulty raising the arms above the head.

LGMD is a genetic disease with many subtypes and gene changes involved in its development. This article explains why these subtypes develop, how a person inherits LGMD, and what this means for the specific type of LGMD they inherit.

What causes limb-girdle muscular dystrophy?

LGMD has genetic causes, meaning it occurs from mutations in many different genes. These genes usually provide instructions for producing proteins that are important for muscle structure, function, maintenance, and repair.

Gene mutations can disrupt the amount or function of these muscle proteins, which in turn lead to muscle weakness. When the genes that control the production of these proteins or enzymes are faulty, these proteins might either not function as they should or be missing entirely.

Why are there many different LGMD subtypes?

Unlike Duchenne and Becker muscular dystrophies, which are linked solely to mutations in the DMD gene, LGMD is linked to mutations in more than 32 different genes that affect muscle function. While each gene change is associated with one or more LGMD subtypes, variants in the CAPN3 and DYSF genes account for most forms of LGMD.

CAPN3

CAPN3 gene LGMD represents the most common type. This gene provides the instructions for building an enzyme called calpain-3, which cuts up damaged proteins so the body can easily clear them from a muscle cell.

In people with calpain-3-related LGMD, this means the enzyme does not function as it should, damaged proteins are not cleared from muscle cells, and muscles do not function properly.

DYSF

Dysferlin-related LGMD, caused by DYSF gene mutations, is another relatively common form. The DYSF gene encodes dysferlin, a protein found in the thin protective layers around muscle fibers that repairs these layers when muscle strain damages them. Mutations in the DYSF gene can lead to an altered form of dysferlin that cannot support muscle repair.

Sarcoglycan genes

Sarcoglycanopathies are a group of rare, autosomal-recessive LGMDs. Sarcoglycan gene mutations can occur in any of four specific genes that provide instructions to make sarcoglycan proteins:

• SGCA (Alpha)
• SGCB (Beta)
• SGCG (Gamma)
• SGCD (Delta)

These proteins form a critical protective complex in muscle cells. When any of these genes mutates, the entire complex becomes less stable, potentially leading to muscle weakness, progressive loss of mobility, and heart or breathing issues.

Inheritance of LGMD

LGMD is an inherited genetic disorder. The pattern of inheritance varies based on the specific genetic mutation causing the disease.

Unlike Duchenne and Becker muscular dystrophies, which are inherited through the X chromosome, LGMD follows an autosomal inheritance pattern. Because the genes involved reside on autosomes rather than sex chromosomes, males and females generally have the same probability of developing the disease.

The different subtypes of LGMD broadly fall under two inheritance patterns:

• Autosomal dominant: A single copy of a faulty gene, inherited from one parent, is sufficient to cause the disease.
• Autosomal recessive: A person must inherit two mutated copies of the disease-causing gene, one from each parent, to develop the symptoms.

For a child to develop an autosomal recessive form of LGMD, both parents must be carriers of the defective genes. Usually, carriers do not show any symptoms and are unlikely to know that they are carriers unless someone in their family is diagnosed with LGMD and they have been genetically tested.

The main types of LGMD inherited in an autosomal recessive manner include:

•  LGMD Type R1, the most common form of LGMD, which accounts for as many as 30% of all LGMD cases. LGMDR1 is caused by mutations in the CAPN3 gene.
• LGMD Type R2, which occurs due to mutations in the DYSF gene.

Autosomal dominant LGMD subtypes include LGMD Type 1B, caused by mutations in the LMNA gene, and LGMD Type 1C, caused by mutations in the CAV3 gene.

Around 30 distinct forms of LGMD exist, with additional unidentified genes likely involved in rarer cases.

Can LGMD occur without a known family history?

LGMD can occur in an individual without any other family member appearing to carry the affected gene.

In autosomal recessive LGMD, a person with one disease-causing gene is usually an unaffected carrier. Because carriers may have no symptoms, LGMD can appear in a family with no previous history of the condition. In recessive inheritance, the affected child develops the disease if both parents are carriers. A carrier of a rare recessive disease may not know they carry the gene until someone else in the family is diagnosed with LGMD.

However, a new mutation can also occur without any family history. This is known as a de novo variant.

How are LGMD subtypes identified?

Doctors identify specific LGMD subtypes using genetic testing, muscle biopsies, and evaluations of symptoms and inheritance patterns.

Before reaching this stage, healthcare professionals must identify the pattern of weakness and confirm that it arises from muscle wasting using several initial evaluations:

• Family history and physical examination: A provider reviews an individual’s personal and family medical history and assesses physical symptoms to support the diagnosis before lab tests.
• Creatine kinase (CK) level: CK is an enzyme that leaks from damaged muscle. Elevated CK levels in the blood indicate active muscle damage, though they do not pinpoint the specific cause, protein, or location of weakness.
• Electromyography: This test records electrical activity in muscle fibers at rest and during contraction, helping clarify whether weakness stems from a primary muscle disorder or a nerve control issue. This can help narrow down the diagnosis toward muscular dystrophy or LGMD.

Genetic testing

Identifying the type of LGMD depends on identifying the affected gene and the protein it encodes. Genetic tests use a blood sample to pinpoint the specific mutated gene.

A specialist in neuromuscular diseases may request targeted DNA tests based on specific clues, such as previous genetic test results from family members, findings from a muscle biopsy, or symptoms that closely resemble certain LGMD subtypes.

Because LGMD has many genetic causes, identifying the specific subtype can be challenging. However, next-generation sequencing allows doctors to analyze dozens of LGMD-related genes simultaneously to yield a definitive diagnosis. For example, programs such as The Lantern Project can test 105 genes linked to LGMD and related conditions.

Muscle biopsy

If a genetic test proves inconclusive or unavailable, a muscle tissue sample can be collected and analyzed to evaluate the presence, quantity, and location of specific muscle proteins. However, the correlation between genetic variants and missing proteins is not always perfect. A combination of these tests might be necessary to determine the exact LGMD subtype.

Why does knowing the genetic cause matter?

Although finding the genetic cause of LGMD can take time, this information is crucial for several reasons:

• Qualifying for targeted clinical trials and therapies: Knowing the gene involved may allow some patients to access emerging, variant-specific treatments and research studies.
• Getting an accurate prognosis and monitoring plan: Understanding the subtype helps anticipate the likely disease course and potential complications, which may require monitoring, although progression can vary between individuals with the same type.
• Enabling appropriate disease management: Clinicians can tailor supportive care and symptom management while avoiding unnecessary interventions.
• Informing genetic counseling and family planning: It clarifies the inheritance pattern and helps determine the risk of inheritance for other family members.

Working with a genetic counselor can help families organize testing, navigate diagnosis, understand test results, and work through the emotional aspects of coming to terms with an LGMD diagnosis. Patients can request a referral from their healthcare provider or locate certified professionals through the Find a Genetic Counselor search tool.

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