Overview of Limb-Girdle Muscular Dystrophy Type 1 (LGMDR1)

2025.08.22

Name and Classification

CAPN3

LGMDR1 was historically referred to as Limb-Girdle Muscular Dystrophy Type 2A (LGMD2A). In 2017, the classification system changed. The “R” in LGMDR1 stands for recessive inheritance, indicating that the disease typically occurs when two copies of the faulty gene are inherited. Both terms—LGMD2A and LGMDR1—refer to the same disorder, and both may appear in medical literature.
The Role of the CAPN3 Gene

Gene Location and Function

The CAPN3 gene is located on chromosome 15 (region 15q15.1) and spans over 52,000 base pairs. It produces Calpain 3, a calcium-dependent cysteine protease. This protein is critical for muscle health, breaking down and recycling damaged proteins and stabilizing the sarcomere, the structural unit within muscle fibers.

When CAPN3 is mutated, the protein either malfunctions or is absent, disrupting muscle repair and leading to progressive weakness.

Alternate Names

CAPN3 is also known by several synonyms, including CANP3, p94, nCL-1, LGMDR1 (Recessive type 1), and the older name LGMD2A.

Clinical Description

LGMDR1 is a progressive muscular dystrophy. It mainly affects proximal muscles—the muscles closer to the body’s center, such as those in the hips, thighs, shoulders, and upper arms. Intellectual function is not impaired, and heart complications are rare but possible.

Onset typically occurs between ages 8 and 30, although earlier or later onset can happen. Over time, the gradual loss of muscle strength impacts mobility, posture, and overall physical function.

Epidemiology

Globally, LGMDR1 affects about 8.3 individuals per million. Some regions report higher rates, such as northeastern Italy at approximately 26.5 cases per million. It accounts for roughly 30–32% of all limb-girdle muscular dystrophies, making it the most common subtype.

Higher prevalence is noted in areas with genetic founder effects, including parts of Brazil, India, and the Mediterranean.

Genetics and Etiology

LGMDR1 is most often inherited in an autosomal recessive pattern, meaning both parents must pass on a mutated CAPN3 gene. Rarely, a dominant form (classified as LGMDD4) occurs when only one altered gene copy is enough to cause the disease.

Over 500 different mutations in CAPN3 have been identified, including:

Missense mutations, where a single amino acid in the protein is replaced
Splice-site mutations that disrupt gene processing
Intron mutations in non-coding regions
Frameshift mutations, insertions, and deletions

These genetic changes impair Calpain 3’s ability to regulate calcium flow, remodel muscle fibers, support mitochondrial function, and maintain structural proteins.

Symptoms

Common Symptoms

Symptoms vary widely but often include:

Gradual weakness in the muscles of the hips, thighs, shoulders, and arms
Difficulty running, climbing stairs, or rising from the floor
Gower’s sign, where hands are used to push oneself upright
Scapular winging, where shoulder blades protrude
Lordosis and other posture-related changes
Muscle pseudohypertrophy, where muscles appear enlarged due to fat infiltration
Joint contractures and stiffness
Muscle pain, fatigue, or soreness after exertion
Elevated blood levels of creatine kinase (CK), sometimes up to 80 times the normal level

Rare Symptoms

Some individuals may also experience facial muscle weakness, camptocormia (forward flexion of the spine), metabolic-like symptoms, or rare childhood-onset associations such as eosinophilic myositis.

Diagnosis

Diagnosis combines clinical evaluation with laboratory and imaging studies to confirm the presence and type of muscular dystrophy.

Blood Tests

Blood tests often reveal significantly elevated CK levels and, in some cases, mild elevation of liver enzymes such as AST and ALT.

Electromyography (EMG)

EMG studies can detect myogenic changes in muscles, though early stages of the disease may yield normal results.

Imaging

Muscle MRI typically shows fatty replacement and muscle atrophy, particularly in the thighs, pelvis, and calves.

Muscle Biopsy

A biopsy may reveal variable fiber size, evidence of muscle cell death and regeneration, fibrosis, central nuclei, and lobulated fibers.

Protein and Genetic Analysis

Protein analysis by immunostaining or Western blot often shows reduced or absent Calpain 3. Genetic testing, using methods such as next-generation sequencing and Sanger sequencing, can identify specific mutations.

New techniques now allow testing for CAPN3 expression in skin fibroblasts or urine, which may eventually reduce the need for invasive muscle biopsies.

Treatment and Management

There is no cure for LGMDR1, but treatment focuses on slowing progression, preserving muscle function, and managing symptoms.

Physical Therapy and Exercise

Regular stretching and low-impact strength training can help maintain range of motion and delay contractures. Exercise should remain within comfortable limits to avoid overexertion.

Assistive Devices

Orthotic supports, braces, and wheelchairs may be used to improve mobility and stability as the disease progresses.

Respiratory and Cardiac Support

Although less common, respiratory decline may require non-invasive positive pressure ventilation. Regular monitoring of cardiac function is also recommended.

Experimental Therapies

Research into potential treatments includes:

Glucocorticoids: Studied for their anti-inflammatory effects, but benefits remain limited.
Myostatin inhibitors: Shown to increase muscle size without significant functional improvement.
Wnt pathway activators: Promising early results for improving slow-twitch muscle fibers.
Gene therapy: Using AAV vectors to deliver a functional CAPN3 gene is under investigation.
Antisense oligonucleotide (ASO) therapy: Designed for certain missense mutations.
Genome editing and stem cell therapy: Still in experimental stages but hold long-term potential.

Prognosis

The disease course varies, influenced by the age of onset, type of genetic mutation, and other factors such as sex.

Individuals with early-onset forms tend to experience faster progression.
Those with complete loss of Calpain 3 generally have more severe symptoms.
On average, loss of independent walking occurs 15–25 years after symptom onset.
Respiratory complications affect about 11% of European cases, while significant cardiac involvement remains rare.

Key Terms

Muscular Dystrophy: A group of genetic conditions causing progressive muscle weakness.
Limb-Girdle: Describes the initial muscle groups affected, mainly around the shoulders and hips.
Calpain 3: The protein encoded by the CAPN3 gene, critical for muscle repair and stability.
Sarcomere: The structural and functional unit of muscle fibers responsible for contraction.
Autosomal Recessive Inheritance: A genetic pattern where two copies of a faulty gene are needed for the disease to appear.
Creatine Kinase (CK): An enzyme released into the bloodstream when muscle tissue is damaged.
Gower’s Sign: Using hands to assist in standing up due to proximal muscle weakness.
Scapular Winging: Shoulder blades protruding abnormally due to muscle weakness.
Contracture: Stiffness or tightening of joints that reduces mobility.

Pseudohypertrophy: Apparent muscle enlargement caused by fatty or fibrous replacement rather than true muscle growth.

References

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