Limb Girdle Muscular Dystrophy Type 2A: Key Diagnostic Steps

Limb-Girdle Muscular Dystrophy Type 2A (LGMD2A) is a progressive muscle-wasting disorder that primarily affects the muscles around the shoulders and hips. It is one of the most common forms of LGMD and can significantly impact mobility. Early diagnosis is essential for managing symptoms, planning supportive care, and providing genetic counseling.

Accurate diagnosis requires a combination of clinical evaluation and specialized testing.

Genetic Causes

LGMD2A is caused by mutations in the CAPN3 gene, which encodes calpain-3, a calcium-dependent cysteine protease involved in muscle maintenance and repair. This enzyme, primarily expressed in skeletal muscle, contributes to sarcomere remodeling and the processing of structural proteins. When CAPN3 is dysfunctional due to genetic mutations, muscle fibers progressively degenerate, leading to characteristic weakness. Unlike some muscular dystrophies, CAPN3 mutations do not cause dystrophin deficiency, distinguishing LGMD2A from Duchenne Muscular Dystrophy.

The disease is inherited in an autosomal recessive manner, requiring two defective copies—one from each parent—for symptoms to manifest. Carriers with a single mutated allele do not exhibit symptoms but can pass the mutation to offspring. More than 400 pathogenic CAPN3 variants have been identified, including missense, nonsense, frameshift, and splice-site mutations. These genetic changes can lead to complete loss or reduced enzymatic activity of calpain-3, with severity varying based on the specific mutation. Some mutations cause protein instability and degradation, while others impair substrate interactions, disrupting muscle function.

The variability in disease progression is influenced by the type of CAPN3 mutation, genetic modifiers, and environmental factors. Some individuals develop symptoms in childhood, while others remain asymptomatic until early adulthood. Certain CAPN3 variants correlate with a more aggressive disease course, leading to earlier loss of ambulation, while others result in a slower progression. Genetic background and epigenetic factors may also affect severity, though these influences are not fully understood.

Recognizing Key Symptoms

LGMD2A primarily weakens the proximal muscles of the shoulder and pelvic girdles. Early signs include difficulty rising from a seated position, climbing stairs, or lifting objects overhead due to weakness in the hip flexors, quadriceps, and shoulder stabilizers. Unlike some neuromuscular disorders, LGMD2A does not cause significant muscle pain or sensory deficits, primarily leading to progressive motor impairment.

As the disease advances, individuals often develop a distinctive gait due to weakening of the gluteal and thigh muscles. This may present as a waddling or Trendelenburg gait, where the pelvis drops on one side while walking due to inadequate hip abductor strength. Contractures, particularly in the Achilles tendons, can lead to toe-walking and reduced ankle dorsiflexion, further impairing mobility and increasing fall risk. Unlike dystrophinopathies, calf hypertrophy is generally absent, and muscle atrophy is more pronounced in the posterior thigh and scapular regions.

Scapular winging is a hallmark symptom resulting from progressive weakening of the serratus anterior and trapezius muscles. This makes tasks requiring arm elevation, such as combing hair or reaching overhead, increasingly difficult. The prominence of the scapulae becomes noticeable, especially when the arms are extended forward. As upper limb strength declines, self-care activities become more challenging. Unlike some muscular dystrophies, facial and extraocular muscles remain unaffected, preserving facial expressions and eye movement.

Respiratory function is usually preserved in early stages, but advanced cases may involve diaphragm and intercostal muscle weakness, leading to restrictive lung disease. Symptoms include exertional dyspnea and reduced exercise tolerance, and in severe cases, nocturnal hypoventilation. While respiratory failure is a major concern in Duchenne Muscular Dystrophy, it is less severe in LGMD2A but still requires monitoring. Cardiac complications, common in some muscular dystrophies, are rare in LGMD2A, distinguishing it from Becker Muscular Dystrophy and certain sarcoglycanopathies.

Diagnostic Procedures

Diagnosing LGMD2A requires clinical assessment and specialized testing. Since muscle weakness can result from various neuromuscular disorders, a systematic approach involving laboratory tests, imaging, genetic analysis, and muscle biopsy helps differentiate LGMD2A from other conditions.

Laboratory Tests

Serum creatine kinase (CK) levels are typically elevated, ranging from 500 to 10,000 IU/L, reflecting ongoing muscle fiber degeneration. While not specific to LGMD2A, persistently high CK levels suggest an underlying muscular dystrophy. Additional blood tests, including lactate dehydrogenase (LDH) and aldolase, may also be elevated but are less commonly used.

Electromyography (EMG) can reveal a myopathic pattern with low-amplitude, short-duration motor unit potentials without nerve conduction abnormalities. However, EMG is not required for diagnosis, as it does not distinguish between different muscular dystrophies. Ruling out inflammatory myopathies may involve testing for autoantibodies or inflammatory markers, though these are typically normal in LGMD2A.

Imaging Methods

Magnetic resonance imaging (MRI) and ultrasound assess muscle involvement. MRI reveals characteristic atrophy and fatty infiltration, particularly in the posterior thigh and medial gastrocnemius, which are often affected early. T1-weighted sequences highlight fat replacement, while short tau inversion recovery (STIR) sequences may detect muscle edema, though inflammation is not a primary feature.

Muscle ultrasound, a less expensive and non-invasive alternative, detects increased echogenicity due to fibrosis and fatty infiltration. While imaging cannot confirm a genetic diagnosis, it helps differentiate LGMD2A from other myopathies with distinct muscle involvement patterns. For example, dystrophinopathies often affect the vastus lateralis early, whereas LGMD2A primarily involves the posterior thigh and hip adductors.

Genetic Analysis

Definitive diagnosis relies on genetic testing to identify CAPN3 mutations. Next-generation sequencing (NGS) panels targeting limb-girdle muscular dystrophies allow simultaneous analysis of multiple genes with similar phenotypes. If a pathogenic variant is detected, confirmatory Sanger sequencing may be performed.

If initial genetic screening is inconclusive, multiplex ligation-dependent probe amplification (MLPA) can detect large deletions or duplications in CAPN3. Carrier testing for family members helps assess inheritance patterns and guide genetic counseling. While genetic analysis is the most definitive diagnostic tool, results should be interpreted alongside clinical findings, as some CAPN3 variants have uncertain significance.

Muscle Biopsy

When genetic testing is inconclusive or unavailable, muscle biopsy provides supportive evidence. Histopathological examination typically shows dystrophic changes, including muscle fiber size variation, increased connective tissue, and fiber necrosis with regeneration. Unlike inflammatory myopathies, LGMD2A lacks significant lymphocytic infiltration, distinguishing it from conditions like polymyositis.

Immunohistochemical staining for calpain-3 protein can be performed, though results may vary due to secondary protein degradation. Western blot analysis quantitatively assesses calpain-3 expression and stability. However, some CAPN3 mutations impair function rather than causing complete protein loss, meaning normal calpain-3 levels do not exclude LGMD2A. Given these limitations, muscle biopsy is generally reserved for cases where genetic testing is inconclusive.