LGMDs represent a heterogeneous group of inherited disorders primarily affecting the pelvic and shoulder girdle muscles, leading to muscle weakness and wasting. These conditions exhibit dystrophic muscle histology, characterized by:

• Ongoing degeneration of muscle fibers
• Increased variability in fiber size
• Replacement of muscle tissue by fat and connective tissue.

Clinical Spectrum

The clinical presentation of LGMDs varies widely:

• Severe forms: Early onset in the first decade, rapid progression, and a phenotype resembling Duchenne Muscular Dystrophy (DMD).
• Milder forms: Later onset, slower progression, and reduced severity.

Common Features

• Predominantly proximal muscle weakness.
• Sparing of facial, extraocular, and distal limb muscles.
• Significant variability in progression even within specific genetic subtypes.

Genetic Basis

LGMDs are classified based on inheritance patterns:

• Autosomal recessive (Type 2): Most common.
• Autosomal dominant (Type 1): Less common.

The estimated prevalence of LGMDs is 2.27 per 100,000 people (Norwood et al., 2009).

Pathophysiology

Most LGMDs involve dysfunction of proteins associated with dystrophin or its related complexes, critical for maintaining the integrity of the sarcolemmal membrane:

1. Dystrophin-associated proteins (DAPs):

   • Include α, β-, δ-, and γ-sarcoglycans.
   • Deficiency disrupts the link between the extracellular matrix and the cytoskeleton, causing sarcolemmal instability and muscle fiber necrosis.

2. Aberrant glycosylation of α-dystroglycan (e.g., LGMDs 2I, 2K, 2N, 2O, and 2P):

   • Glycosylation defects destabilize the muscle fibers, predisposing them to chronic dystrophic changes.

3. Other structural muscle proteins:

   • Dysferlin: Implicated in vesicle fusion in muscle repair.
   • Calpain: A calcium-sensitive protease.
   • Caveolin-3: Part of membrane lipid rafts.
   • Nuclear envelope proteins: Includes lamin A/C and emerin.
   • Sarcomeric proteins: Such as telethonin and myotilin.
   • TRIM32: A putative ubiquitin ligase.

Pathogenic Mechanisms

Abnormalities in these proteins lead to:

• Disrupted cellular pathways, causing chronic dystrophic changes.
• Impaired structural and functional integrity of the sarcolemmal membrane.

Clinical Correlates and Diagnostic Approach to LGMDs

A comprehensive review of all Limb-Girdle Muscular Dystrophies (LGMDs) is challenging due to their heterogeneity, but certain clinical patterns and diagnostic strategies can assist in narrowing down the diagnosis.

Key Clinical Correlates

1. Muscle Involvement:

   • Proximal muscle weakness (shoulder and pelvic girdle) is characteristic.
   • Patterns of muscle group involvement can guide diagnosis.
   • Calf hypertrophy: Common in most LGMDs but rare in LGMD2B (dysferlinopathy), where calf atrophy is seen.

2. Systemic Involvement:

   • Cardiac involvement (cardiomyopathy): Common in sarcoglycanopathies, LGMD2I, 2J, and 1B.
   • CNS involvement: Rare but may be present in some subtypes.

3. Onset and Progression:

   • Early onset, severe weakness (Duchenne-like phenotype): Sarcoglycanopathies, LGMD2A, and LGMD2I.
   • Later childhood onset: Suggests calpainopathy.
   • Adolescent or early adult onset: Suggests dysferlinopathy.

4. Family History:

   • May indicate dominant or recessive inheritance.
   • Significant inter- and intra-familial variability in phenotypes.

5. Differential Diagnosis:

   • Includes Duchenne/Becker muscular dystrophies, myotonic dystrophy, facioscapulohumeral muscular dystrophy (FSHD), and juvenile acid maltase deficiency.
   • Females with mild symptoms may be manifesting carriers of DMD.

Diagnostic Tests

1. Creatine Kinase (CK):

   • Almost always elevated in LGMDs.
   • The degree of elevation can provide diagnostic clues.

2. Imaging:

   • MRI: May show specific patterns of muscle group involvement.

3. Muscle Biopsy:

   • Histopathology: Dystrophic changes.
   • Immunohistochemistry (IHC): Can identify protein deficiencies (e.g., sarcoglycan, dysferlin).
   • Western blot: Confirms specific protein deficiencies but is less reliable for some proteins like calpain.

4. Genetic Testing:

   • Next-generation sequencing (NGS) panels or whole exome sequencing (WES):
     • Enables testing of multiple genes simultaneously.
     • May miss large deletions or duplications.
   • Targeted mutation analysis can be used to confirm findings from protein studies.

5. Limitations of IHC and Western Blot:

   • Abnormalities on IHC are not always specific.
   • Mutations in sarcoglycan genes can result in deficiencies across the entire sarcoglycan complex.
   • Calpain deficiency on Western blot is about 70% specific but can occur in other dystrophies.
   • Some cases with calpain gene mutations may show normal Western blot results.

Summary

• A specific diagnosis in LGMDs often relies on molecular genetic testing as the gold standard.
• Clinical patterns (age of onset, muscle involvement, systemic features) combined with CK levels, imaging, and muscle biopsy findings provide essential diagnostic clues.
• Advances in NGS and WES have improved diagnostic accuracy, though limitations persist in detecting large-scale mutations.