What is limb girdle muscular dystrophy (LGMD)?

Limb Girdle Muscular Dystrophy (LGMD)

Limb girdle muscular dystrophy (LGMD) is a genetically heterogeneous group of inherited muscle disorders characterized by progressive weakness and wasting of the proximal muscles in the hip and shoulder girdles, with significant variability in age of onset, severity, and systemic complications depending on the specific genetic subtype. 1

Classification and Genetics

• LGMD is classified into two main categories based on inheritance pattern: autosomal dominant (LGMD1) and autosomal recessive (LGMD2), with mutations identified in over 30 different genes 1, 2
• Autosomal dominant forms (LGMD1A-H) account for 10-25% of cases and include mutations in genes encoding myotilin, lamin A/C, caveolin-3, DNAJB6, desmin, transportin 3, and HNRPDL 3, 2
• Autosomal recessive forms (LGMD2A-W) represent 75-90% of cases and include mutations in calpain-3, dysferlin, sarcoglycans, telethonin, TRIM32, FKRP, titin, and many others 3, 2
• Prevalence of LGMD is estimated at 1 in 14,500 to 1 in 123,000 individuals 1, 3

Clinical Presentation

• The hallmark feature is progressive weakness primarily affecting the pelvic and shoulder girdle musculature 1
• Age of onset varies widely from early childhood to middle age, depending on the specific genetic subtype 1, 3
• LGMD2 (recessive forms) typically presents during childhood or adolescence with more severe and rapidly progressive disease 1, 4
• LGMD1 (dominant forms) often has later onset and slower progression 4, 3
• Common clinical features include:
  • Difficulty climbing stairs, rising from chairs, and raising arms above the head 4, 5
  • Proximal muscle weakness that is greater than distal 1
  • Scapular winging, progressive contractures, and scoliosis in some subtypes 1
  • Calf pseudohypertrophy in certain subtypes 1
• Loss of ambulation varies from early teens to adulthood depending on subtype 1

Systemic Complications

Cardiac Involvement

• Cardiac complications vary significantly by subtype and include:
  • Dilated and hypertrophic cardiomyopathies 1
  • Atrial and ventricular arrhythmias 1
  • Various degrees of heart block 1
• Cardiac involvement is particularly common in:
  • Lamin A/C-related LGMD (LGMD1B) 1
  • Sarcoglycan-deficient LGMD (LGMD2C-F) 1
  • FKRP-related LGMD (LGMD2I) 1, 6
• Cardiomyopathy without skeletal muscle involvement has been reported in LGMD2I 1

Respiratory Involvement

• Respiratory muscle weakness varies in severity but can lead to:
  • Progressive respiratory insufficiency 1
  • Sleep-disordered breathing 1, 6
  • Increased risk of respiratory infections 1, 6

Diagnosis

• Serum creatine kinase (CK) is typically elevated, though levels vary by subtype and can occasionally be normal in some adult patients 1, 6
• Electromyography (EMG) typically shows myopathic features 1, 5
• Muscle biopsy may show dystrophic changes with variation in fiber size, necrosis, and fibrosis 1, 5
• Genetic testing is essential for definitive diagnosis:
  • Next-generation sequencing panels are now the preferred approach due to genetic heterogeneity 4, 5
  • Whole-exome sequencing may be necessary for cases that remain undiagnosed after panel testing 5

Differential Diagnosis

• Duchenne and Becker muscular dystrophies 1
• Scapuloperoneal syndromes 1
• Rigid spine syndrome 1
• Myasthenia gravis 1
• Spinal muscular atrophy 1
• Polymyositis 1
• Other glycogen storage diseases 1
• Danon disease 1
• Mitochondrial myopathies 1

Management

Cardiac Management

• Regular cardiac evaluation with echocardiography and ECG is recommended:
  • At least annually for all LGMD subtypes with known cardiac involvement 1, 6
  • More frequent monitoring if abnormalities are detected 6
• Early initiation of standard heart failure therapies when cardiac dysfunction is detected 6

Respiratory Management

• Regular assessment of respiratory function 1, 6
• Evaluation for sleep-disordered breathing when clinically indicated 1, 6
• Implementation of non-invasive ventilation when needed 1
• Aggressive management of respiratory infections 1

Musculoskeletal Management

• Regular assessment of muscle strength, range of motion, and function 6, 5
• Physical therapy to maintain mobility and prevent contractures 1, 5
• Orthotic devices and mobility aids as needed 1, 5
• Surgical interventions for severe contractures or scoliosis when appropriate 1

Other Management Considerations

• Maintaining ideal body weight to optimize respiratory and cardiac function 1, 6
• Genetic counseling for affected individuals and families 6, 5
• Multidisciplinary care involving neurology, cardiology, pulmonology, rehabilitation medicine, and genetics 6, 5

Emerging Therapies

• No disease-modifying therapies have been FDA-approved specifically for LGMD 4, 7
• Gene replacement therapies are in clinical trials for some recessive forms, particularly sarcoglycanopathies and FKRP-related LGMD 4, 7
• RNA-based therapeutic approaches are being investigated for dominant forms 4, 7
• CRISPR-Cas9 gene editing shows potential for future therapeutic applications 7

Prognosis

• Prognosis varies widely depending on the specific genetic subtype 1, 3
• Disease progression and life expectancy differ even among members of the same family with identical mutations 3
• Cardiac and respiratory complications are major determinants of morbidity and mortality 1