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Limb-Girdle Muscular Dystrophies - LGMD

Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of hereditary myopathies characterized by muscle weakness and atrophy that primarily affect the proximal muscles of the shoulder and pelvic girdles. They constitute the third most common form of muscular dystrophy, with a prevalence ranging from 1:14,500 to 1:123,000 individuals. The age of onset can vary from early childhood to adulthood. In the early stages, distal, facial, and ocular muscles are generally spared

LGMDs are genetically heterogeneous diseases with over 30 identified subtypes. They are classified into autosomal dominant forms (LGMDD) and recessive forms (LGMDR). Each subtype features a characteristic age of onset, a specific clinical pattern, and variable extramuscular involvement. The main forms include LGMDR1 (CAPN3, calpainopathy 30-40%), LGMDR2 (DYSF, dysferlinopathy), LGMDR3-6 (SGCA, SGCB, SGCG, SGCD, sarcoglycanopathies), and LGMDR9 (FKRP)

LGMDs present a characteristic pattern with variability within each subtype. Here is a breakdown of the common muscular symptoms, specific patterns, and extramuscular manifestations translated and organized for clarity:

Common Muscular Symptoms

Symmetric Proximal Weakness: Affecting the pelvic girdle (glutei, hip flexors, quadriceps) and the scapular girdle (deltoid, pectoralis major, latissimus dorsi, rhomboids).
Characteristic Functional Difficulties: Difficulty rising from a seated position, climbing stairs, and lifting objects above the head.
Gait Alterations: “Waddling” gait (Trendelenburg gait) and compensatory lumbar lordosis.
Relative Preservation: Distal, facial, and ocular muscles are typically spared, at least in the early stages.

Subtype-Specific Patterns

LGMDR1 (Calpainopathy)

Onset: 8–15 years.
Features: Prominent winged scapulae, selective atrophy of the posterior thigh muscles, and early Achilles tendon contractures.
Note: Cardiomyopathy is rare.

LGMDR2 (Dysferlinopathy)

Onset: 15–25 years.
Phenotypes: Variable presentations including Miyoshi distal myopathy (calves), classic proximal LGMD, or asymptomatic hyperCKemia.
Note: Cardiomyopathy is possible in advanced stages.

LGMDR3-6 (Sarcoglycanopathies)

Onset: Childhood to adolescence.
Features: Rapid progression and calf pseudohypertrophy.
Note: Cardiomyopathy is frequent (40–50%).

LGMDR9 (FKRP-pathy)

Onset: Childhood to adulthood.
Note: Frequent and early dilated cardiomyopathy and frequent respiratory impairment.

Extramuscular Manifestations

Cardiomyopathy: Most common in sarcoglycanopathies and FKRP deficiencies; annual screening via echocardiogram is mandatory.
Respiratory Impairment: Occurs in severe forms and may require non-invasive ventilatory support.
Cognitive Difficulties: Rare, observed primarily in specific sarcoglycanopathies.

Clinical Evaluation
- Family History: Assessment of inheritance patterns (autosomal pattern).
- Neurological Examination: Evaluation of muscle strength and its distribution.
- Muscle Weakness Distribution Pattern: Identifying specific areas of involvement.
Laboratory Tests
- CK Elevation: Variable increases (3-50x normal).
- High Values: Dysferlinopathies and sarcoglycanopathies represent the forms with the highest levels (>5,000 U/L).
Genetic Diagnostics (Gold Standard)
- Systematic Approach: Utilizing NGS panels for multiple LGMD gene screening.
- Exome Sequencing: For difficult cases.
- Family Segregation Analysis: To confirm the genetic transmission within the family.
Electromyography (EMG)
- Myopathic Pattern: Characterized by short, polyphasic potentials.
- Note: Results may be normal in certain specific subtypes.
Muscle Imaging
- MRI: Identifying subtype-specific patterns of muscle involvement.
Muscle Biopsy
- Purpose: Allows confirmation of a dystrophic framework.
- Immunohistochemistry: Used to analyze specific proteins.

Available therapies

Currently, there are no approved specific therapies for LGMD. Management is predominantly supportive, although recent years have seen several clinical trials evaluating potential new therapeutic approaches.

Management of Complications

Cardiomyopathy: Annual echocardiogram and Holter ECG screening; possible use of cardioactive therapy.
Respiratory Failure: Annual spirometry, non-invasive ventilation when necessary, and respiratory physiotherapy.

Multidisciplinary Rehabilitative Approach

Physiotherapy: Active exercises to maintain residual strength, stretching to prevent contractures, aquatic exercises, and respiratory training.
Occupational Therapy: Mobility aids (canes, walkers, wheelchairs), environmental adaptations, and assistive devices for ADL (Activities of Daily Living).
Orthopedic Support: AFO braces for drop-foot, scoliosis corsets, and surgery for contracture correction or spinal stabilization.

Lifestyle Management

Weight Control: Obesity prevention and a balanced diet to support muscle metabolism.
Supplementation: Vitamin D and calcium for bone health.
Adapted Physical Activity: Light aerobic exercise.

Experimental Therapies Under Development

Gene Therapies: Using viral vectors for various LGMD forms.
Exon-skipping: Utilizing antisense oligonucleotides for specific mutations.
Cell Therapies: Muscle stem cell transplantation.
Pharmacological Modulators: Protein upregulators and anti-inflammatories.

Research in progress

- Current Research and Clinical Trials
  - Gene Therapy Development: Specific treatments targeting the most common LGMD subtypes.
  - Antisense Oligonucleotides Trials: Aimed at the correction of specific mutations.
  - Cell Therapies: Utilizing muscle stem cells and satellite cells.
  - Pharmacological Modulators: Focused on the upregulation of residual proteins.
  - Anti-inflammatory and Anti-fibrotic Approaches: Strategies to slow disease progression.
  - Biomarker Identification: For monitoring progression and assessing therapeutic response.
  Active Clinical Trials at the Neurology Unit
  
  Specifically, the following clinical trials are currently active at the Neurology Unit (UO di Neurologia):
  - MLB-01-005 (Fortify): A study to evaluate the efficacy and safety of BBP-418 (Ribitol) in patients affected by LGMD2I.
  - SRP-9003-301 (Emergene): Gene therapy with Bidridistrogene Xeboparvovec (SRP-9003) as a potential treatment for LGMD 2E/R4.
  Natural History Studies
  
  Additionally, the collection of clinical and functional data is ongoing through targeted tests performed by physiotherapists to study the natural history of LGMD. Patients followed at our facility undergo an annual clinical evaluation and blood sampling for data collection purposes.