What are the clinical presentation, diagnostic evaluation, and management recommendations for limb‑girdle muscular dystrophy?

Limb Girdle Muscular Dystrophy: Clinical Presentation, Diagnosis, and Management

Clinical Presentation

LGMD presents with progressive proximal muscle weakness affecting the hip and shoulder girdles, with proximal weakness consistently greater than distal weakness. 1

Key Clinical Features to Identify

• Proximal muscle weakness and wasting: Progressive weakness primarily in pelvic and shoulder girdle musculature, with hip and shoulder muscles affected before distal muscles 1, 2
• Scapular winging: Common finding in many subtypes, particularly visible when arms are raised 1
• Calf pseudohypertrophy: Present in certain subtypes, mimicking Duchenne muscular dystrophy 1
• Progressive contractures: Develop over time, particularly in hip flexors, knee flexors, and ankle plantar flexors 1
• Scoliosis: Emerges as paraspinal muscle weakness progresses 1

Distinctive Clinical Signs by Subtype

Specific clinical clues help differentiate LGMD subtypes and are present in approximately half of patients 2:

• Hip adductor weakness: Disproportionate to other muscle groups in certain subtypes 2
• "Biceps lump": Visible bulging of biceps muscle with elbow flexion 2
• "Diamond on quadriceps" sign: Characteristic appearance of quadriceps muscle 2
• Predominant upper girdle weakness: Some subtypes preferentially affect shoulders over hips 2
• Disproportionate respiratory muscle involvement: Early respiratory weakness relative to limb weakness 2

Age of Onset and Inheritance Patterns

• Autosomal recessive (LGMDR): Typically younger age of onset with more rapidly progressive disease due to loss-of-function mutations in muscle structural or repair proteins 3
• Autosomal dominant (LGMDD): Often older age of presentation with chronic progressive disease course 3
• Prevalence: 1 in 14,500 to 1 in 123,000 individuals, with regional and ethnic variations due to founder mutations 1, 2

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Diagnostic Evaluation

Genetic testing is essential for definitive diagnosis and should be pursued after initial screening tests suggest a muscular dystrophy. 1

Initial Laboratory Testing

• Serum creatine kinase (CK): Typically elevated, though levels vary significantly by subtype and do not correlate with disease severity 1, 4
• CK elevation: Can range from mildly elevated to 10-50 times normal, but normal CK does not exclude LGMD 4

Electromyography (EMG)

• Myopathic features: Polyphasic motor unit action potentials of short duration and low amplitude with increased insertional and spontaneous activity, fibrillation potentials, sharp waves, or repetitive discharges 5
• Dual purpose: Confirms myopathic process and targets appropriate muscle for biopsy 5

Muscle Biopsy

Muscle biopsy remains one of the most important investigative tools for differentiating inflammatory from noninflammatory myopathy and confirming LGMD diagnosis. 5

• Histopathologic features: Reduction or absence of dystrophin with degenerating and regenerating muscle fibers, replacement of muscle with fat or connective tissue 5
• Biopsy technique: Choose a weak muscle demonstrated by EMG abnormalities; biopsy the same muscle on the opposite side to maximize diagnostic yield and reduce sampling error 5
• Protein analysis: Immunohistochemistry can identify specific protein deficiencies (e.g., sarcoglycans, dysferlin, calpain-3) 6

Genetic Testing

• Next-generation sequencing (NGS): Comprehensive LGMD gene panels containing all 29+ LGMD genes allow earlier genetic confirmation 6, 3
• Whole-exome sequencing: Used when targeted panels are negative but clinical suspicion remains high 6
• Genetic confirmation: Always required for certain molecular diagnosis, fundamental for selecting homogeneous patient groups for future pharmaceutical and gene trials 6
• Variants of uncertain significance: NGS has led to more individuals with uncertain variants requiring careful clinical correlation 3

Differential Diagnosis Considerations

LGMD must be distinguished from other noninflammatory myopathies 5:

• Late-onset muscular dystrophies: Including dysferlinopathies with adult-onset 5
• Mitochondrial myopathies: Classic histopathologic findings include subsarcolemmal and interfibrillar accumulation of mitochondria with "ragged red fibers" on Gomori trichrome stain 5
• Drug-induced myopathy: Statins, corticosteroids, other medications 5
• Endocrine myopathy: Thyroid disorders, hyperparathyroidism 5
• Inflammatory myopathies: Polymyositis, dermatomyositis (distinguished by muscle biopsy showing inflammatory infiltrates) 5

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Management Recommendations

Cardiac Management

Cardiac complications significantly increase mortality risk and require proactive monitoring—do not wait for symptoms to appear, as cardiac dysfunction can be asymptomatic until advanced stages. 4

• Baseline and annual cardiac evaluation: Echocardiography and ECG for all LGMD subtypes, particularly those with known cardiac involvement (lamin A/C-related LGMD1B, sarcoglycan-deficient LGMD2C-F) 1, 4
• Increased monitoring: Every 6 months if any cardiac abnormalities detected 4
• Cardiac manifestations: Dilated or hypertrophic cardiomyopathy, atrial and ventricular arrhythmias, various degrees of heart block 1, 4
• Immediate treatment: When cardiac dysfunction detected on echocardiography, initiate standard heart failure therapies immediately (ACE inhibitors, beta-blockers, diuretics as indicated) 4

Respiratory Management

Regular respiratory assessment is critical, as respiratory muscle weakness leads to progressive respiratory insufficiency and increased risk of respiratory infections. 1, 4

• Annual pulmonary function tests: Start at diagnosis or when respiratory symptoms emerge 1, 4
• Sleep-disordered breathing evaluation: When patients report daytime somnolence, morning headaches, or nocturnal dyspnea 4
• Non-invasive ventilation (BiPAP): Implement when forced vital capacity (FVC) falls below 50% predicted or when symptomatic nocturnal hypoventilation documented 4
• Aggressive infection management: Prompt treatment of respiratory infections to prevent complications 1
• Weight management: Maintain ideal body weight, as both obesity and malnutrition negatively impact respiratory and cardiac function 4

Musculoskeletal and Functional Management

Physical therapy should focus on maintaining mobility and preventing contractures through gentle stretching and low-resistance exercise, while avoiding high-resistance or eccentric exercises that accelerate muscle damage. 1, 4

Regular Assessments

• Neuromuscular clinic visits: Every 6 months 1, 4
• Physical/occupational therapy assessment: Every 4 months 1, 4
• Strength testing: Manual muscle testing (MRC scale) or quantitative myometry for muscles with strength 3-5 on MRC scale 5
• Range of motion: Goniometry focusing on hip, knee, ankle joints, iliotibial band, hamstrings, gastrocnemius (lower extremities); elbow, wrist, long finger flexors (upper extremities) 5, 1

Functional Testing

• Ambulatory phase: Timed 10-meter walk, timed Gowers' maneuver, time to climb 4 stairs, time to rise from chair, 6-minute walk test 5, 1
• Late ambulatory/non-ambulatory: Time to put on shirt, self-care skills, writing, computer use, wheelchair control 5
• Validated scales: Vignos lower extremity scale, North Star Ambulatory Assessment, Brooke upper extremity scale, motor function measures 5

Therapeutic Interventions

• Orthotic devices: Ankle-foot orthoses for foot drop, splinting to prevent contractures 1, 4
• Mobility aids: Canes, walkers, manual or electric wheelchairs as weakness progresses 1, 4
• Contracture prevention: Gentle stretching, use of standers, consideration of iliotibial band lengthening when indicated 5
• Exercise prescription: Low-resistance exercise to maintain function; avoid high-resistance or eccentric exercises 4

Pharmacological Considerations

Do not prescribe high-dose corticosteroids for LGMD, as these are beneficial only in dystrophinopathies (DMD/BMD), not LGMD. 4

• No FDA-approved disease-altering therapies: Currently available for LGMD 3
• Gene replacement therapies: Clinical trials underway for recessive LGMDs (sarcoglycan and FKRP mutations) 3
• RNA-based approaches: Potential future therapies for dominant LGMDs 3

Genetic Counseling

• Family screening: All first-degree relatives should receive genetic counseling and consideration for testing 1
• Inheritance patterns: Autosomal dominant (LGMDD) with variable penetrance or autosomal recessive (LGMDR) 1, 3
• Reproductive options: Prenatal diagnosis and preimplantation genetic diagnosis available for future pregnancies 4

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Monitoring Schedule Summary

Assessment	Frequency	Purpose
Neuromuscular clinic	Every 6 months	Monitor disease progression [1,4]
Physical/occupational therapy	Every 4 months	Assess function, adjust interventions [1,4]
Cardiology (echo + ECG)	Annually (every 6 months if abnormal)	Detect cardiomyopathy, arrhythmias [1,4]
Pulmonary function tests	Annually or when symptomatic	Monitor respiratory insufficiency [1,4]
Functional assessments	Every 6 months	Track progression objectively [1]

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Critical Pitfalls to Avoid

• Delaying cardiac evaluation: Cardiac dysfunction can be asymptomatic until advanced stages; annual screening is mandatory 4
• Attributing all symptoms to LGMD: Screen for treatable comorbidities (thyroid disease, vitamin D deficiency, sleep apnea) 4
• Prescribing corticosteroids: Not beneficial in LGMD and may cause harm 4
• Excessive immobilization: Accelerates contracture formation and muscle atrophy; maintain activity within safe limits 4
• Ignoring respiratory symptoms: Early intervention with non-invasive ventilation improves quality of life and survival 4
• Overlooking genetic counseling: Family members may be at risk and benefit from early diagnosis 1