What are the diagnostic approach and management recommendations for limb‑girdle muscular dystrophy?

Limb Girdle Muscular Dystrophy: Diagnostic Approach and Management

Diagnostic Approach

Begin diagnostic evaluation with serum creatine kinase (CK) measurement, which is typically markedly elevated in LGMD, followed by genetic testing using next-generation sequencing panels covering all LGMD genes, as this has become the primary diagnostic modality that enables earlier molecular confirmation than traditional muscle biopsy approaches. 1, 2, 3

Clinical Recognition

Suspect LGMD when patients present with:

• Progressive proximal weakness affecting hip and shoulder girdles with relative sparing of distal muscles initially 1, 3
• Age at onset ranging from severe childhood-onset to adult-onset forms, depending on the specific genetic subtype 2, 3
• Gowers' sign indicating difficulty rising from the floor due to hip girdle weakness 1
• Waddling gait from pelvic girdle muscle involvement 1

Key Clinical Clues for Subtype Differentiation

Nearly half of LGMD patients exhibit distinctive clinical features that narrow the differential diagnosis 1:

• Predominant upper girdle weakness suggests specific subtypes like LGMDD1 (DNAJB6-related) 1, 4
• Disproportionate respiratory muscle involvement early in disease course 1
• Distal weakness in addition to proximal involvement 1
• Hip adductor weakness out of proportion to other muscle groups 1
• "Biceps lump" and "diamond on quadriceps" sign are pathognomonic physical findings 1
• Calf hypertrophy mimicking Duchenne muscular dystrophy 1
• Contractures developing early in disease course 1
• Cardiac involvement varies by subtype and significantly impacts mortality 5, 1

Diagnostic Testing Algorithm

1. Serum CK measurement: Typically elevated 5-100 times normal, though levels vary by subtype and do not correlate with disease severity 5, 1

2. Genetic testing: Next-generation sequencing panels containing all 29+ LGMD genes should be ordered early, as this has revolutionized diagnosis 2, 3, 6

   • Whole-exome sequencing can identify variants when panels are negative 2
   • Genetic confirmation is mandatory for clinical trial enrollment and future gene therapies 2, 3

3. Muscle biopsy: Now reserved for cases where genetic testing yields variants of uncertain significance or is negative 2, 3

   • Immunohistochemistry can identify absent or reduced proteins (sarcoglycans, dysferlin, calpain-3) 2
   • Western blot quantifies protein expression 2

4. Electromyography: Shows myopathic features (short-duration, low-amplitude motor unit potentials) but is not specific for LGMD subtypes 5, 2

Inheritance Pattern Recognition

• Autosomal recessive LGMDs (LGMDR): Loss-of-function mutations causing younger onset, more rapidly progressive disease (CAPN3, DYSF, ANO5, sarcoglycans, FKRP) 3, 6, 4
• Autosomal dominant LGMDs (LGMDD): Older onset, chronic progressive course (DNAJB6) 3, 6, 4

---

Management Recommendations

LGMD management requires multidisciplinary monitoring with specific surveillance schedules, as there are currently no FDA-approved disease-modifying therapies, unlike Duchenne muscular dystrophy where glucocorticoids provide proven mortality and morbidity benefits. 7, 5, 3

Cardiac Management (Critical for Mortality Reduction)

Cardiac complications significantly increase mortality risk and must be addressed proactively, not reactively. 5

• Baseline cardiac evaluation at diagnosis with ECG and echocardiography 5
• Annual cardiac monitoring with echocardiography and ECG for all LGMD patients 5
• Increase monitoring to every 6 months if any cardiac abnormalities detected 5
• Immediate initiation of standard heart failure therapies (ACE inhibitors, beta-blockers, diuretics as indicated) when cardiac dysfunction appears on echocardiography 5
• Common cardiac manifestations: Dilated or hypertrophic cardiomyopathy, atrial and ventricular arrhythmias, heart block 5

Critical pitfall: Do not wait for cardiac symptoms to appear before screening, as cardiac dysfunction can be asymptomatic until advanced stages 5

Respiratory Management

• Annual pulmonary function tests measuring forced vital capacity (FVC), maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP) 5
• Evaluate for sleep-disordered breathing when patients report daytime somnolence, morning headaches, or nocturnal dyspnea 5
• Initiate non-invasive ventilation (BiPAP) when FVC falls below 50% predicted or when symptomatic nocturnal hypoventilation is documented 5
• Maintain ideal body weight, as both obesity and malnutrition negatively impact respiratory and cardiac function 5

Musculoskeletal and Rehabilitation Management

• Physical therapy assessment every 4 months to monitor functional decline 5
• Low-resistance aerobic exercise programs to maintain function without accelerating muscle damage 5
• Avoid high-resistance or eccentric exercises that may accelerate muscle damage 5
• Prescribe orthotic devices (ankle-foot orthoses for foot drop) as weakness progresses 5
• Mobility aids (canes, walkers, wheelchairs) prescribed based on functional assessments 5
• Avoid excessive immobilization, which accelerates contracture formation and muscle atrophy 5

Functional Assessment Schedule

• Neuromuscular clinic visits every 6 months 5
• Functional assessments every 6 months: Timed 10-meter walk, 6-minute walk test, upper extremity function tests 5, 4
• Strength testing: Manual muscle testing and quantitative myometry 5
• Range of motion monitoring: Goniometry focusing on hip, knee, ankle joints 5

Pharmacological Considerations

Do not prescribe high-dose corticosteroids for LGMD, as these are beneficial only in dystrophinopathies (Duchenne/Becker muscular dystrophy), not LGMD. 5

• No FDA-approved disease-modifying therapies currently exist for LGMD 3, 6
• Gene replacement therapies are in clinical trials for recessive LGMDs (sarcoglycan, FKRP mutations) 3
• RNA-based therapeutic approaches are being explored for dominant LGMDs 3

Genetic Counseling and Family Planning

• Genetic counseling is mandatory for all diagnosed patients and at-risk family members 5
• Prenatal diagnosis and preimplantation genetic diagnosis are options for future pregnancies in families with known mutations 5

Common Management Pitfalls

• Do not delay cardiac evaluation until symptoms appear; asymptomatic cardiac dysfunction is common 5
• Do not attribute all symptoms to LGMD; screen for treatable comorbidities (thyroid disease, vitamin D deficiency, sleep apnea) 5
• Do not prescribe glucocorticoids as they lack evidence in LGMD and cause significant side effects 7, 5
• Do not allow prolonged immobilization during acute illnesses, as this accelerates muscle atrophy 5

Emerging Therapies and Clinical Trial Readiness

• Accurate genetic diagnosis is essential for enrollment in mutation-specific gene therapy trials 3, 6, 4
• International registries and biorepositories are being established to accelerate clinical research 4
• Standardized outcome measures are being validated across LGMD subtypes to enable efficient clinical trial design 4