What is the initial diagnostic and treatment approach for a 30-year-old woman with rapidly progressive limb weakness, selective muscle involvement, and no family history of muscle disorders?

Differential Diagnoses for Rapidly Progressive Selective Proximal Weakness in a 30-Year-Old Woman

The most likely diagnoses are immune-mediated necrotizing myopathy (IMNM), particularly anti-SRP myopathy, followed by inflammatory myositis (polymyositis/dermatomyositis), and limb-girdle muscular dystrophy (LGMD), specifically dysferlinopathy. The rapid progression, selective pattern with shoulder girdle predominance, and age of onset strongly favor an inflammatory/immune-mediated process over hereditary myopathy. 1, 2

Immediate Diagnostic Priorities

Critical Initial Assessment

• Measure respiratory function immediately with negative inspiratory force and vital capacity, as respiratory failure can develop insidiously before sudden decompensation in inflammatory myopathies. 2
• Obtain urgent creatine kinase (CK) and aldolase levels - markedly elevated CK (often >10× normal) suggests IMNM, while moderate elevation (3-10× normal) suggests polymyositis or dermatomyositis. 1, 2
• Assess for bulbar symptoms including dysphagia, dysarthria, and facial weakness which indicate impending respiratory compromise. 2
• Check troponin and ECG to evaluate myocardial involvement, as cardiac manifestations can be life-threatening in inflammatory myopathies. 2

Key Laboratory Workup

• Myositis-specific antibodies are essential: anti-SRP antibody indicates necrotizing myopathy with acute onset, dilated cardiomyopathy, and poor response to standard immunosuppression. 3
• Anti-Jo-1 and other anti-synthetase antibodies (anti-PL-7, anti-PL-12, anti-EJ, anti-OJ) - positive in 20-30% of inflammatory myositis cases. 3
• Anti-Mi2 antibody suggests dermatomyositis with classic cutaneous features. 3
• Thyroid function tests and 25-OH vitamin D levels to exclude endocrine and metabolic causes. 4
• Urinalysis for myoglobinuria to assess for rhabdomyolysis. 2

Primary Differential Diagnoses

1. Immune-Mediated Necrotizing Myopathy (IMNM) - Most Likely

This is the top differential given the rapidly progressive course and selective pattern. Anti-SRP myopathy presents with acute or subacute onset of severe proximal weakness, CK levels often exceeding 10 times normal, and minimal inflammatory infiltrate on biopsy. 1 Patients with anti-SRP antibody have necrotizing myopathy that is acute in onset with dilated cardiomyopathy and poor response to standard immunosuppression. 3

2. Polymyositis/Dermatomyositis

Symmetric proximal muscle weakness developing over weeks to months with elevated muscle enzymes characterizes these conditions. 1 The selective involvement pattern with shoulder girdle predominance fits this diagnosis. Dermatomyositis would be accompanied by characteristic skin findings including Gottron papules, heliotrope rash, shawl sign, and V-sign. 3 The absence of family history and non-consanguinity make this more likely than hereditary causes. 3

3. Limb-Girdle Muscular Dystrophy (LGMD) - Less Likely but Must Exclude

Late-onset LGMD, particularly dysferlinopathies (LGMD R2), can present in adult years with proximal weakness and elevated CK. 3, 1 However, the rapidly progressive course over weeks to months is atypical for LGMD, which usually shows slow progression over years. 5, 6 The selective pattern with shoulder girdle predominance over hip girdle is somewhat unusual for typical LGMD presentation. 7, 6

4. Anti-HMGCR Myopathy

This can rarely present with slowly progressive limb-girdle weakness resembling LGMD phenotype, though typically it is rapidly progressive. 5 Patients with clinical LGMD phenotype, degenerative changes in muscle biopsy but without genetic confirmation should be tested for HMG-CoA-myopathy. 5

Diagnostic Algorithm

First-Line Investigations

1. CK and aldolase - elevation ≥3× upper limit of normal suggests inflammatory myositis; >10× suggests IMNM. 1, 2
2. Myositis-specific autoantibodies panel including anti-SRP, anti-Jo-1, anti-Mi2, anti-HMGCR. 3, 2, 5
3. ESR, CRP, ANA, RF to evaluate inflammatory markers and differential diagnosis. 2
4. Thyroid function and 25-OH vitamin D to exclude metabolic causes. 4

Second-Line Investigations

1. EMG to confirm myopathic process characterized by polyphasic motor unit action potentials of short duration and low amplitude with increased insertional and spontaneous activity with fibrillation potentials. 3, 2
2. MRI of affected muscle groups to identify extent of involvement and guide biopsy site. 2
3. Muscle biopsy is the gold standard for confirming inflammatory myopathy diagnosis and differentiating inflammatory from noninflammatory causes. 1 Choose a weak muscle demonstrated by EMG abnormalities; biopsy the same muscle on the opposite side. 3

Genetic Testing - If Inflammatory Workup Negative

Comprehensive genetic testing including exome sequencing should be performed if muscle biopsy shows dystrophic features without inflammation and autoantibodies are negative. 5, 6 Testing should include dystrophin gene, CAPN3, DYSF, and other LGMD-associated genes. 3, 6

Critical Pitfalls to Avoid

• Do not delay respiratory assessment - respiratory muscle involvement can rapidly progress to life-threatening failure in inflammatory myositis. 1, 2
• Do not assume hereditary myopathy based on age alone - inflammatory myopathies commonly present in the third decade, and anti-HMGCR myopathy can mimic LGMD phenotype. 5
• Do not perform plasmapheresis immediately after IVIG as it will remove the immunoglobulin. 2
• Do not overlook cardiac involvement - obtain troponin and ECG as myocarditis can be life-threatening. 2
• Muscle weakness is more typical of myositis than pain - pain predominance suggests neuropathy or radiculopathy rather than primary muscle disease. 1

Initial Management Approach

If Severe Weakness (Grade 3-4)

• Initiate methylprednisolone 1-2 mg/kg IV daily for severe inflammatory myositis while awaiting confirmatory testing. 2
• Consider plasmapheresis for acute or severe disease - preferred over IVIG when rapid response is needed. 2
• Urgent referral to rheumatology and/or neurology is mandatory. 2

If Moderate Weakness

• Hold statins immediately as they can contribute to myopathy. 2
• Avoid medications that worsen neuromuscular weakness including β-blockers, IV magnesium, fluoroquinolones, aminoglycosides, macrolides, and anticholinergics. 2
• Consider hospitalization for patients with severe weakness limiting mobility, respiratory involvement, or dysphagia. 2