What are the causes of myopathies with normal Creatine Phosphokinase (CPK) levels but elevated aldolase?

Myopathies with Normal CPK but Elevated Aldolase

Dermatomyositis is the most common myopathy presenting with isolated aldolase elevation and normal creatine kinase, accounting for approximately 24% of such cases in the largest published cohort. 1

Primary Causes

Inflammatory Myopathies

Dermatomyositis represents the leading etiology and demonstrates unique characteristics when presenting with normal CPK:

• Patients have significantly less frequent cutaneous involvement (50% vs 100% in hyperCKemic dermatomyositis) 1
• Higher median erythrocyte sedimentation rate (33.5 vs 13.5 mm/h) 1
• More common perifascicular mitochondrial pathology (37.5% vs 4.2%) 1
• Less frequent fibrillation potentials on EMG (50% vs 90.5%) 1
• Classic cutaneous features may include Gottron papules, heliotrope rash, and V-sign when present 2

Overlap myositis is the second most common inflammatory cause, representing approximately 12% of cases with isolated aldolase elevation 1

Immune-mediated myopathy with perimysial pathology specifically presents with this biochemical pattern:

• Perimysial inflammation, fragmentation, or vasculitis on biopsy 1
• Found in 50% of patients with isolated aldolase elevation across all myopathy types 1

Non-Inflammatory Causes

Metabolic myopathies should be strongly considered when inflammatory markers are absent:

• Glycogen storage diseases (Types IIIa, IV, V, VII) can present with elevated aldolase 2
• Mitochondrial myopathies demonstrate ragged red fibers on Gomori trichrome stain 2, 3
• These patients typically lack inflammatory changes on EMG, MRI, or muscle histology 4
• The forearm ischemic exercise test is useful for screening glycogen metabolism defects 4

Fasciitis with associated myopathy has been specifically reported with this biochemical pattern 1

Nonspecific myopathy accounts for approximately 12% of cases and requires muscle biopsy for diagnosis 1

Critical Diagnostic Pitfall

The absence of CPK elevation does NOT exclude significant myopathy. Approximately 5% of late-onset Pompe disease patients and a subset of dermatomyositis patients have normal CK levels despite active muscle disease 2, 1. This represents a common diagnostic trap where clinicians may falsely reassure themselves based on normal CPK alone.

Diagnostic Algorithm

When aldolase is elevated but CPK is normal:

1. Assess for dermatomyositis features first 1:

   • Examine for any cutaneous manifestations (even subtle)
   • Check inflammatory markers (ESR, CRP)
   • Perform nailfold capillaroscopy 2

2. Obtain EMG to differentiate myopathic from neuropathic processes 2:

   • Myopathic changes include polyphasic motor unit potentials of short duration and low amplitude 2
   • Fibrillation potentials may be less frequent in normal-CPK dermatomyositis 1

3. Consider MRI of affected muscles 2, 3:

   • T2-weighted/STIR sequences detect muscle inflammation 2
   • Helps target muscle for biopsy 2

4. Proceed to muscle biopsy as the gold standard 2, 3:

   • Look specifically for perimysial pathology (present in 50% of cases) 1
   • Assess for inflammatory infiltrates versus metabolic changes 4
   • Use Gomori trichrome stain to identify ragged red fibers if mitochondrial disease suspected 2, 3

5. If biopsy shows no inflammation, pursue metabolic workup 4:

   • Forearm ischemic exercise test 4
   • Genetic testing for glycogen storage diseases 5
   • Mitochondrial DNA analysis if indicated 5

Additional Laboratory Considerations

Other muscle enzymes may provide clues 2:

• AST, ALT, and LDH may be elevated, reflecting muscle enzyme release 2
• Glucose tetrasaccharide (Glc4) in urine is sensitive for Pompe disease but nonspecific 2

Autoantibody testing should include 2:

• Myositis-specific antibodies (anti-Jo-1, anti-Mi2, anti-SRP) 2
• Anti-synthetase panel 2
• Note that many patients remain seronegative 2

Treatment Implications

Most myopathies with isolated aldolase elevation are treatable (79% in the largest cohort), making accurate diagnosis critical for patient outcomes 1. Inflammatory myopathies require immunosuppression, while metabolic myopathies need enzyme replacement or metabolic management, underscoring why distinguishing these entities is essential 2, 4.