What are the next steps in diagnosing and managing mitochondrial myopathies in a patient with negative initial bloodwork, including Creatine Kinase (CK) and other labs, who experiences intermittent symptoms?

Diagnosing Mitochondrial Myopathies with Negative Initial Bloodwork and Intermittent Symptoms

For patients with suspected mitochondrial myopathy who have negative initial bloodwork (including normal CK levels) and intermittent symptoms, cardiopulmonary exercise testing (CPET) should be the next diagnostic step, followed by muscle biopsy if CPET results are abnormal. 1

Understanding Mitochondrial Myopathies

Mitochondrial myopathies are progressive muscle conditions caused by impairment of oxidative phosphorylation (OXPHOS) in the mitochondria, resulting in energy production deficits particularly affecting skeletal muscle. 2

• Mitochondrial myopathies present with prominent muscular symptoms such as muscle weakness but typically involve multiple organ systems 2
• These disorders can be caused by mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) 2, 3
• Adult-onset cases are more frequently related to mtDNA mutations, while pediatric-onset cases are more commonly associated with nDNA mutations 3
• The fluctuating nature of symptoms (days with symptoms alternating with symptom-free days) is characteristic of mitochondrial disorders due to varying energy demands and mitochondrial heteroplasmy 3, 4

Diagnostic Algorithm for Mitochondrial Myopathies

Step 1: Initial Assessment and Laboratory Testing

• Normal CK levels do not rule out mitochondrial myopathy, as many patients have normal or only mildly elevated CK 4, 5
• Initial bloodwork should include lactate and pyruvate levels, as these may be elevated during symptomatic periods 6
• Consider testing during both symptomatic and asymptomatic periods, as laboratory abnormalities may be intermittent 3, 6

Step 2: Cardiopulmonary Exercise Testing (CPET)

• CPET is a crucial diagnostic tool for patients with suspected mitochondrial myopathy and normal bloodwork 1
• Key CPET parameters to evaluate include:
  • Percent-predicted peak VO₂ (oxygen consumption) - values below 75% suggest mitochondrial dysfunction 1
  • Peak VE/VO₂ (minute ventilation/oxygen consumption) - values ≥50 are indicative of mitochondrial myopathy 1
  • DQ/DVO₂ (change in cardiac output/change in oxygen consumption) - values ≥7 suggest mitochondrial myopathy 1

Step 3: Muscle Biopsy

• If CPET results are abnormal (particularly DQ/DVO₂ and peak VE/VO₂ in the abnormal range), muscle biopsy should be performed for definitive diagnosis 1
• Muscle biopsy analysis should include:
  • Histochemical staining for ragged red fibers and cytochrome c oxidase-negative fibers 4
  • Biochemical assessment of respiratory chain enzyme activities 4
  • Ultrastructural examination for abnormal mitochondria 6

Step 4: Genetic Testing

• Next-generation sequencing approaches are now the gold standard for molecular diagnosis 3, 4
• Options include:
  • Targeted gene panels for mitochondrial disorders 3
  • Whole exome or genome sequencing 3
  • Mitochondrial DNA sequencing to detect heteroplasmy 3, 4

Management Approach

• Management requires a multidisciplinary approach focusing on symptom management and supportive care 2, 3
• Exercise training is both diagnostic and therapeutic - a structured exercise program can improve mitochondrial function and reduce symptoms 6
• Consider supplementation with:
  • Coenzyme Q10 and riboflavin (electron donors and acceptors) 6
  • Creatine monohydrate (alternative energy source) 6
  • Antioxidants such as vitamin E and alpha-lipoic acid 6
• Avoid substances that inhibit the respiratory chain, including certain antibiotics, statins, and alcohol 3
• Regular surveillance for multisystem complications is essential 3

Important Caveats and Pitfalls

• Normal bloodwork, including normal CK levels, does not exclude mitochondrial myopathy, especially in patients with intermittent symptoms 4, 5
• Symptoms may fluctuate based on energy demands, making diagnosis challenging if testing is performed during asymptomatic periods 3, 6
• The multisystemic nature of mitochondrial disorders means that other organ systems may be involved even if muscle symptoms predominate 2, 3
• Genetic testing results may be complex to interpret due to heteroplasmy and the large number of potential causative genes 3, 4