What are mitochondrial myopathies?

Mitochondrial Myopathies: Definition, Diagnosis, and Clinical Implications

Mitochondrial myopathies are a group of genetic disorders characterized by defects in oxidative phosphorylation that primarily affect skeletal muscle, resulting in impaired energy production and causing symptoms such as exercise intolerance, muscle weakness, and fatigue. 1

Pathophysiology

Mitochondrial myopathies result from genetic mutations that directly affect the electron transport chain (ETC) function, leading to:

• Impaired oxygen utilization for oxidative phosphorylation
• Early accumulation of lactic acid during exercise
• Exaggerated circulatory and ventilatory responses to exercise
• Reduced aerobic capacity and exercise tolerance 2

These disorders can be caused by mutations in either:

• Mitochondrial DNA (mtDNA)
• Nuclear DNA genes that affect mitochondrial function 1, 3

Clinical Presentation

The clinical manifestations of mitochondrial myopathies include:

• Muscle-specific symptoms:

  • Exercise intolerance and early fatigue
  • Muscle weakness (often affecting extraocular muscles)
  • Ptosis (droopy eyelids)
  • Progressive external ophthalmoplegia
  • Muscle cramps
  • Recurrent myoglobinuria 4

• Systemic manifestations (in multisystem disorders):

  • Cardiac involvement (cardiomyopathy)
  • Neurological symptoms
  • Respiratory muscle weakness 2

Diagnostic Approach

Diagnosis of mitochondrial myopathies requires a comprehensive approach:

1. Initial laboratory testing:

   • Muscle enzymes (CPK, LDH, AST, ALT, aldolase)
   • Lactate and pyruvate levels (typically elevated) 5

2. Specialized testing:

   • Cardiopulmonary exercise testing (CPET): Shows characteristic patterns:

     • Low peak VO₂
     • Abnormally elevated VE/VO₂ ratio
     • Significantly increased Q/VO₂ slope (15 L/min vs. 5 L/min in healthy controls)
     • Early lactic acid accumulation 2

   • Muscle biopsy: Gold standard for confirmation

     • Ragged red fibers
     • Mitochondrial proliferation
     • Paracrystalline inclusions 6

   • Genetic testing:

     • Whole mitochondrial genome sequencing
     • Nuclear DNA testing for mitochondrial-related genes 5, 3

Distinctive Exercise Physiology

Mitochondrial myopathies have a unique exercise physiology profile that helps distinguish them from other conditions:

• Q/VO₂ relationship: In normal individuals, the Q/VO₂ slope is approximately 5 L/min, but in mitochondrial myopathies, this slope is significantly higher (approximately 15 L/min) 2

• Ventilatory response: Elevated VE/VO₂ ratio at peak exercise due to aerobic inefficiency 2

• Early fatigue: Patients experience early fatigue due to inability to adequately utilize oxygen for oxidative phosphorylation 2

Differential Diagnosis

Mitochondrial myopathies must be differentiated from:

• Cardiovascular disorders
• Deconditioning
• Other neuromuscular diseases
• Myofibrillar myopathies 2

CPET can help distinguish mitochondrial myopathies from cardiovascular disorders by demonstrating high rather than low values of cardiac output relative to VO₂ 2.

Management Considerations

Treatment approaches include:

• Antioxidants (vitamin E, alpha-lipoic acid)
• Electron donors and acceptors (coenzyme Q10, riboflavin)
• Alternative energy sources (creatine monohydrate)
• Lactate reduction strategies (dichloroacetate)
• Exercise training programs 7

Prognosis

The prognosis varies widely depending on:

• Specific genetic mutation
• Age of onset
• Extent of multisystem involvement
• Degree of mitochondrial mutation load 2

Early diagnosis is crucial for timely intervention, genetic counseling, and access to emerging treatments that may modify disease progression 3.