What are the clinical presentations, symptoms, and diagnostic findings of mitochondrial myopathy (mito myopathy)?

Clinical Presentations and Diagnostic Findings of Mitochondrial Myopathy

Mitochondrial myopathy presents primarily with progressive proximal muscle weakness, exercise intolerance, and fatigue, with potential multisystem involvement including cardiac conduction abnormalities, respiratory insufficiency, and central nervous system manifestations.

Clinical Presentations and Symptoms

Primary Muscle Manifestations

• Progressive muscle weakness

  • Predominantly proximal muscle groups
  • Symmetric distribution
  • Slow progression (decline in strength of approximately 0.01/year) 1
  • Median time to requiring gait assistance: 5.5 years from diagnosis, 17 years from symptom onset 1

• Exercise intolerance

  • Early fatigue with physical activity
  • Post-exertional malaise
  • Myalgia (muscle pain) during or after exertion

• Chronic progressive external ophthalmoplegia (CPEO)

  • Ptosis (drooping eyelids)
  • Limited eye movements
  • Present in approximately 12-24% of adult patients 1

Associated Systemic Manifestations

• Cardiac involvement (21% of adult patients) 1

  • Cardiomyopathy (dilated, hypertrophic, or restrictive) 2
  • Conduction defects and arrhythmias
  • Associated with increased mortality (HR 2.36) 1

• Respiratory manifestations

  • Respiratory muscle weakness
  • Acute respiratory failure (rare but life-threatening) 3
  • Dyspnea with exertion

• Neurological manifestations (69% have CNS involvement) 1

  • Stroke-like episodes (in MELAS syndrome)
  • Seizures
  • Ataxia
  • Cognitive impairment
  • Peripheral neuropathy (42%, more common with nuclear DNA variants) 1

• Other manifestations

  • Sensorineural hearing loss 2
  • Visual impairment (retinal disease, optic nerve atrophy) 2
  • Lactic acidosis (especially during acute exacerbations) 3

Diagnostic Findings

Laboratory Findings

• Elevated muscle enzymes

  • Creatine kinase (CK) - may be normal or mildly elevated
  • Lactate dehydrogenase (LDH)
  • Aspartate aminotransferase (AST) 2

• Metabolic abnormalities

  • Elevated serum lactate (at rest or post-exercise)
  • Elevated lactate/pyruvate ratio
  • Metabolic acidosis (especially during exacerbations)

Electrophysiologic Studies

• Electromyography (EMG)

  • Myopathic pattern (77% of patients) 1
  • Short duration, low amplitude, polyphasic motor unit potentials 2
  • Fibrillation potentials (27% of patients) 1
  • Increased insertional activity

• Nerve conduction studies

  • Axonal peripheral neuropathy in 42% of cases 1
  • More common with nuclear DNA variants

Muscle Biopsy Findings (Gold Standard)

• Histological abnormalities

  • "Ragged red fibers" on Gomori trichrome stain (0.5% median percentage) 1
  • "Ragged blue fibers" (1.4% median percentage) 1
  • Cytochrome C oxidase (COX) negative fibers (5.1% median percentage) 1
  • Subsarcolemmal accumulation of abnormal mitochondria 2
  • Interfibrillar accumulation of mitochondria 2

• Electron microscopy

  • Abnormal size, shape, and structure of mitochondria
  • Paracrystalline inclusions
  • Abnormal cristae

Genetic Testing

• Mitochondrial DNA (mtDNA) mutations

  • Single large deletions
  • Point mutations (MT-TL1 most common) 1
  • Maternal inheritance pattern

• Nuclear DNA mutations

  • POLG gene mutations (common in adults) 1
  • Mendelian inheritance patterns

Functional Testing

• Cardiopulmonary exercise testing (CPET)
  • Elevated VE/VO₂ ratio at peak exercise 2
  • Abnormal ΔQ/ΔVO₂ slope (higher than normal 5 L/min) 2
  • Reduced peak VO₂ 2

Clinical Phenotypes and Syndromes

• Isolated limb myopathy (27% of adult patients) 1
• Chronic progressive external ophthalmoplegia (CPEO)
• CPEO-plus (CPEO with additional systemic manifestations)
• MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, Stroke-like episodes)
• MERRF (Myoclonic Epilepsy with Ragged Red Fibers)
• Multisystem disorders

Prognosis

• Median survival of 33.4 years from symptom onset and 10.9 years from diagnosis 1
• Median age at death: 55 years 1
• Cardiac involvement significantly increases mortality risk 1

Diagnostic Challenges

• Significant diagnostic delay (median 11 years from symptom onset to diagnosis) 1
• Heterogeneous clinical presentations
• Overlap with other neuromuscular disorders
• Need for specialized testing (muscle biopsy, genetic analysis)

Mitochondrial myopathy should be suspected in patients with progressive proximal muscle weakness, exercise intolerance, and multisystem involvement, particularly when there is a maternal inheritance pattern or characteristic findings on muscle biopsy.