What tests are indicated to investigate potential mitochondrial issues?

Diagnostic Tests for Mitochondrial Issues

A comprehensive mitochondrial evaluation should include oxygen consumption rate (OCR) measurement, mitochondrial membrane potential assessment, and biochemical testing for lactate/pyruvate ratio as the primary diagnostic approach for suspected mitochondrial disorders.

First-Line Diagnostic Tests

Biochemical Testing

• Blood lactate and pyruvate levels
  • Elevated venous peak lactate (>19.2 mg/dL or 2.13 mM) is seen in 50% of mitochondrial disease patients 1
  • Lactate-to-pyruvate ratio >20 is highly specific for mitochondrial disease 1
  • More than 2-fold increase in venous lactate from baseline during exercise testing is seen in 66.7% of mitochondrial disease patients 1

Functional Mitochondrial Assessment

• Oxygen consumption rate (OCR) measurement

  • Gold standard for determining underlying mitochondrial dysfunction 2
  • Sequential addition of mitochondrial inhibitors allows assessment of:
    • Basal respiration
    • Maximal respiration
    • Proton leak
    • ATP turnover 2

• Mitochondrial membrane potential (Δψm) assessment

  • Using membrane-permeant fluorescent probes (e.g., TMRM)
  • Provides complementary information to OCR experiments 2
  • Changes in Δψm can indicate disrupted respiration, ATP synthesis, or ionic fluxes 2

Second-Line Diagnostic Tests

Molecular and Genetic Testing

• Mitochondrial DNA (mtDNA) analysis

  • Mutations in mtDNA can cause primary mitochondrial disease 3
  • Next-generation sequencing is crucial for diagnosis 3

• Nuclear DNA testing

  • Over 250 genes have been identified to cause mitochondrial disease 3
  • Panel testing or whole exome sequencing may be indicated

Tissue-Specific Testing

• Muscle biopsy (if clinically indicated)
  • Histochemical staining (COX and SDH)
  • Respiratory complex activity measurement 2
  • Electron microscopy for mitochondrial morphology 4

Special Considerations

Exercise Testing

• Aerobic exercise test (15W for 15 minutes protocol)
  • Measures lactate production during controlled exercise
  • More sensitive than resting lactate levels 1
  • Particularly useful when symptoms are exercise-related

Metabolic Profiling

• Plasma amino acid profile

  • Elevated branched-chain amino acids (BCAAs)
  • Increased ratios of BCAAs to glutamate are common in mitochondrial disease 5

• Blood triglyceride levels

  • Significantly elevated in primary mitochondrial disease 5

Clinical Correlation

• Neuroimaging should be considered in patients with:

  • Neuroregression
  • Major neurological abnormalities
  • Microcephaly 2
  • Consider magnetic resonance spectroscopy with standard neuroimaging when metabolic etiology is suspected 2

• Metabolic screening should be considered with:

  • True developmental regression (neurodegeneration)
  • Worsening neurological symptoms
  • Lethargy
  • Poor physical endurance
  • Seizures
  • Physiologic abnormalities such as acidosis 2

Pitfalls and Caveats

• Mitochondrial disease presents with vast clinical heterogeneity, affecting single or multiple organ systems 3
• Elevated lactate alone is not specific - occurs in 33.3% of patients with non-mitochondrial diseases 1
• Metabolic abnormalities may be intermittent - consider repeat testing during periods of illness or stress
• Lack of abnormal findings does not rule out mitochondrial disease - sensitivity of individual tests is limited
• Interpretation requires correlation with clinical features - isolated laboratory abnormalities may not be diagnostic

The diagnostic approach should be tailored based on clinical presentation, with OCR measurement, mitochondrial membrane potential assessment, and lactate/pyruvate ratio forming the cornerstone of evaluation for suspected mitochondrial dysfunction.