What is the diagnostic approach and treatment for a patient suspected of having mitochondrial dysfunction?

Diagnostic Approach to Mitochondrial Dysfunction

For patients with suspected mitochondrial dysfunction, proceed with initial laboratory screening followed by cardiopulmonary exercise testing (CPET), and if abnormal, obtain muscle biopsy for definitive diagnosis. 1

Initial Laboratory Screening

Begin with targeted blood tests to identify metabolic signatures and exclude secondary causes:

• Plasma lactate (may be elevated but normal levels do not exclude mitochondrial disease) 2, 3
• Creatine phosphokinase (elevated in metabolic disorders including mitochondrial disease) 2
• Plasma and urine thymidine and deoxyuridine with white blood cell thymidine phosphorylase activity 2
• Fasting glucose (may be elevated in some mitochondrial DNA disorders or low in fatty acid/carnitine disorders) 2
• Renal function including GFR (impaired GFR and proteinuria suggest mitochondrial DNA disorders) 2
• Liver transaminases (abnormal in mitochondrial disorders, Danon disease, and β-oxidation defects) 2

Additional screening should include complete blood count, thyroid function (screen for hypothyroidism), and basic metabolic panel with electrolytes 2, 4

Cardiopulmonary Exercise Testing (CPET)

When initial bloodwork is negative or inconclusive, CPET is the crucial next diagnostic step before proceeding to invasive testing. 1

Key CPET Parameters to Evaluate:

• Percent-predicted peak VO₂: Values <75% predicted suggest mitochondrial dysfunction; <50% predicted indicates severe dysfunction 2, 1
• Peak VE/VO₂ ratio: Values ≥50 are highly indicative of mitochondrial myopathy (normal is ≤40) 2, 1
• ΔQ/ΔVO₂ ratio: Values ≥7 suggest mitochondrial myopathy (normal is approximately 5) 2, 1

Important caveat: CPET requires peak respiratory exchange ratio (RER) ≥1.00 for valid interpretation, or test termination due to abnormal hemodynamic/ECG response. 2

CPET Interpretation Algorithm:

When both peak VE/VO₂ ≥50 and ΔQ/ΔVO₂ ≥7 are present in the red zone, this strongly indicates mitochondrial myopathy and warrants muscle biopsy for definitive diagnosis. 2, 1

Genetic Testing Strategy

If high clinical suspicion exists despite negative biochemical testing:

• Targeted genetic testing for specific mitochondrial syndromes (e.g., TYMP gene, m.3243A>G mutation for MELAS) when clinical features suggest a particular syndrome 2
• Whole exome sequencing should be considered as first or second-tier testing when clinical presentation is complex or atypical 4, 5
• Mitochondrial genome sequencing may be indicated after initial screening 2

Muscle Biopsy Indications

Proceed to full-thickness muscle biopsy when: 2, 1

• CPET demonstrates abnormal parameters (peak VE/VO₂ ≥50 and/or ΔQ/ΔVO₂ ≥7)
• High clinical suspicion persists despite negative initial testing
• Genetic testing identifies variants of uncertain significance requiring biochemical phenotype confirmation 6

The muscle biopsy should include histopathology, respiratory chain enzyme activity measurements, and mitochondrial respiration analysis. 2, 6

Common Diagnostic Pitfalls

• Do not exclude mitochondrial disease based on normal plasma lactate alone - many confirmed cases have normal lactate levels, particularly in pediatric patients 5, 3
• Avoid using standard reference ranges without disease-specific context - this leads to misinterpretation of borderline results 4
• Do not rely on single biochemical tests - mitochondrial disorders require integration of clinical, biochemical, and genetic data 5, 7
• Ensure proper CPET technique - optimize uncoupler concentration and verify adequate effort (RER ≥1.00) for valid interpretation 2

Clinical Suspicion Triggers

Suspect mitochondrial dysfunction when patients present with multi-system involvement affecting high-energy organs:

• Neurological: encephalopathy, stroke-like episodes, seizures 2, 3
• Gastrointestinal: chronic intestinal pseudo-obstruction, severe dysmotility 2
• Cardiac: hypertrophic cardiomyopathy, conduction defects 2
• Muscular: exercise intolerance, myopathy, elevated CK 2, 3

The heterogeneity of presentation means any organ system may be affected, but brain, muscle, heart, and liver are most commonly involved due to high energetic demands. 3, 8