Diagnosing mitochondrial disease requires a multidisciplinary, stepwise approach. The process blends clinical suspicion with targeted biochemical, imaging, tissue, and genetic methods.
Comprehensive history (developmental, neurological, cardiac, endocrine)
Physical exam focusing on neuromuscular signs (ptosis, weakness), sensory deficits (hearing, vision), and cardiac rhythm abnormalities
Identify red flags: exercise intolerance, multi-system involvement, regression, stress-triggered episodes
Lactate and pyruvate (resting and post-exercise)
Ketone bodies
Carnitine (free and total)
Amino acids, acylcarnitines
CSF studies (in suspected CNS involvement) These tests can point to mitochondrial dysfunction but are not definitive on their own.
Brain MRI: May reveal stroke-like lesions that do not follow vascular territories (suggestive of MELAS), basal ganglia changes, or white matter abnormalities.
Cardiac imaging: Echocardiography or MRI for cardiomyopathy.
Ophthalmologic imaging: Retinal and optic nerve assessments.
Muscle biopsy may show ragged-red fibers (accumulated abnormal mitochondria) with special stains.
Biochemical assays can measure respiratory chain complex activities. Biopsy is less commonly first-line today due to advances in genetic testing but remains valuable in certain cases.
Targeted mtDNA mutation testing for common variants
Next-Generation Sequencing (NGS) panels covering nuclear genes involved in mitochondrial function
Whole exome or whole genome sequencing when panel testing is inconclusive
mtDNA sequencing/deletion analysis Results guide prognosis, family counseling, and sometimes treatment choices.
Consider and rule out:
Inflammatory or autoimmune disorders
Metabolic conditions (e.g., fatty acid oxidation defects)
Neuromuscular diseases (e.g., myopathies, channelopathies)
Vascular stroke vs. stroke-like episodes
A structured diagnostic approach that integrates clinical acumen with modern genetics is crucial for recognizing mitochondrial disease and avoiding misdiagnosis.