Advantages and limitations of diagnostic tests used to evaluate individuals suspected of having a mitochondrial disorder
The diagnosis of mitochondrial disease requires a detailed knowledge of the strengths and weaknesses of different diagnostic techniques.
No single test or combination of tests can be used to confirm or exclude the diagnosis of mitochondrial disease in every patient.
For instance, neuroimaging, and blood or CSF lactate may be useful in supporting a clinical suspicion of mitochondrial disease.
However, lactic acidosis should not be considered either a prerequisite for diagnosis or a reliably sensitive and specific marker of mitochondrial dysfunction. Similarly, elevations of serum alanine, tricarboxylic acid cycle intermediates, or plasma acylcarnitine suggest the presence of mitochondrial dysfunction, but normal results do not exclude the diagnosis.
In the muscle biopsy, mitochondrial proliferation in the form of ragged red fibers is suggestive of a mitochondrial respiratory chain defect.
However, ragged red fibers may not be seen in early childhood and may be absent in patients with proven mitochondrial disease such as neurogenic muscle weakness, ataxia, and retinitis pigmentosa.
Ragged red fibers or cytochrome C oxidase deficiency may also be found in nonrespiratory chain defects and in normal individuals over 60 years of age.
Respiratory chain enzymatic activity is an important aid in diagnosis, but partial deficiencies, secondary or compensatory effects, and nonstandardized methods of analysis may lead to results that are difficult to interpret. DNA-based testing is a powerful tool.
Absence of mutations in certain tissues, presence of low-level heteroplasmy—the presence of more than one type of mitochondrial DNA within a cell or tissue—and sequence VUSs need to be considered in interpreting the results and remain important challenges.