Diagnosis of Primary Mitochondrial Diseases

Primary mitochondrial diseases are clinically heterogeneous and present diagnostic challenges due to the highly variable genotype-phenotype correlation. Clinical symptoms can range from non-specific fatigue, exercise intolerance, and weakness to syndromic phenotypes. Though multiple testing modalities exist to identify mitochondrial diseases, most of these tests are nonspecific, or results are associated with other diseases. Molecular testing can provide an efficient path toward diagnosis, as molecular detection techniques have improved and become less costly. A "genetics first" approach can reduce diagnostic delay and improve management, where the diagnostic pathway can be an invasive or noninvasive combination of targeted or comprehensive molecular testing. Prior to ordering these tests, clinicians must consider the ambiguities and nuances of various testing modalities during the work-up for mitochondrial diseases. Therefore, due to the diagnostic challenges associated with primary mitochondrial diseases, diagnosis should be made in the context of clinical and molecular data, potentially supplemented with histochemical and biochemical evidence. Confirmation of a diagnosis leads to improvements in the management of the disease, decreases unnecessary testing, informs reproductive planning, and improves research pipelines.