When to suspect mitochondrial disease and how to investigate it

Mitochondrial diseases are caused by mutations in nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). They are characterized by heterogeneous clinical presentations due to the potential affection of each body organ, particularly those with high energy requirements. The most common clinical presentations of mitochondrial defects are mitochondrial myopathy, central nervous system manifestations including cerebral, cerebellar, brainstem and spinal cord atrophy, white matter disease, stroke‐like episodes and epilepsy, peripheral neuropathy, optic atrophy, pigmentary retinopathy, sensorineural deafness, cardiomyopathy, diabetes and kidney disorders. Sporadic cases are also possible, and this particularly applies to single mtDNA deletions and nuclear de‐novo mutations. Biochemical analysis of muscle biopsy is also essential to evaluate the presence of single/multiple respiratory chain complex defects. The most common mitochondrial disorder due to mtDNA mutations is Leber's Hereditary Optic Neuropathy, Mitochondrial Encephalopathy, Lactic Acidosis and Stroke‐like Episodes (MELAS). In contrast, among the nuclear genes, OPA1 gene mutations are the most common cause of Dominant Optic Atrophy.