Over the past decades, mitochondrial disease classification has been mainly based on molecular defects. We aim to analyze phenotype-genotype correlation of mitochondrial disorders according to molecular classification.

In this cohort study, we identified 135 individuals diagnosed with mitochondrial disorders, and all patients were divided into four subgroups based on molecular functions: the Respiratory Chain group (including subunits and assembly proteins in the respiratory chain), the Protein Synthesis group (including mitochondrial RNA metabolism, mitochondrial translation), the mitcohindrial DNA (mtDNA) Replication group, and the Others group (including cofactors, homeostasis, substrates, and inhibitors).

We found that in China, patients with the mtDNA variant constituted a large percentage of mitochondrial disease and were associated with a male preponderance in the Respiratory Chain group, whereas those in the Protein Synthesis group showed a relatively later onset and higher serum lactate level. In contrast, patients with nuclear DNA variants were younger at onset, with no specific lactate or cranial imaging features, especially in the Others group, which contained several mitochondrial diseases with corresponding treatment.

The mtDNA was recommended to detect first in patients with typical lactate and cranial imaging features. A broader consideration and detection are necessary for a better prognosis in an atypical patient.