Mitochondrial mutation status, symptom prevalence, and neuroimaging characteristics in MELAS: a systematic review and...

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a rare mitochondrial disorder characterized by a wide range of systemic manifestations. MELAS is challenging to diagnose in its early stages and currently lacks targeted treatments. This systematic review and meta-analysis aim to validate the mitochondrial 3243A > G (m.3243A > G) mutation status, symptom prevalence, and neuroimaging characteristics in patients with MELAS. The review also seeks to consolidate and clarify the pathogenic pathways of MELAS while pinpointing potential therapeutic targets.

We searched four databases for relevant studies. Study selection, data extraction, and quality assessment using the JBI (Joanna Briggs Institute) scale were performed by two reviewers. We conducted meta-analyses to estimate the pooled proportions for genetic, symptomatic, and imaging features using the random-effects generalized linear mixed model. In addition, seven MELAS-related pathways were researched, and their gene information was expanded through computational retrieval from the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases. A total of 13 studies involving 988 subjects were included, covering one mutant gene (m.3243A > G), ten clinical symptoms, and four imaging features. The meta-analyses showed a pooled m.3243A > G mutation prevalence of 78% (95% CI: 68%, 86%). The most frequent clinical manifestations were stroke-like episodes (99%; 95% CI: 29%, 100%), seizures (89%; 95% CI: 65%, 97%), and elevated lactate (81%; 95% CI: 50%, 95%). The temporal lobe was the most commonly affected brain region on imaging (87%; 95% CI: 13%, 100%). Pathway analysis revealed mitophagy/autophagy, ROS generation, and energy metabolism as core mechanisms in MELAS, with MNRR1, L-arginine, PI3K-AKT-mTOR, and ETC as potential therapeutic targets.

This study collects evidence for the confirmatory diagnosis of MELAS, integrating its genetic, clinical, and neuroimaging spectra. Furthermore, by elucidating the core pathological network, our work provides a potential framework for developing multi-targeted therapeutic strategies.