One mutation, three phenotypes: novel metabolic insights on MELAS, MIDD and myopathy caused by the m.3243A > G mutation.

Introduction: The m.3243A > G mitochondrial DNA mutation is one of the most common mitochondrial disease-causing mutations, with a carrier rate as high as 1:400. This point mutation affects the MT-TL1 gene, ultimately affecting the oxidative phosphorylation system and the cell's energy production. Strikingly, the m.3243A > G mutation is associated with different phenotypes, including mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), maternally inherited diabetes and deafness (MIDD) and myopathy.

Objectives: We investigated urine metabolomes of MELAS, MIDD and myopathy patients in order to identify affected metabolic pathways and possible treatment options.

Methods: A multiplatform metabolomics approach was used to comprehensively analyze the metabolome and compare metabolic profiles of different phenotypes caused by the m.3243A > G mutation. Our analytical array consisted of NMR spectroscopy, LC-MS/MS and GC-TOF-MS.

Results: The investigation revealed phenotypic specific metabolic perturbations, as well as metabolic similarities between the different phenotypes. We show that glucose metabolism is highly disturbed in the MIDD phenotype, but not in MELAS or myopathy, remodeled fatty acid oxidation is characteristic of the MELAS patients, while one-carbon metabolism is strongly modified in both MELAS and MIDD, but not in the myopathy group. Lastly we identified increased creatine in the urine of the myopathy patients, but not in MELAS or MIDD.

Conclusion: We conclude by giving novel insight on the phenotypes of the m.3243A > G mutation from a metabolomics point of view. Directives are also given for future investigations that could lead to better treatment options for patients suffering from this debilitating disease.