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.

Urinary Metabolites and Their Link with Premature Arterial Stiffness in Black Boys: The ASOS Study.

BACKGROUND AND AIMS: Black boys (6-8 years of age) were shown to have higher pulse wave velocity with potential early vascular compromise. We aimed to compare predefined urinary metabolites in black and white boys to explore associations of pulse wave velocity with these metabolites. METHODS AND RESULTS: We included 40 white and 40 black apparently healthy boys between the ages of 6 and 8 years. Femoral pulse wave velocity was measured along with various metabolites using liquid chromatography tandem mass spectrometry (LC-MS/MS) and gas chromatography-time of flight-mass spectrometry (GC-TOF-MS) methods. Pulse wave velocity and diastolic blood pressure were higher in the black compared to the white boys (both p ≤ 0.002). Isovalerylcarnitine was lower and 1-metylhistidine tended to be lower (p = 0.002 and p = 0.073, respectively), whereas L-proline levels tended to be higher (p = 0.079) in the black compared to the white boys. In single, partial, and multiple regression analyses, pulse wave velocity correlated inversely with ß-alanine (ß = -0.414; p = 0.008) and 1-methylhistidine (ß = -0.347; p = 0.032) and positively with L-proline (ß = 0.420; p = 0.008), threonic acid (ß = 0.977; p = 0.033), and malonic acid (ß = 0.348; p = 0.030) in black boys only. CONCLUSION: Our study is the first to discover the associations of pulse wave velocity with ß-alanine, 1-methylhistidine, and L-proline in children from South Africa, which may suggest potential early compromise in cardiac protective metabolic pathways in black boys as young as 6 years of age.

A urinary biosignature for mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes (MELAS).

We used a comprehensive metabolomics approach to study the altered urinary metabolome of two mitochondrial myopathy, encephalopathy lactic acidosis and stroke like episodes (MELAS) cohorts carrying the m.3243A>G mutation. The first cohort were used in an exploratory phase, identifying 36 metabolites that were significantly perturbed by the disease. During the second phase, the 36 selected metabolites were able to separate a validation cohort of MELAS patients completely from their respective control group, suggesting usefulness of these 36 markers as a diagnostic set. Many of the 36 perturbed metabolites could be linked to an altered redox state, fatty acid catabolism and one-carbon metabolism. However, our evidence indicates that, of all the metabolic perturbations caused by MELAS, stalled fatty acid oxidation prevailed as being particularly disturbed. The strength of our study was the utilization of five different analytical platforms to generate the robust metabolomics data reported here. We show that urine may be a useful source for disease-specific metabolomics data, linking, amongst others, altered one-carbon metabolism to MELAS. The results reported here are important in our understanding of MELAS and might lead to better treatment options for the disease.