In 1984, we described two patients with Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like Episodes.1 We proposed the acronym MELAS for this newly described distinctive clinical entity, and speculated about maternal non-Mendelian inheritance, and a mitochondrial DNA (mtDNA) mutation disturbing synthesis of proteins embedded in the respiratory chain. Six years later, Goto and colleagues identified a point mutation in mtDNA (m.3243A>G) of MELAS patients.2 This mutation now accounts for 80% of MELAS cases (commonly referred to as MELAS/3243). For two decades, our team has conducted a long-term longitudinal study of MELAS/3243 patients, establishing a strong foundation in terms of natural history, outcome measures, and biomarkers. However, since there are no clearly validated biomarkers for predicting the risk of conversion, prodromal and mildly symptomatic family relatives continue to live with the uncertainty of converting to the severe MELAS phenotype. This reality emphasizes the need to expand our nascent observations about the natural history of MELAS and the predictive value of brain biomarkers. Our strategies are based on (Specific Aim #1) the need to replicate, using 1H MRSI, our highly promising, preliminary observations of abnormal levels of lactate, NAA, tCr and tCho, in 100 mutation carriers and 30 group-matched healthy control subjects, first at baseline and then again at 2-year follow-up; (Specific Aim #2) the need to measure, using 31P MRSI in synchrony with 1H MRSI, brain levels of (a) phosphocreatine (PCr) to complement and corroborate tCr levels, measured by 1H MRSI, as a marker of cell energetics; b) ATP, to complement and corroborate the 1H MRSI measures of NAA and lactate as indices of mitochondrial dysfunction; c) phosphomonoesters (PME) and phosphodiesters (PDE), to complement and corroborate tCho levels, measured by 1H MRSI, as indices of membrane biosynthesis and turnover, and (d) inorganic phosphate (Pi) as an index of intracellular pH; and (Specific Aim #3) the need to measure temporally concordant levels of metabolite biomarkers in the plasma and urine samples collected from all 130 participants. These three Aims will strengthen our earlier findings of predictive neuroimaging biomarkers, inform us of brain mechanisms underlying metabolic and clinical disturbances, and provide complementary plasma and urine metabolites that, if correlated with the brain biomarkers, will serve as less expensive and more accessible biomarkers predicting risk of conversion to the severe MELAS phenotype.
| Wang, Dan; Li, Jia; Song, Chun-Qing et al. (2018) Cas9-mediated allelic exchange repairs compound heterozygous recessive mutations in mice. Nat Biotechnol 36:839-842 |
| Hirano, Michio; Emmanuele, Valentina; Quinzii, Catarina M (2018) Emerging therapies for mitochondrial diseases. Essays Biochem 62:467-481 |
| Raghavan, Neha S; Brickman, Adam M; Andrews, Howard et al. (2018) Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease. Ann Clin Transl Neurol 5:832-842 |
| Barca, Emanuele; Ganetzky, Rebecca D; Potluri, Prasanth et al. (2018) USMG5 Ashkenazi Jewish founder mutation impairs mitochondrial complex V dimerization and ATP synthesis. Hum Mol Genet 27:3305-3312 |
| Garone, Caterina; Taylor, Robert W; Nascimento, Andrés et al. (2018) Retrospective natural history of thymidine kinase 2 deficiency. J Med Genet 55:515-521 |
| Kleiner, Giulio; Barca, Emanuele; Ziosi, Marcello et al. (2018) CoQ10 supplementation rescues nephrotic syndrome through normalization of H2S oxidation pathway. Biochim Biophys Acta Mol Basis Dis 1864:3708-3722 |
| Siegmund, Stephanie E; Grassucci, Robert; Carter, Stephen D et al. (2018) Three-Dimensional Analysis of Mitochondrial Crista Ultrastructure in a Patient with Leigh Syndrome by In Situ Cryoelectron Tomography. iScience 6:83-91 |
| Winawer, Melodie R; Griffin, Nicole G; Samanamud, Jorge et al. (2018) Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy. Ann Neurol 83:1133-1146 |
| Pera, Marta; Larrea, Delfina; Guardia-Laguarta, Cristina et al. (2017) Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease. EMBO J 36:3356-3371 |
| Quinzii, Catarina M; Luna-Sanchez, Marta; Ziosi, Marcello et al. (2017) The Role of Sulfide Oxidation Impairment in the Pathogenesis of Primary CoQ Deficiency. Front Physiol 8:525 |
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