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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
1P01HD080642-01
Application #
8741705
Study Section
Developmental Biology Subcommittee (CHHD)
Project Start
2014-09-30
Project End
2019-05-31
Budget Start
2014-09-30
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10032
Sondheimer, Neal; Hewson, Stacy; Cameron, Jessie M et al. (2017) Novel recessive mutations in COQ4 cause severe infantile cardiomyopathy and encephalopathy associated with CoQ10 deficiency. Mol Genet Metab Rep 12:23-27
Lopez-Gomez, Carlos; Levy, Rebecca J; Sanchez-Quintero, Maria J et al. (2017) Deoxycytidine and Deoxythymidine Treatment for Thymidine Kinase 2 Deficiency. Ann Neurol 81:641-652
Luna-Sánchez, Marta; Hidalgo-Gutiérrez, Agustín; Hildebrandt, Tatjana M et al. (2017) CoQ deficiency causes disruption of mitochondrial sulfide oxidation, a new pathomechanism associated with this syndrome. EMBO Mol Med 9:78-95
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
Ziosi, Marcello; Di Meo, Ivano; Kleiner, Giulio et al. (2017) Coenzyme Q deficiency causes impairment of the sulfide oxidation pathway. EMBO Mol Med 9:96-111
Barca, Emanuele; Tang, Maoxue; Kleiner, Giulio et al. (2016) CoQ10 Deficiency Is Not a Common Finding in GLUT1 Deficiency Syndrome. JIMD Rep 29:47-52
Perales-Clemente, Ester; Cook, Alexandra N; Evans, Jared M et al. (2016) Natural underlying mtDNA heteroplasmy as a potential source of intra-person hiPSC variability. EMBO J 35:1979-90
Joseph, Leroy C; Barca, Emanuele; Subramanyam, Prakash et al. (2016) Inhibition of NAPDH Oxidase 2 (NOX2) Prevents Oxidative Stress and Mitochondrial Abnormalities Caused by Saturated Fat in Cardiomyocytes. PLoS One 11:e0145750
Piekutowska-Abramczuk, Dorota; Kocy?a-Karczmarewicz, Beata; Ma?kowska, Maja et al. (2016) No Evidence for Association of SCO2 Heterozygosity with High-Grade Myopia or Other Diseases with Possible Mitochondrial Dysfunction. JIMD Rep 27:63-8

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