Encephalopathies associated with mt-DNA point mutations have been recognized with increasing frequency as a cause of mental retardation and developmental disabilities. This proposal addresses some of the important clinical issues that confront the physician when evaluating and managing patients and family members with these maternally-inherited conditions. Probands and oligosymptomatic relatives will be admitted to the Irving Clinical Research Center for a comprehensive evaluation including neuropsychological assessment to define their cognitive and neurobehavioral profiles longitudinally, in collaboration with Dr. Sano. Parallel studies of cerebral energetics will be performed in the HATCH NMR Research Center using the 5.0 Tesla scanner in collaboration with Drs. Hilal and Shungu. A questionnaire will be developed as part of the neuropsychological inventory to evaluate the natural history of these clinical syndromes. This questionnaire also will be designed for telephone use to evaluate other patients who have come to our attention, in an effort to expand our understanding of the natural history and prognosis of these conditions. This information is vitally important as baseline information for future therapeutic efforts. A screening test will be developed using cultured human skin fibroblasts from these patients to evaluate the energy-dependent buffering of intracellular calcium following depolarization. Preliminary studies in collaboration with Dr. Rothman show impaired buffering in MELAS, and other mitochondrial diseases when the affected cell lines are loaded with the calcium-sensitive dye, fura-2. These findings will be correlated with the point mutation abundance in collaboration with Dr. DiMauro (Project 2). These studies will be extended to cultured muscle cells from the same patients in collaboration with Dr. Miranda (Project 6), and correlated with parallel observations being made by Dr. Schon (Project 4) using aggregation dyes to evaluate the mitochondrial membrane potential. These cells will be examined by 1H and 31P NMR spectroscopy in collaboration with Drs. Hilal and Shungu. These studies are intended to expand our understanding of the cognitive and neurobehavioral disturbances, and natural history of these clinical syndromes, and to correlate these clinical domains with in vivo and in vitro measures of cellular energy failure. A sensitive and specific screening test will provide important information regarding the frequency of these conditions in a pediatric setting.

Project Start
1997-12-01
Project End
1998-11-30
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
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
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
Cloonan, Suzanne M; Glass, Kimberly; Laucho-Contreras, Maria E et al. (2016) Mitochondrial iron chelation ameliorates cigarette smoke-induced bronchitis and emphysema in mice. Nat Med 22:163-74
Engelstad, Kristin; Sklerov, Miriam; Kriger, Joshua et al. (2016) Attitudes toward prevention of mtDNA-related diseases through oocyte mitochondrial replacement therapy. Hum Reprod 31:1058-65
Fryer, Robert H; Bain, Jennifer M; De Vivo, Darryl C (2016) Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-Like Episodes (MELAS): A Case Report and Critical Reappraisal of Treatment Options. Pediatr Neurol 56:59-61
Varma, Hemant; Faust, Phyllis L; Iglesias, Alejandro D et al. (2016) Whole exome sequencing identifies a homozygous POLG2 missense variant in an infant with fulminant hepatic failure and mitochondrial DNA depletion. Eur J Med Genet 59:540-5
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
Ripolone, Michela; Ronchi, Dario; Violano, Raffaella et al. (2015) Impaired Muscle Mitochondrial Biogenesis and Myogenesis in Spinal Muscular Atrophy. JAMA Neurol 72:666-75
Quinzii, Catarina M; Hirano, Michio; DiMauro, Salvatore (2014) Mutant COQ2 in multiple-system atrophy. N Engl J Med 371:81-2
Area-Gomez, Estela; Schon, Eric A (2014) Mitochondrial genetics and disease. J Child Neurol 29:1208-15

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