Mitochondrial cytopathy is characterized by ragged-red muscle fibers (RRF), abnormal mitochondria, and lactic acidosis. This class of diseases is frequently associated with central nervous system, cardiac, kidney, and/or liver dysfunction. Onset occurs in the neonate, infant, child or adult. Heterogeneity of expression occurs within the same pedigree. Oxidative phosphorylation (OXPHOS) proteins are encoded by both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) with resulting Mendalian and maternal modes of inheritance. The grant afford application of the clinical, biochemical, somatic cell genetic, and molecular genetic approaches required to identify the defects responsible for mitochondrial disorders and to subsequently influence their treatment. EBV-transformed lymphocytes from the patient are established and the OXPHOS defect is identified in muscle mitochondria by enzymatic analysis. Cultured lymphocytes and lymphoblasts are screened for altered mitochondrial translation products and for expression of the biochemical defect. Nuclear and cytoplasmic mutations are distinguished by substituting the patient's lymphoblasts mtDNAs with those of a cell with normal OXPHOS (cybrid fusion). The implicated mtDNA genes of cytoplasmic mutants are amplified using the polymerase chain reaction (PCR) and sequenced using the double-stranded dideoxy procedure. Mutant and wild- type oligonucleotide probes are prepared to confirm the mutation and for use in diagnosis. Development of this approach insures long term career growth in the investigation of basic mechanisms of neurologic disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
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Neurological Disorders Program Project Review B Committee (NSPB)
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Emory University
Schools of Medicine
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