FAMILIAL CARDIOMYOPATHY WITH CATARACTS AND LACTIC-ACIDOSIS - A DEFECTIN COMPLEX-I (NADH-DEHYDROGENASE) OF THE MITOCHONDRIA RESPIRATORY-CHAIN

Four patients in one generation of a multiply consanguineous pedigree died with cardiomyopathy, cataracts, and lactic acidemia. Postmortem h eart and skeletal muscle tissues from one patient were analyzed. A low (12% control) activity of NADH-CoQ reductase (complex I) in heart and normal activity in skeletal muscle mitochondria was found. Cultured s kin fibroblasts obtained from two individuals in the pedigree showed e levated lactate to pyruvate ratios in the range of 2 to 3.5 times norm al and decreased complex I + III activity (42 and 54% of control activ ities) in isolated mitochondria. Western blot analysis and enzymatic a ssay showed normal levels of CuZn-superoxide dismutase, but grossly el evated levels of the mitochondrial Mn-superoxide dismutase. Southern b lot analysis in heart muscle cells from the patient tested revealed mu ltiple mitochondrial DNA deletions which indicate free oxygen radical damage. We hypothesize that a nuclear-encoded defect in the respirator y chain is responsible for excessive free oxygen radical production in these infants which contributes to the prenatal onset of cardiomyopat hy and cataracts.