Inter- and/or intra-organ distribution of mitochondrial C3303T or A3243G mutation in mitochondrial cytopathy

Fatal infantile mitochondrial cytopathy associated with a C3303T mutation i n the mitochondrial tRNA(Leu(UUR)) gene has been reported clinically, bioch emically and genetically. Here we have analyzed the percentage of this muta tion in various autopsied tissues, and also in single muscle fibers using a micromanupulator, to evaluate the correlation between the pathology and he teroplasmic condition using polymerase chain reaction/restriction fragment length polymorphism. A 5-month-old Japanese girl was admitted to our hospit al showing generalized muscle weakness, hepatomegaly, and cardiomegaly with lactic acidosis, and died at 6 months of age. Skeletal muscle showed sever e degenerating myopathy found to be full of ragged-red fibers (RRFs), an in creased number of lipid droplets, and severe cytochrome c oxidase (COX) def iciency. Microscopically hepatocytes showed massive accumulation in lipid d roplets, and the heart muscle showed a network pattern suggesting metabolic cardiomyopathy. The activities of respiratory chain enzyme complex I and c omplex IV in the skeletal muscle were significantly decreased to 23.4% and 5.0%, respectively, of the control value. The percentage of C3303T mutation in the patient tissues were variable, and ranged from 25% in the pancreas to 99% in the spinal cord. By single fiber analy sis, the percentages of C3 303T mutation in RRFs with COX negative (group 1; 42.4+/-7.0) and with COX positive (group 2; 58.2+/-5.8) were significantly higher than in non RRFs w ith normal COX staining (group 3; 10.7+/-6.3) (both P>0.001). Our patient s howed a fatal infantile form of encephalopathy, myopathy and cardiomyopathy associated with widely distributed C3303T mutation in all of somatic cells .