LETHAL INFANTILE MITOCHONDRIAL DISEASE WITH ISOLATED COMPLEX-I DEFICIENCY IN FIBROBLASTS BUT WITH COMBINED COMPLEX-I AND COMPLEX-IV DEFICIENCIES IN MUSCLE

A 2-month-old boy died of a lethal infantile mitochondrial disease wit h severe lactic acidosis and involvement of the CNS. Histochemical ana lysis of skeletal muscle showed that cytochrome c oxidase staining was lacking in all muscle fibers but was present in arterioles. Ragged re d fibers were not seen, but some fibers showed excessive staining for succinate dehydrogenase. Biochemical analysis revealed a combined comp lex I and IV deficiency in skeletal muscle but only a complex I defici ency in his fibroblasts. Two-dimensional native SDS electrophoresis co nfirmed these enzymatic findings at the protein level. Analysis of mit ochondrial translation products in fibroblasts revealed no abnormaliti es, and analysis of mitochondrial DNA in muscle showed no depletion, l arge-scale deletions, or frequently occurring point mutations. We conc lude that this disease must have been the result of either a nuclear D NA mutation in a gene controlling the expression or assembly of both c omplex I and the muscle-specific isoform of complex IV or, alternative ly, a heteroplasmic point mutation in a mitochondrial tRNA, which codo n is used more often by mtDNA encoded subunits of complex I than by mt DNA encoded subunits of complex IV. A different degree of heteroplasmy in skeletal muscle and fibroblasts would then explain the curious het erogeneous tissue expression of defects in this patient.