PYRUVATE-DEHYDROGENASE COMPLEX DEFICIENCY AND ALTERED RESPIRATORY-CHAIN FUNCTION IN A PATIENT WITH KEARNS-SAYRE MELAS OVERLAP SYNDROME AND A3243G MTDNA MUTATION/

Combined alteration of the pyruvate dehydrogenase complex and respirat ory chain function is described in a 21 year-old male patient with ove rlapping MELAS (mitochondrial encephalomyopathy, lactic acidosis, and 'stroke-like' episodes) and Keams-Sayre syndrome. Progressive external ophthalmoplegia, pigmentary retinopathy and right bundle branch block were present when he experienced the first 'stroke-like' episode at 1 8 years old. The A>G tRNA(Leu(UUR)) point mutation at nucleotide 3243 of the mitochondrial DNA was predominant in muscle tissue (79%) and pr esent, but at lower levels in fibroblasts (49%) and blood cells (37%). Biochemical analysis revealed diminished activities of pyruvate dehyd rogenase (23%) and respiratory chain complexes I and IV (57%, respecti vely) in muscle, but normal activities in the fibroblasts. Immunochemi cal studies of the muscular pyruvate dehydrogenase components showed n ormal content of E1 alpha, E1 beta and E2 protein. Molecular screening of the E1 alpha gene did not indicate a nuclear mutation. These obser vations suggest that mitochondrial DNA defects may be associated with altered nuclear encoded enzymes which are actively imported into mitoc hondria and constitute components of the mitochondrial matrix. Biochem ical workup of mitochondrial disorders should not be restricted to the respiratory chain even if mitochondrial DNA mutations are present. (C ) 1998 Elsevier Science B.V.