Biochemical and molecular basis for mitochondrial cardiomyopathy in neonates and children

Defects in myocardial bioenergetics have been reported in patients with car diomyopathy but their molecular basis and role in pathophysiology remain un clear. We sought to establish a molecular basis for cardiac mitochondrial r espiratory enzyme abnormalities frequently present (75%) in a group of 16 c hildren (including 2 neonates) with end-stage cardiomyopathy. Decreased spe cific activity levels were found in complexes I, III, IV and V but not in I I, the only complex that is entirely nuclear encoded. Sequence analysis of cardiac mtDNA revealed 4 patients harbouring heteroplasmic mtDNA mutations in cytb, tRNA(Arg), and ND5 at highly conserved positions. These mutations were present neither in controls nor in patients without enzymatic defect. In addition, 4 patients exhibited marked reduction in cardiac mtDNA levels. The basis for respiratory enzyme abnormalities can be explained in a subse t of our patients as a result of either pathogenic mtDNA mutation or deplet ion. Patients harbouring both DNA and enzymatic defects fulfil rigorous cri teria defining mitochondrial cardiomyopathy.