Fatal neonatal liver failure and depletion of mitochondrial DNA in three children of one family.

Abstract

Mitochondria contain enzymes for important pathways in intermediary metabolism and are the main suppliers of cellular energy since they produce ATP as the result of oxidative phosphorylation. The oxidative phosphorylation system comprises approximately 100 polypeptides of which the majority function as subunits of five large enzyme complexes. Normally, each mitochondrion contains a number of copies of circular DNA molecules (mtDNA) which encode 13 different subunits of four of the enzyme complexes (complexes I, III, IV and V) that are involved in the oxidative phosphorylation process. Dysfunction of these enzyme complexes is a frequent observation in mitochondrial diseases and point mutations and deletions of mtDNA are regular findings in patients with mitochondrial encephalomyopathies (DiMauro and Moraes 1993). Depletion of mtDNA, characterized by very low levels of normal mtDNA in the affected tissues, can also be associated with mitochondrial encephalomyopathies (Moraes 1993). Severe infantile liver disorders with oxidative phosphorylation defects are relatively rare. However, in three cases these diseases were associated with depletion of mtDNA (Moraes et al 1991 ; Mazziotta et al 1992 ; Maaswinkel-Mooy et al 1995). In addition to these single cases, we identified a family in which three of the four children of healthy consanguineous parents died in the neonatal period because of progressive liver failure that was associated with severe depletion of mtDNA.