Depletion of mitochondrial DNA in the liver of a patient with lactic acidemia and hypoketotic hypoglycemia.

An infant with feeding difficulties, hypotonia, lactic acidemia, and severe hypoketotic hypoglycemia died at the age of 7 months of liver disease. Electron microscopy revealed abnormal mitochondria. Biochemical studies of mitochondrial enzymes in liver showed a decreased activity of complexes I, III, and IV. Mitochondrial DNA (mtDNA) content was reduced in liver 7% of the mean value in control subjects) and in muscle (50%). In kidney, brain, and heart, the mtDNA content was normal. The liver-specific mtDNA depletion syndrome in this patient manifested itself with features of both a respiratory chain defect and a mitochondrial fatty acid oxidation defect. Syndromes involving depletion of mtDNA can be diagnosed only when the activity of the respiratory chain enzymes and the content of mtDNA are investigated in the most affected tissues.

Depletion of mitochondrial deoxyribonucleic acid in a family with fatal neonatal liver disease.

We describe a family in which three children of consanguineous parents died of hepatic failure before the age of 3 months. The first child had clinical symptoms of liver disease with hypoglycemia that were evident at birth. The second child was healthy and has normal development. The third child had severe liver dysfunction noted a few days after birth. Liver failure also developed in the fourth child soon after birth. Recently a mitochondrial disorder was considered as a possible cause. Deficiency of respiratory chain enzymes that contain polypeptides encoded by mitochondrial DNA (mtDNA) and depletion of mtDNA were found in the liver of the fourth child, but mitochondrial abnormalities were absent in muscle of the third child. The similarities in clinical presentation suggest that liver-specific depletion of mtDNA was the cause of the hepatic failure in all three children. We conclude that liver dysfunction with onset in the perinatal period can be caused by depletion of mtDNA.