Liver Pathology in Infantile Mitochondrial DNA Depletion Syndrome
Abstract Mitochondrial DNA (mtDNA) depletion syndrome is a rare cause of hepatic dysfunction in the pediatric population. It is caused by mutations in either mitochondrial or nuclear DNA (nDNA) that result in a quantitative reduction in mtDNA and, in turn, dysfunctional oxidative phosphorylation. In infants, it results in the hepatocerebral phenotype characterized by hyperbilirubinemia, coagulopathy, lactic acidosis, hypoglycemia, lethargy, encephalopathy, developmental delay, and hypotonia. Three infants diagnosed with mtDNA depletion syndrome at The Children's Hospital of Philadelphia were identified and their clinical presentation, disease course, and histologic and ultrastructural features of liver samples (premortem and postmortem) were characterized. While a different mutant gene was identified in each child, they all showed clinical evidence of metabolic dysfunction soon after birth and expired by 1 year of age. Steatosis, cholestasis, and cytoplasmic crowding by atypical mitochondria were consistent pathologic liver findings. Other findings included hepatocyte hypereosinophilia, fibrosis, and hemosiderosis. The infantile form of mtDNA depletion syndrome is exceedingly rare with few published case reports. This study presents a series of 3 patients with mtDNA depletion syndrome diagnosed at a single institution. Although the number of affected patients is small, it represents one of the largest reported series and is the first to establish the important clinical and pathologic features of mtDNA depletion syndrome in infants and young children. Recognizing these characteristics will facilitate early recognition and appropriate treatment of this rare disorder. Key Words: DNA depletion, liver, metabolic dysfunction, mitochondria, pediatric.