Depletion of mitochondrial DNA associated with infantile cholestasis and progressive liver fibrosis

Few cases of infantile liver disease associated with mitochondrial DNA (mtD NA) depletion have been reported. Most of the patients died before 1 year o f age of severe liver failure. We describe a new case, a 28-month-old child , presenting with cholestasis at age 2 months, complicated by progressive p ortal and lobular liver fibrosis, Growth and psychomotor development are un disturbed. There is no clinical evidence of either myopathy or neurological involvement. Metabolic investigation in plasma revealed an abnormal oxide- reduction status after fasting and after carbohydrate-rich meals. Light mic roscopy performed on liver biopsies revealed steatosis, abnormal hepatocyte s with an "oncocytic" appearance and extensive fibrosis, Electron microscop ic investigation showed an increased number of mitochondria with rare or en larged cristae, Biochemical studies of liver biopsies showed that the respi ratory chain activities containing mtDNA-encoded subunits were severely dec reased (complexes I, III and IV). In contrast, the complex II activity was normal and the citrate synthase activity was greatly increased, Southern bl otting analysis revealed that the ratio of mtDNA to nuclear DNA in liver wa s only 15% and 20% of the mean control value at ages 12 and 21 months, resp ectively. For this mtDNA depletion syndrome which is clinically expressed i n the liver, a liver transplantation is discussed.