Severe complex I deficiency in a case of neonatal‐onset lactic acidosis and fatal liver failure

Abstract

We report a newborn admitted to our service on the 2nd day of life because of hypotonia and metabolic acidosis. A progressive hepatocellular dysfunction dominated the clinical picture and the patient died at 13 months of age because of severe hepatic failure. Persistent lactic acidosis, high ketone bodies levels and high-normal lactate/pyruvate and 3-hydroxybutyrate/acetoacetate molar ratios in plasma were found. Investigation of a liver biopsy revealed low activities of all the mitochondrial respiratory chain enzymes but in particular a marked decrease of complex I (NADH cytochrome c reductase) activity. All respiratory chain enzyme activities were normal in cultured skin fibroblasts. Mitochondrial DNA analysis failed to detect any major rearrangements. Although only a few cases have been reported so far, it is becoming clear that liver should be considered as one of the organs involved in oxidative phosphorylation disorders. The finding of unexplained progressive liver failure with poor neurological conditions, lactic acidaemia and ketonuria strongly warrants investigation for a respiratory chain disorder. Moreover, the finding of normal respiratory enzyme activities in a tissue other than liver does not rule out the existence of an oxidative phosphorylation disorder in patients with hepatocellular disease of unexplained origin.

The p.M292T NDUFS2 mutation causes complex I-deficient Leigh syndrome in multiple families

“…However, cultured skin fibroblasts were available from Patients 3, 5, 19, 22 and 27. As cell lines do not consistently exhibit the complex I deficient phenotype (Mazzella et al , 1997; Benit et al , 2001; Antonicka et al , 2003), the activity of the complex was first assessed in these fibroblasts. In-gel complex I activity assays were performed on protein samples separated on 1D blue-native PAGE.…”

Fatal deterioration of neurological disease after orthotopic liver transplantation for valproic acid‐induced liver damage

“…They vary, however, depending on the redox state of the mitochondria ( 2). The repeated mitochondrial assays in muscle biopsy specimens might have been false‐negative; either because their mitochondrial fraction was not representative or because the mitochondrial failure was organ‐specific ( 3, 4). Furthermore, the fast‐growing number of disease states regarded as induced by mitochondrial damage renders the results of mitochondrial assays more difficult to interpret ( 2).…”

Liver transplantation in mitochondrial respiratory chain disorders

“…The disease may start in the neonatal period or later in childhood [1,2,5,7]. In rare cases, the liver is the only organ involved in the disease process [5,7]. More commonly, the liver disease is associated with nervous or muscular system involvement.…”