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Liver cytochrome c oxidase deficiency in a case of neonatal-onset hepatic failure
P Edery1, B Gérard, D Chretien
1Département de Pédiatrie, Hôpital des Enfants-Malades, Paris, France.
Insights
Inborn errors of oxidative phosphorylation can cause infant liver failure. Testing liver tissue is crucial, as normal results in other tissues do not rule out this condition.
Area of Science:
- Biochemistry
- Genetics
- Pediatrics
Background:
- Inborn errors of oxidative phosphorylation are increasingly recognized causes of hepatic failure in infants.
- Respiratory enzyme deficiencies have been documented in various tissues of affected individuals.
Observation:
- A 5-month-old girl presented with hepatic failure and persistent hyperlactatemia with high lactate/pyruvate ratios.
- Cytochrome c oxidase deficiency was identified in the liver but not skeletal muscle.
Findings:
- No mutations in liver-specific cytochrome c oxidase subunits or mitochondrial DNA abnormalities were found.
- Normal respiratory enzyme activity in peripheral tissues (skeletal muscle, lymphocytes, fibroblasts) did not exclude the diagnosis.
Implications:
- Inborn errors of oxidative phosphorylation should be considered in diagnosing severe, unexplained infant liver dysfunction, especially with abnormal plasma oxidation-reduction status.
- Negative enzyme activity tests in peripheral tissues warrant specific assays in liver tissue for definitive diagnosis.
Abstract:
In the last few years, inborn errors of oxidative phosphorylation have been recognized as possible causes of hepatic failure in infancy and respiratory enzyme deficiencies have been described in several tissues of affected individuals. Here, we report on cytochrome c oxidase deficiency in the liver but not in the skeletal muscle of a 5-month-old girl who presented hepatic failure in early infancy. Persistent hyperlactatemia (> 4 mM, normal < 2.4) with high lactate/pyruvate (L/P) molar ratios in plasma, and their further elevation in the post-absorptive period were suggestive of an inborn error of oxidative phosphorylation. However, no mutation in the coding sequences of the liver-specific subunits of cytochrome c oxidase (VIa and VIIa) has been detected and no major rearrangement or depletion of the mitochondrial DNA has been observed. Based on this observation we suggest that inborn errors of oxidative phosphorylation be considered in the diagnosis of severe hepatocellular dysfunction of unknown origin, especially when an abnormal oxidation-reduction status is found in the plasma and even if normal respiratory enzyme activities are found in peripheral tissues. The findings of normal respiratory enzyme activities in skeletal muscle, circulating lymphocytes or cultured skin fibroblasts does not rule out this diagnosis. Instead, the negativity of these tests should prompt one to carry out the specific enzyme assays in the tissue which expresses the disease, namely the liver.