Secondary Mitochondrial Respiratory Chain Defect Can Delay Accurate PFIC2 Diagnosis

Abstract

Multiple respiratory chain deficiencies represent a common cause of mitochondrial diseases and often result in hepatic failure. There is no gold-standard test for diagnosing mitochondrial disease, and the current diagnosis relies on establishing a consistent pattern of evidence from clinical data, neuroimaging, tissue biopsy, and biochemical investigations. In some patients, the mitochondrial respiratory chain defect (MRCD) diagnosis is confirmed by genetic investigations. In most cases, genetic investigations are not informative and a number of cases remain unexplained.

Here, we report on two children presenting with liver disease in whom first investigations suggested MRCD, due to decreased liver respiratory chain activities and decreased mitochondrial DNA copy number. However, sequencing of the genes known to be associated with mitochondrial DNA instability did not identify any pathogenic mutations. Further investigations including exome analysis, biliary bile salt analysis, and/or BSEP immunostaining detected a defect in the bile salt export pump (BSEP). Diagnosis of progressive familial intrahepatic cholestasis type 2 (PFIC2), a hereditary disorder in bile formation due to BSEP deficiency was confirmed by ABCB11 gene sequencing. Deleterious mutations were identified in both patients: one harboring compound heterozygous mutations (p.Arg470*/c.1308+2T>A) and the other homozygous nonsense mutation (p.Tyr354*). This report increases awareness of a possible secondary mitochondrial respiratory chain defect in the liver tissue associated with other underlying causes such as PFIC2.

Competing interests: None declared

Appendices

One-Sentence Take-Home Message

Hepatic mitochondrial respiratory chain defect may be secondary to severe cholestasis and liver failure.

Contribution of Individual Authors

Anne SPRAUL: identification of patient defect (genetic analysis), manuscript writing

Marine BEINAT: identification of patient defect (exome analysis)

Dominique DEBRAY: diagnosis and follow-up of patient 2, revising manuscript

Agnes ROTIG: identification of patient defect (exome analysis), revising manuscript

Abdelhamid SLAMA: biochemical and genetic analysis of MRCD, revising manuscript

Emmanuel JACQUEMIN: diagnosis and follow-up of patient 1, manuscript writing and supervision