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.

Fig. 1

Liver histology and liver immunostaining studies in patient 1. (a) Patient: Picro Sirius staining, x40. Presence of hepatocellular cholestasis with a canalicular bile plug (arrow) and of lobular fibrosis. (b) Patient: Hematoxylin and eosin (HES), x40. Note the oncocytic aspect of hepatocytes (arrow). Presence of multinucleated and giant hepatocytes (arrowheads, also in panel C). (c) Patient: BSEP immunostaining, x40. Absence of BSEP canalicular expression. (d) Upper panel: Patient, MDR3 immunostaining, x40. MDR3 is expressed at the canalicular membrane (arrow). Lower panel: Normal human liver, BSEP immunostaining, x40. BSEP is expressed at the canalicular membrane (arrow)