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Case Reports
. 2016 Oct 4;113(40):11289-11293.
doi: 10.1073/pnas.1613228113. Epub 2016 Sep 19.

ACOX2 deficiency: A disorder of bile acid synthesis with transaminase elevation, liver fibrosis, ataxia, and cognitive impairment

Sílvia Vilarinho  1 , Sinan Sari  2 , Francesca Mazzacuva  3 , Kaya Bilgüvar  4 , Güldal Esendagli-Yilmaz  5 , Dhanpat Jain  6 , Gülen Akyol  5 , Buket Dalgiç  2 , Murat Günel  7 , Peter T Clayton  3 , Richard P Lifton  8
Affiliations
Case Reports

ACOX2 deficiency: A disorder of bile acid synthesis with transaminase elevation, liver fibrosis, ataxia, and cognitive impairment

Sílvia Vilarinho et al. Proc Natl Acad Sci U S A. .

Abstract

Acyl CoA Oxidase 2 (ACOX2) encodes branched-chain acyl-CoA oxidase, a peroxisomal enzyme believed to be involved in the metabolism of branched-chain fatty acids and bile acid intermediates. Deficiency of this enzyme has not been described previously. We report an 8-y-old male with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Exome sequencing revealed a previously unidentified homozygous premature termination mutation (p.Y69*) in ACOX2 Immunohistochemistry confirmed the absence of ACOX2 expression in the patient's liver, and biochemical analysis showed marked elevation of intermediate bile acids upstream of ACOX2. These findings define a potentially treatable inborn error of bile acid biosynthesis caused by ACOX2 deficiency.

Keywords: bile acid metabolism; branched-chain acyl-CoA oxidase; idiopathic liver disease; peroxisomal disorder; whole-exome sequencing.

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Conflict of interest statement

Dr. Lifton and Dr. Valle were coauthors (neither of them first or last author) on a 40-author review of progress in Mendelian genetics published in 2015. This paper came about because they are independently funded grantees from NIH for discovery of new Mendelian loci. They have never been research collaborators.

Figures

Fig. 1.
Fig. 1.
Liver histology and ACOX2 mutation in a subject with an unrecognized bile acid synthesis disorder. (A) Liver parenchyma of the proband shows many thin fibrous septa (black arrows) and some nodularity (“incomplete septal cirrhosis”). Features of well-established cirrhosis are not seen. (B) Details of the lobular parenchyma show swollen hepatocytes (asterisks), glycogenated nuclei (black arrows), and very thin incomplete fibrous septa (blue arrow). (C) Liver parenchyma from age- and sex-matched patient showing normal-appearing portal tracts and a central venule (asterisk). The lobular architecture is preserved with no fibrosis. (D) The affected proband and unaffected subjects are shown in black and white symbols, respectively. Consanguineous union is represented by a double line. ACOX2 alleles are denoted as WT or Mut (p. Y69*). (E) Sanger sequencing chromatograms of the proband, his unaffected parents, and his brother. The ACOX2 p.Y69* mutation is homozygous in the proband and heterozygous in the unaffected parents and sibling. (Scale bars: 50 μm.)
Fig. S1.
Fig. S1.
Additional histological findings in the proband’s liver. (A) Hepatocytes are pale and swollen with focal acinar transformation (black arrows). (Scale bar: 50 μm.) (B) Low-magnification of liver biopsy showing thin fibrous septa (black arrows) and some nodularity on Trichrome stain. (Scale bar: 200 μm.)
Fig. 2.
Fig. 2.
Absence of ACOX2 in the proband’s liver. (A–C) Immunohistochemistry for ACOX2 in normal liver shows intense granular staining in the pericentral (zone 3) hepatocytes, but faint staining in remaining hepatocytes, including periportal hepatocytes (zone 1). (D–F) Immunohistochemistry for ACOX2 in the proband’s liver biopsy, showing complete absence of staining. (Scale bars: 50 μm.)
Fig. 3.
Fig. 3.
Schematic representation of the ACOX2 β-oxidation of trihydroxycholestanoyl-CoA. CA, cholic acid.
See this image and copyright information in PMC

Comment in

  • ACOX2 deficiency in primary malignant cardiac tumors.
    Zhou X, Wang H. Zhou X, et al. Proc Natl Acad Sci U S A. 2017 May 2;114(18):E3590-E3591. doi: 10.1073/pnas.1701212114. Epub 2017 Apr 11. Proc Natl Acad Sci U S A. 2017. PMID: 28400508 Free PMC article. No abstract available.

References

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