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Proc Natl Acad Sci U S A. 2016 Oct 4;113(40):11289-11293. Epub 2016 Sep 19.

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

Author information

  • 1Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06517; Department of Genetics, Yale University School of Medicine, New Haven, CT 06517; silvia.vilarinho@yale.edu rickl@rockefeller.edu.
  • 2Division of Gastroenterology, Department of Pediatrics, Faculty of Medicine, Gazi University, Ankara, TB 06500, Turkey.
  • 3Center for Translational Omics, Institute of Child Health, University College London, London WC1N 1EH, United Kingdom.
  • 4Department of Genetics, Yale University School of Medicine, New Haven, CT 06517; Yale Center for Mendelian Genomics, Yale University School of Medicine, New Haven, CT 06517.
  • 5Department of Pathology, Faculty of Medicine, Gazi University, Ankara, TB 06500, Turkey.
  • 6Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06517; Department of Pathology, Yale University School of Medicine, New Haven, CT 06517.
  • 7Department of Genetics, Yale University School of Medicine, New Haven, CT 06517; Yale Center for Mendelian Genomics, Yale University School of Medicine, New Haven, CT 06517; Yale Program in Brain Tumor Research, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06517.
  • 8Department of Genetics, Yale University School of Medicine, New Haven, CT 06517; Yale Center for Mendelian Genomics, Yale University School of Medicine, New Haven, CT 06517; Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06517; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06517; Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY 10065 silvia.vilarinho@yale.edu rickl@rockefeller.edu.

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

PMID:
27647924
PMCID:
PMC5056113
[Available on 2017-04-04]
DOI:
10.1073/pnas.1613228113
[PubMed - in process]
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