Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 40, Pages 11289-11293Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1613228113
Keywords
branched-chain acyl-CoA oxidase; bile acid metabolism; peroxisomal disorder; whole-exome sequencing; idiopathic liver disease
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Funding
- National Institutes of Health's Center for Mendelian Genomics [U54 HG006504]
- National Institutes of Health-Yale Liver Center [P30DK034989]
- American Association for the Study of Liver Diseases Foundation Sheila Sherlock Clinical and Translational Research Award in Liver Diseases
- Great Ormond Street Hospital Childrens Charity [V1254] Funding Source: researchfish
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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.
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