title: ACOX2 deficiency: A disorder of bile acid synthesis with transaminase elevation, liver fibrosis, ataxia, and cognitive impairment.
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.
authors.affiliation: Section 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.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Vilarinho
authors.affiliation: Division of Gastroenterology, Department of Pediatrics, Faculty of Medicine, Gazi University, Ankara, TB 06500, Turkey.
authors.forename: Sinan
authors.initials: S
authors.lastname: Sari
authors.affiliation: Center for Translational Omics, Institute of Child Health, University College London, London WC1N 1EH, United Kingdom.
authors.forename: Francesca
authors.initials: F
authors.lastname: Mazzacuva
authors.affiliation: Department 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.
authors.forename: Kaya
authors.initials: K
authors.lastname: Bilgüvar
authors.affiliation: Department of Pathology, Faculty of Medicine, Gazi University, Ankara, TB 06500, Turkey.
authors.forename: Güldal
authors.initials: G
authors.lastname: Esendagli-Yilmaz
authors.affiliation: Section 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.
authors.forename: Dhanpat
authors.initials: D
authors.lastname: Jain
authors.affiliation: Department of Pathology, Faculty of Medicine, Gazi University, Ankara, TB 06500, Turkey.
authors.forename: Gülen
authors.initials: G
authors.lastname: Akyol
authors.affiliation: Division of Gastroenterology, Department of Pediatrics, Faculty of Medicine, Gazi University, Ankara, TB 06500, Turkey.
authors.forename: Buket
authors.initials: B
authors.lastname: Dalgiç
authors.affiliation: Department 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.
authors.forename: Murat
authors.initials: M
authors.lastname: Günel
authors.affiliation: Center for Translational Omics, Institute of Child Health, University College London, London WC1N 1EH, United Kingdom.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Clayton
authors.affiliation: Department 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.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
mesh_terms: D001259:Ataxia / Q000150:complications / Q000201:enzymology* / Q000235:genetics; D001647:Bile Acids and Salts / Q000096:biosynthesis* / Q000737:chemistry; D002648:Child; D060825:Cognitive Dysfunction / Q000150:complications / Q000201:enzymology* / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000150:complications / Q000201:enzymology* / Q000235:genetics; D000073658:Loss of Function Mutation / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000172:deficiency* / Q000235:genetics; D000637:Transaminases / Q000378:metabolism*
chemical_list: D001647:Bile Acids and Salts; D010088:Oxidoreductases; C576470:ACOX2 protein, human; D000637:Transaminases
keywords: bile acid metabolism; branched-chain acyl-CoA oxidase; idiopathic liver disease; peroxisomal disorder; whole-exome sequencing