title: Clinical, biochemical, and mutational spectrum of peroxisomal acyl-coenzyme A oxidase deficiency.
abstract: Peroxisomal acyl-coenzyme A (acyl-CoA) oxidase deficiency is an autosomal recessive inborn error of peroxisomal fatty acid oxidation due to a deficiency of straight-chain acyl-CoA oxidase (SCOX). The biochemical hallmark of this disorder is the accumulation of very long-chain fatty acids. Although some case reports and small series of patients have been published, a comprehensive overview of the clinical, biochemical, and mutational spectrum of this disorder is still lacking. For this reason, we report clinical information for a cohort of 22 patients with peroxisomal acyl-CoA oxidase deficiency and the results from biochemical and mutation analyses in fibroblasts of the patients. No clear genotype-phenotype correlation was observed. An intriguing mutation in the alternatively-spliced transcript encoding the isoform SCOX-exon 3II in a patient with normal expression of the transcript encoding the isoform SCOX-exon 3I, prompted us to characterize these two isoforms of human SCOX. The recombinant SCOX-exon 3I displayed activity toward medium-chain fatty acyl-CoAs and was not active with very long-chain fatty acyl-CoAs. In contrast, recombinant SCOX-exon 3II was capable of oxidizing a broad range of substrates, including very long-chain fatty acyl-CoAs. These results explain why this patient with a mutation in exon 3II of the ACOX1 gene, but with normal expression of exon 3I, was indistinguishable from other patients with peroxisomal acyl-CoA oxidase deficiency with respect to his clinical presentation and the biochemical abnormalities in his fibroblasts.
authors: Laboratory Genetic Metabolic Diseases, Academic Medical Center at the University of Amsterdam, Amsterdam, The Netherlands. S.Ferdinandusse@amc.uva.nl
authors: Sacha
authors: S
authors: Ferdinandusse
authors: Simone
authors: S
authors: Denis
authors: Eveline M
authors: EM
authors: Hogenhout
authors: Janet
authors: J
authors: Koster
authors: Carlo W T
authors: CW
authors: van Roermund
authors: Lodewijk
authors: L
authors: IJlst
authors: Ann B
authors: AB
authors: Moser
authors: Ronald J A
authors: RJ
authors: Wanders
authors: Hans R
authors: HR
authors: Waterham
mesh_terms: D042962:Acyl-CoA Oxidase; D000595:Amino Acid Sequence; D015415:Biomarkers / Q000032:analysis; D002478:Cells, Cultured; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005227:Fatty Acids / Q000032:analysis; D005347:Fibroblasts / Q000737:chemistry / Q000201:enzymology; D005838:Genotype; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D008052:Lipid Metabolism, Inborn Errors / Q000235:genetics* / Q000473:pathology*; D008969:Molecular Sequence Data; D009154:Mutation; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism*; D018901:Peroxisomal Disorders / Q000235:genetics* / Q000473:pathology*; D010641:Phenotype; D017386:Sequence Homology, Amino Acid
chemical_list: D015415:Biomarkers; D005227:Fatty Acids; D007527:Isoenzymes; D010088:Oxidoreductases; C107176:peroxisomal acyl-CoA oxidase; D042962:Acyl-CoA Oxidase