Clinical, biochemical, and mutational spectrum of peroxisomal acyl-coenzyme a oxidase deficiency

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.