Peroxisomal acyl CoA oxidase deficiency (original) (raw)
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Adult peroxisomal acyl-coenzyme A oxidase deficiency with cerebellar and brainstem atrophy
Journal of Neurology, Neurosurgery & Psychiatry, 2010
Peroxisomal acyl-CoA oxidase deficiency (formerly also called pseudoneonatal adrenoleukodystrophy) is a disorder of peroxisomal fatty acid oxidation with a severe presentation. Most patients present at birth or in early infancy, and the mean age of death was 5 years in a recently published cohort of 22 patients. Brain imaging shows a progressive leukodystrophy. We report here the first adult patients (two siblings, 52 and 55 years old) with peroxisomal acyl-CoA oxidase deficiency with a remarkably mild clinical presentation. Magnetic resonance brain imaging showed profound atrophy of the brainstem and cerebellum.
Peroxisomal acyl‐CoA‐oxidase deficiency: Two new cases
American Journal of Medical Genetics Part A, 2008
We report on two new patients with straight-chain acylcoenzyme A oxidase deficiency. Early onset hypotonia, seizures and psychomotor delay were observed in both cases. Plasma very-long-chain fatty acids were abnormal in both patients, whereas the plasma levels of phytanic acid, pristanic acid, the bile acid intermediates DHCA and THCA, and erythrocyte plasmalogen levels were normal. Studies in fibroblasts from the two patients revealed a deficiency of one of the two peroxisomal acyl-CoA oxidases, that is, straightchain acyl-CoA oxidase (ACOX1). Subsequent molecular analysis of ACOX1 showed a homozygous deletion, which removes a large part of intron 3 and exons 4-14 in the first patient. Mutation analysis in the second patient revealed compound heterozygosity for two mutations, including: (1) a c.692 G > T (p.G231V) mutation and (2) skipping of exon 13 (c.1729_1935del (p.G577_E645del). ß
A novel case of ACOX2 deficiency leads to recognition of a third human peroxisomal acyl-CoA oxidase
Biochimica et biophysica acta. Molecular basis of disease, 2018
Peroxisomal acyl-CoA oxidases catalyze the first step of beta-oxidation of a variety of substrates broken down in the peroxisome. These include the CoA-esters of very long-chain fatty acids, branched-chain fatty acids and the C27-bile acid intermediates. In rat, three peroxisomal acyl-CoA oxidases with different substrate specificities are known, whereas in humans it is believed that only two peroxisomal acyl-CoA oxidases are expressed under normal circumstances. Only three patients with ACOX2 deficiency, including two siblings, have been identified so far, showing accumulation of the C27-bile acid intermediates. Here, we performed biochemical studies in material from a novel ACOX2-deficient patient with increased levels of C27-bile acids in plasma, a complete loss of ACOX2 protein expression on immunoblot, but normal pristanic acid oxidation activity in fibroblasts. Since pristanoyl-CoA is presumed to be handled by ACOX2 specifically, these findings prompted us to re-investigate th...
Proceedings of the National Academy of Sciences, 1996
Peroxisomes in human liver contain two distinct acyl-CoA oxidases with different substrate specificities: (i) palmitoyl-CoA oxidase, oxidizing very long straight-chain fatty acids and eicosanoids, and (ii) a branched-chain acyl-CoA oxidase (hBRCACox), involved in the degradation of long branched fatty acids and bile acid intermediates. The accumulation of branched fatty acids and bile acid intermediates leads to severe mental retardation and death of the diseased children. In this study, we report the molecular characterization of the hBRCA-Cox, a prerequisite for studying mutations in patients with a single enzyme deficiency. The composite cDNA sequence of hBRCACox, derived from overlapping clones isolated via immunoscreening and hybridization of human liver cDNA expression libraries, consisted of 2225 bases and contained an open reading frame of 2046 bases, encoding a protein of 681 amino acids with a calculated molecular mass of 76,739 Da. The C-terminal tripeptide of the protein is SKL, a known peroxisome targeting signal. Sequence comparison with the other acyl-CoA oxidases and evolutionary analysis revealed that, despite its broader substrate specificity, the hBRCACox is the human homolog of rat trihydroxycoprostanoyl-CoA oxidase (rTHCCox) and that separate gene duplication events led to the occurrence in mammals of acyl-CoA oxidases with different substrate specificities. Northern blot analysis demonstrated that-in contrast to the rTHC-Cox gene-the hBRCACox gene is transcribed also in extrahepatic tissues such as heart, kidney, skeletal muscle, and pancreas. The highest levels of the 2.6-kb mRNA were found in heart, followed by liver. The enzyme is encoded by a single-copy gene, which was assigned to chromosome 3p14.3 by fluorescent in situ hybridization. It was absent from livers of Zellweger patients as shown by immunoblot analysis and immunocytochemistry.
Microcephaly and developmental delay caused by short-chain acyl-CoA dehydrogenase deficiency
The Turkish journal of pediatrics, 2017
Kılıç M, Şenel S, Karaer K, Ceylaner S. Microcephaly and developmental delay caused by short-chain acyl-CoA dehydrogenase deficiency. Turk J Pediatr 2017; 59: 708-710. We report a four-year-old girl who presented with intrauterine growth retardation, mild dysmorphism, cleft palate, microcephaly, developmental delay, epilepsy and recurrent lower respiratory tract infection and diagnosed short-chain acyl-CoA dehydrogenase deficiency. Metabolic evaluation and molecular analysis confirmed the diagnosis. In spite of many patients already known in literature, this is one of the rarest reports of a Turkish patient. This suggests selective metabolic screening should be done in every patient with unknown etiology of neurological disorder. Furthermore, newborn screening using tandem mass spectrometry may prevent this severe neurological impairment.
Immunocytochemical localization of acyl-CoA oxidase in the rat central nervous system
Journal of Neurocytology, 2001
Peroxisomal β-oxidation, consisting of four steps catalysed by an acyl-CoA oxidase, a multifunctional protein and a thiolase, is responsible for the shortening of a variety of lipid compounds. The first reaction of this pathway is catalysed by a FAD-containing acyl-CoA oxidase, three isotypes of which have been so far recognised. Among these, straight-chain acyl-CoA oxidase (ACOX) acts on long and very long chain fatty acids, prostaglandins and some xenobiotics. We investigated ACOX localisation by means of a sensitive, tyramide based, immunocytochemical technique, thus obtaining a complete distribution atlas of the enzyme in adult rat CNS. Granular immunoreaction product was found in the cytoplasm of neuronal and glial cells, both in the perikarya and in the cell processes. ACOX immunoreactive neurons were present to variable extent, in either forebrain or hindbrain areas. Specifically, the strongest signal was detected in the pallidum, septum, red nucleus, reticular formation, nuclei of the cranial nerves, and motoneurons of the spinal cord. We then compared the ACOX immunoreactivity pattern with our previous distribution maps of other peroxisomal enzymes in the adult rat brain. While ACOX appeared to colocalise with catalase in the majority of cerebral regions, some differences with respect to d-amino acid oxidase were noted. These observations support the hypothesis of heterogeneous peroxisomal populations in the nervous tissue. The wide distribution of the enzyme in the brain is consistent with the severe and generalised neurological alterations characterising the peroxisomal disorder caused by ACOX deficiency (pseudo-neonatal adrenoleukodystrophy).
American journal of human genetics, 1988
In the present paper two siblings are presented with clinical manifestations very similar to those of patients affected by neonatal adrenoleukodystrophy. In contrast to neonatal adrenoleukodystrophy patients, hepatic peroxisomes in these siblings were enlarged in size and not decreased in number. Accumulation of very-long-chain fatty acids (VLCFA) was associated with an isolated deficiency of the fatty acyl-CoA oxidase, the enzyme that catalyzes the first step of the peroxisomal beta-oxidation. Plasma levels of di- and trihydroxy-coprostanoic acid, phytanic acid, and pipecolic acid were normal; furthermore, acyl-CoA:dihydroxyacetone phosphate acyltransferase activity in cultured fibroblasts was also found to be normal. The clinical, biochemical, and cytochemical features found in these two siblings are compared with those seen in two other disorders characterized by the absence of a decreased number of hepatic peroxisomes and the presence of VLCFA: (1) pseudo-Zellweger syndrome (def...