No approved-drug candidate for peroxisomal acyl-coa oxidase deficiency is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
In a 2004 study using deuterium-labelled tetracosanoic acid (D3-C24:0) to measure peroxisomal β-oxidation in cultured skin fibroblasts, six cell lines from patients with acyl-CoA oxidase (AOX) deficiency or bifunctional protein deficiency produced no detectable D3-C16:0 after three days of incubation, whereas control fibroblasts produced measurable amounts. The authors concluded that β-oxidation of C24:0 to C16:0 takes place exclusively in peroxisomes and not in mitochondria. In the same assay, fibroblasts from X-linked adrenoleukodystrophy patients showed a mean D3-C16:0 concentration of 0.60 nmol/mg protein, about 15% of control values, with no correlation between residual activity and clinical phenotype. Fibroblasts from peroxisome biogenesis disorder patients produced only 5% of the control amount, and no D3-C16:0 was detectable in eight cell lines from the severe Zellweger phenotype.
A 1990 study using immunofluorescence and density gradient centrifugation found that fibroblasts from Zellweger syndrome patients contain unprocessed acyl-CoA oxidase and unprocessed 3-oxoacyl-CoA thiolase associated with structures that also contain a 69 kDa peroxisomal integral membrane protein and residual dihydroxyacetonephosphate acyltransferase activity. These structures had a density much lower than normal peroxisomes and were interpreted as defectively assembled peroxisomes that may still import some peroxisomal proteins.
A 2004 reinvestigation of a patient previously diagnosed with trihydroxycholestanoyl-CoA oxidase deficiency found that the patient actually had a peroxisome biogenesis disorder caused by mutations in the PEX12 gene. All peroxisomal functions in cultured skin fibroblasts were normal, including catalase localisation. The authors stated that there is no longer evidence for trihydroxycholestanoyl-CoA oxidase deficiency as a distinct disease entity. A 1989 conference abstract reported separate peroxisomal oxidases for long-chain acyl-CoA and trihydroxycoprostanoyl-CoA, but this work predates the 2004 finding that the latter deficiency does not exist as a separate disorder.
No clinical trial data, no survival statistics, and no treatment outcomes for peroxisomal acyl-CoA oxidase deficiency were provided in any of these abstracts. What is missing is any clinical study of patients with confirmed AOX deficiency, any trial of a potential therapy, and any systematic characterisation of the natural history of this specific single-enzyme disorder. The diagnostic methods described rely on fibroblast assays that are not widely standardised outside research laboratories, and no patient stratification by genotype or residual enzyme activity has been linked to clinical outcomes.
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Human Mutation · 2007 · 152 citations
Clinical, biochemical, and mutational spectrum of peroxisomal acyl–coenzyme A oxidase deficiency
AbstractPeroxisomal 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.
https://doi.org/10.1002/humu.20535Clinical Chemistry · 2004 · 45 citations · open access
Method for Measurement of Peroxisomal Very-Long-Chain Fatty Acid β-Oxidation in Human Skin Fibroblasts Using Stable-Isotope-Labeled Tetracosanoic Acid
AbstractPeroxisomes are present in virtually every eukaryotic cell type except the mature erythrocyte. In higher eukaryotes, one of the main functions of peroxisomes is the β-oxidation of very-long-chain fatty acids (VLCFA; > 22 carbon atoms) (1). The importance of peroxisomal β-oxidation is emphasized by the existence of a variety of different diseases in which peroxisomal β-oxidation is impaired and VLCFA concentrations are increased (1)(2)(3)(4). Peroxisomal disorders can be categorized as (a) single peroxisomal enzyme deficiencies, including X-linked adrenoleukodystrophy (X-ALD) and disorders attributable to defects in one of the peroxisomal β-oxidation enzymes, such as acyl-CoA oxidase (AOX) deficiency and bifunctional protein (DBP) deficiency; and (b) disorders attributable to defects in peroxisome biogenesis. The peroxisome biogenesis disorders (PBDs) represent a continuum of clinical features ranging from the most severe form, Zellweger syndrome, through neonatal adrenoleukodystrophy to the least severe form, infantile Refsum disease. Currently, measurement of the peroxisomal fatty acid β-oxidation activity is performed with 1-[14C]-radiolabeled VLCFA substrates and one of two available methods: either in intact human skin fibroblasts cultured in monolayer (5); or in isolated fibroblasts permeabilized with digitonin (6). We investigated the feasibility of using deuterium-labeled tetracosanoic acid (D3-C24:0) as an alternative substrate to radiolabeled 1-[14C]-labeled C24:0 for the measurement of peroxisomal β-oxidation activity in cultured primary human skin fibroblasts. Before use, the purity of 24,24,24-D3-C24:0 (Larodan Fine Chemicals AB) was determined. The D3-C24:0 substrate contained ∼6% deuterium-labeled octadecanoic acid (D3-C18:0). Acetone was used to purify D3-C24:0 according to the following procedure: 4 mL of acetone was added to 20 mg of D3-C24:0. The sample was vortex-mixed vigorously, left at room temperature for 30 min, and centrifuged at 1600g for 10 min; approximately 80% of the acetone was then removed, and 3 mL of fresh acetone was added. This procedure was repeated two more times. After three washing steps with acetone, ∼80% of the acetone was removed, and the remaining acetone was evaporated at room temperature under a constant stream of nitrogen. The residue was weighed, and a stock solution of 10 mmol/L D3-C24:0 in absolute ethanol was prepared. After purification, the purity of D3-C24:0 was analyzed, and the contribution of the D3-C18:0 contaminant was determined to be <0.2%. Fibroblasts from healthy controls and patients with X-ALD were cultured in the absence or presence of 20 μmol/L D3-C24:0 in HAM-F10 tissue culture medium supplemented with 100 mL/L fetal calf serum, penicillin (100 IU/mL), streptomycin (100 IU/mL), and glutamine (2 mmol/L). Before usage, the D3-C24:0 stock solution was put in a water bath for 5 min, vortex-mixed, and diluted in HAM-F10 tissue culture medium to a final concentration of 20 μmol/L. Cells were used between passage numbers 6 and 18. For fatty acid analysis, cells were harvested with trypsin, washed twice with phosphate-buffered saline (PBS) and once with 9 g/L NaCl, dissolved in 200 μL of deionized water, and sonicated, and the protein concentration was determined. The peroxisomal β-oxidation activity was calculated by measurement of the amount of intracellular deterium-labeled hexadecanoic acid (D3-C16:0) present in nmol/mg of protein. In our method we chose D3-C16:0 as a marker for peroxisomal β-oxidation because of the availability of a D3-C16:0 internal standard, which enabled accurate calculation of the amount of D3-C16:0 present in the cells. Fatty acids were analyzed by electrospray ionization mass spectrometry using a recently described isotope-dilution method (7). For calculation of the amount of D3-C16:0, we constructed a five-point calibration curve. Of a calibration mixture containing D3-C16:0 (40 μmol/L), we added 0, 25, 50, 100, and 200 μL to 100 μL of internal standard containing deuterium-labeled behenic acid (D4-C22:0; 50.0 μmol/L), D4-C24:0 (50.0 μmol/L), and deuterium-labeled hexacosanoic acid (D4-C26:0; 1.0 μmol/L). Samples were extracted and analyzed as described previously (7). The input concentration of D3-C16:0 (in nmol) was plotted against the ratio of the peak height of D3-C16:0 to the peak height of the D4-C22:0 internal standard. The trend line and the intercept were used to calculate the D3-C16:0 concentration in the samples. The effect of incubation time on the production of D3-C16:0 from D3-C24:0 in fibroblasts from healthy individuals and patients with X-ALD is shown in Fig. 1 . At all time points investigated, the amount of D3-C16:0 in the X-ALD cell lines was markedly lower than that in the control cell lines. Because D3-C16:0 is an intermediate of peroxisomal β-oxidation and not an end product, the amount of D3-C16:0 measured in the cells at the different time points reflects the flux through the β-oxidation pathway and hence is an indicator of the overall activity of the pathway. After 2–3 days, the amount of D3-C16:0 present in control and X-ALD cell lines plateaued, indicating that a steady state was reached. To exclude depletion of the substrate in the medium, we measured the amount of D3-C24:0 present in the medium after 72 h. The medium of the control cells still contained >80% of the initial D3-C24:0 concentration. On the basis of the data presented in Fig. 1 , we selected a 3-day incubation period with 20 μmol/L D3-C24:0 for subsequent studies. Effect of incubation time on D3-C16:0 concentrations. Primary human skin fibroblasts from healthy individuals (▪) and X-ALD patients (○) were cultured under standard tissue culture conditions, for the time indicated, in the presence of 20 μmol/L D3-C24:0, and harvested. The amount of D3-C16:0 present in the cells was then measured. P values were calculated by the two-tailed Student t-test. Values are the mean (SD; error bars). ∗, P <0.01. The intraassay CV was determined by the following procedure: the cells were divided into five separate tissue culture flasks, treated with 20 μmol/L D3-C24:0, and after 3 days, the amount of D3-C16:0 present in the cells was measured. The intraassay CV obtained was 5.8%. The interassay CV, determined by assaying control cell lines during 5 separate weeks, was 8.8%. The D3-C16:0 concentrations present after 3 days of incubation with 20 μmol/L D3-C24:0 of fibroblasts from controls and patients with different peroxisomal β-oxidation disorders, including X-ALD, AOX deficiency, and DBP deficiency, are summarized in Table 1 . In addition, cells from different PBD patients were analyzed as well. D3-C16:0 concentrations in skin fibroblasts from controls and patients after 3 days of incubation with D3-C24:0. D3-C16:0 concentrations in cultured skin fibroblasts after 3 days of incubation with 20 μmol/L D3-C24:0. D3-C16:0 concentrations in control fibroblasts were used to calculate the relative amounts in patient cell lines. P values were calculated by use of the two-tailed Student t-test. D3-C16:0 concentrations in skin fibroblasts from controls and patients after 3 days of incubation with D3-C24:0. D3-C16:0 concentrations in cultured skin fibroblasts after 3 days of incubation with 20 μmol/L D3-C24:0. D3-C16:0 concentrations in control fibroblasts were used to calculate the relative amounts in patient cell lines. P values were calculated by use of the two-tailed Student t-test. In none of the six AOX- or DBP-deficient cell lines could D3-C16:0 be detected. The cells had taken up the D3-C24:0 substrate, as we concluded from measurement of intracellular D3-C24:0 concentrations. These data indicate that β-oxidation of C24:0 to C16:0 takes place exclusively in peroxisomes and not in mitochondria. In fibroblasts derived from PBD patients, the amount of D3-C16:0 was only 5% of the amount in control fibroblasts (Table 1 ). Among the different PBD patient cell lines analyzed, however, we observed variation in residual peroxisomal β-oxidation activity, as indicated by the amount of intracellular D3-C16:0 present. No D3-C16:0 was detectable in eight cell lines derived from patients with the severe Zellweger phenotype, whereas D3-C16:0 was detectable in four cell lines derived from patients with the milder neonatal adrenoleukodystrophy or infantile Refsum disease phenotypes. These observations are in agreement with a previous study that reported the predictive value of dihydroxyacetonephosphate acyltransferase (DHAPAT) activity and residual peroxisomal VLCFA β-oxidation activity, measured with 1-[14C]-C24:0 as substrate, for the life expectancy of PBD patients (8). Fibroblasts derived from patients with X-ALD had the highest (15%) relative amount of D3-C16:0 formed (Table 1 ). The mean (SD) amount of D3-C16:0 in X-ALD fibroblasts was 0.60 (0.42) nmol/mg of protein. Within the group of 12 X-ALD patients included in the analysis, no correlation was observed between the peroxisomal β-oxidation activity and the phenotype of the patient. In conclusion, we have developed an easy, sensitive, nonradioactive method for analysis of peroxisomal β-oxidation activity in fibroblasts. We thank Herman ten Brink and Rob Ofman for helpful technical suggestions and discussion. This work was supported by grants from the Netherlands Organization for Scientific Research (NWO-MW: No. 903-42-077), the European Leukodystrophy Association, and European Union Project LSHM-CT-2004-502987.
https://doi.org/10.1373/clinchem.2004.038539European Journal of Biochemistry · 2004 · 41 citations · open access
β‐Oxidation of fatty acids
AbstractThe β-oxidation of fatty acids is a central metabolic process providing electrons to the respiratory chain and thus energy for a multitude of needs in aerobic organisms. It is a complex process occurring inside mitochondria, involves more than a dozen enzymes and must be carefully regulated, in particular in its relationship to the other sources of energy such as carbohydrate and amino acid catabolism. The consequences of dysfunctions in β-oxidation can be many-fold and severe with regard to human health, and thus an understanding of the basic mechanisms is of great relevance. The scope of the present series of minireviews is to highlight aspects of β-oxidation from different, complementary points of view. Thus, in the first review, Bartlett and Eaton address the interplay and regulation of the various enzymes involved in the β-oxidation cycle itself, and of those involved in the transport and transformation of fatty acids and conjugates. They also deal with the effects of malfunction of these enzymes, e.g. as a consequence of genetic defects. The second review is by Gregersen, Bross and Andresen and addresses a topic that has increased in importance in the recent past: the consequences on human health of genetic defects affecting β-oxidation. Since the discovery of the first defects in the 1970s, this field has gained steadily in relevance. One reason is undoubtedly the central role of β-oxidation in ‘energy metabolism’. The second is associated with the finding that one specific mutation affecting medium-chain acyl-CoA dehydrogenase is among the most common genetic defects in humans of Caucasian descent, its frequency being higher than that of phenylketonuria. This has spurred great advances in the methodologies for the detection of specific metabolites in clinical chemistry, in genetic analysis and by this in the identification of specific defects. The review also draws attention to the importance of the interplay of medical studies with basic biochemical investigations that aim to elucidate the molecular basis of genetic defects. The third (Kim and Miura) and fourth contributions (Ghisla and Thorpe) deal with the family of enzymes involved in β-oxidation that has received most attention recently: the enzymes involved in the first step of the cycle, the α,β-dehydrogenation of fatty acid acyl-CoA conjugates. These enzymes constitute a family of flavoproteins whose chemistries regarding the catalytic event are similar. However, they differ significantly in their specificity, tissue distribution and quantitative occurrence. The members of this family have grown steadily and reach nine at present. The last two and most recent additions have emerged from the identification of corresponding genes in the human genome. The characteristics of this family raise the question of why nature evolved to use such a large number of related enzymes instead of a small number to do the same job. The answer is still uncertain though it can be speculated that it resides in control and in the fact that α,β-dehydrogenation is the slowest step in the β-oxidation cycle and has fostered a corresponding evolutionary pressure. Medium-chain acyl-CoA dehydrogenase, one of the ‘oldest members’ of the family, has received much attention from a biochemical/mechanistic point of view, and has advanced to become a model enzyme for the study of the chemistry underlying α,β-dehydrogenation. Also, with its cousin, the acyl-CoA oxidase(s), it shares the mechanism of substrate dehydrogenation but has completely different tastes for electron acceptor. It transfers electrons to a specific acceptor (electron transferring flavoprotein) and protects its redox equivalent from reaction with oxygen. This contrasts with the oxidase that specifically uses O2 as an acceptor. The two enzymes have thus recently become models for investigating the factors that govern oxygen reactivity of flavoproteins. In their review, Kim and Miura highlight the salient features of the 3D structure of medium-chain acyl-CoA dehydrogenase in comparison with that of related members of the family and, importantly, with that of the specified acyl-CoA oxidase. Perhaps the most surprising aspect emerging from this comparison is the fact that the two enzymes do not differ in their functional groups at the active site. They differ, however, in subtle aspects such as the presence of a ‘more open’ active site in the case of the oxidase that might facilitate physical access of dioxygen to the active site, whereas access of solvent and dioxygen to that of the dehydrogenase appears to be repressed. The fourth contribution by Ghisla and Thorpe discusses primarily mechanistic aspects of acyl-CoA dehydrogenases from a (bio) chemical point of view. Although a number of important details still elude our understanding, it is fair to say that we have advanced to the point where there is a consensus on the basic mechanism shared by this class of enzyme and that of the oxidases. Importantly, there is good agreement between the deductions drawn from 3D data and biochemical studies. Finally, this digression into biochemical aspects brings us to the appreciation of the prominent role of H. Beinert, who has been a pioneer in the study of enzymes involved in β-oxidation, and to whom this series is dedicated on the occasion of his 90th birthday. The following section is his retrospective view of the progress that has occurred in the last century in this field. The mechanism by which saturated fatty acids, i.e. essentially saturated hydrocarbons, are degraded and utilized in living organisms has been a matter of keen interest to physiologists and biochemists for many years. It was a long and arduous road until the basic processes, and the catalytic proteins and necessary cofactors were recognized and obtained as pure substances. There were a number of crucial observations and developments in adjacent fields, scattered through the years for almost half a century, which eventually had to come together to lead to the final clarification of the processes and ingredients involved. In the following I intend to point out the various crucial stations along the way to success. In 1904 Franz Knoop did his famous experiments [1], probably the first ‘tracer’ experiments, by feeding dogs phenylated fatty acids of various chain lengths, from which it became clear that fatty acids are degraded by successively chopping off two-carbon units at a time through introduction of a double bond between the β- and γ-carbon of the fatty acid, hence the name β-oxidation. This was supported in experiments with unlabeled fatty acids in 1908 by Dakin [2]. It was established that special attention should be given to the role of a two-carbon fragment, presumably some form of acetate. However, acetate is known to be a fairly unreactive substance. In experiments on yeast, Lynen [3] observed in Wieland's laboratory in the early 1940s that, when respiring yeast was oxygenated until its endogenous substrates had been exhausted, it was only able to resume oxidation of acetate after a lag period, as though acetate had to be prepared for oxidation by some activation process. This process could be facilitated by adding small quantities of a readily oxidizable substrate such as ethanol, indicating that some energy had to be provided by the cosubstrate, which was therefore called the ‘sparker’. Out of such observations arose the idea of an ‘activated’ form of acetate. In the same period, there happened to be interest in an ‘active form’ of acetate among pharmacologists and neurologists, because such a compound was obviously required for the enzymatic acetylation of choline [4,5] and of sulfanilamide [6], through which the latter lost its antibacterial activity. These acetylation reactions then furnished simple and practical assays for ‘active acetate’. It was also noticed that, in addition to the respective acetylase proteins, a water-soluble substance of low molecular mass was required, which was called the coenzyme of acetylation, CoA [7]. Lipmann and his group were able, following the sulfanilamide assay, to obtain active concentrates of the new coenzyme, which they then subjected to various analyses for its constituents [8,9]. In this endeavour, the availability of qualitative and quantitative microbial assays for various growth factors, which had been or were developed just in those years, became of critical importance. The CoA concentrates contained β-alanine, which pointed to the presence of pantothenic acid [10], and it was shown that the activity of the preparations in the acetylation assay were parallel to the pantothenic acid content. Pantothenic acid, an amide of pantoic acid and β-alanine, had been established as a vitamin in 1938 [11–13]. However, these ingredients could not account for the function of CoA. The crucial observation came via yet another growth factor, namely Snell's Lactobacillus bulgaricus factor, LBF [14]. LBF is the acid amide of pantothenic acid and cysteamin, called pantethein. CoA was shown to be pantethein-4′ phosphate [15]. With a crude liver extract it was possible to synthesize CoA from LBF [16,17]. The substance obtained was able to catalyze the formation of citrate from acetate and oxaloacetic acid with Ochoa's ‘condensing enzyme’[18]. Work on LBF was considered important as it established the presence of cysteamine and, now for the first time, it gave a hint as to a plausible reactive site in the CoA molecule, which had up to this point not been obvious. We must digress here for a moment and mention work that had a considerable bearing on the search for the identity of active acetate. In the late 1930s and early 1940s, Lipmann found with Lactobacillus delbrueckii that oxidation of pyruvate led to the formation of acetylphosphate [19]. Similarly, Barker and Stadtman, in their work with Clostridium kluyveri, had identified acetylphosphate [20], which was involved in performing acetyl- and phosphate-transfer reactions. This was taken as a first hint as to what kind of compound ‘active acetate’ could be. However, as an anhydride of a strong acid with a weaker acid, acetylphosphate was far less stable than the ‘active acetate’ being sought and was unable to act as an acetyl donor for citrate formation or for acetylation of sulfanilamide [7]. However, pantetheine, as an acetylmercaptan, would be more prone to acetylate a suitable substrate, rather than undergo hydrolysis. Thus, the SH-function of CoA, as it had been revealed by the work on LBF, furnished the critical clue to the behaviour observed with the so far hypothetical active acetate. At this point Lynen resumed the studies with starved yeast and obtained concentrates of the substance that was produced in the sparking process, which he expected to be ‘active acetate’. Indeed, all the reactions observed with acetyl-CoA were produced [21]. All these events occurred within a span of at most two years in a breathtaking and often highly competitive race. With acetyl-CoA in hand it was now possible to understand the process of β-oxidation, namely that hydration of the carbon–carbon double bond would follow the dehydrogenation step, with a second oxidation to the keto-form, acetoacetate, and a thiolase to separate the two acetyl CoA residues. The primary oxidizing enzymes, specific for certain carbon chain lengths, or branched chains, all turned out to be flavoproteins without transition-metal constituents [22] and the second oxidizing enzyme, a hydroxy-acid dehydrogenase, was dependent on NAD. Many of these and other enzymes of the pathway have now been crystallized and their structures and mechanisms of action have been determined. The connection of this oxidation system to the respiratory chain, i.e. the cytochrome system, was not clear. It was found in 1954 that, for the oxidation of the flavoproteins of the β-oxidation system, yet another flavoprotein was required, ETF: the ‘electron transfer flavoprotein’. However, this protein would still not communicate with the terminal electron transport system; for this an Fe-S-flavoprotein, ETF-ubiquinone oxidoreductase, was needed, which was only identified in 1975–77 [23].
https://doi.org/10.1046/j.1432-1033.2003.03952.xJournal of Inherited Metabolic Disease · 1990 · 21 citations
Acyl‐CoA oxidase, peroxisomal thiolase and dihydroxyacetone phosphate acyltransferase: Aberrant subcellular localization in Zellweger syndrome
AbstractWe have studied the presence and subcellular localization of peroxisomal 3-oxoacylcoenzyme A thiolase, acylcoenzyme A oxidase and acyl-CoA: dihydroxyacetonephosphate acyltransferase (DHAPAT) in fibroblasts from control subjects and patients with an inherited deficiency of peroxisomes (Zellweger syndrome), using immunofluorescence spectroscopy and density gradient centrifugation techniques. The results show that Zellweger cells contain unprocessed thiolase and unprocessed acyl-CoA oxidase which are associated with structures containing a peroxisomal integral membrane protein of 69 kDa and having a density much lower than that of normal peroxisomes. The residual DHAPAT activity present in Zellweger cells is also contained in these structures. We conclude that these structures represent defectively assembled peroxisomes which may still be capable of importing some peroxisomal proteins.
https://doi.org/10.1007/bf01800588Neurology · 2004 · 21 citations
Reinvestigation of trihydroxycholestanoic acidemia reveals a peroxisome biogenesis disorder
AbstractOBJECTIVE: To determine the enzymatic defect in a patient with ataxia, dysarthric speech, dry skin, hypotonia, and absent reflexes. The patient was previously diagnosed with a presumed deficiency of trihydroxycholestanoyl-CoA oxidase. BACKGROUND: Peroxisomes harbor a variety of metabolic functions, including fatty acid beta-oxidation, etherphospholipid biosynthesis, phytanic acid alpha-oxidation, and L-pipecolic acid oxidation. This patient was previously described with an isolated peroxisomal beta-oxidation defect caused by a deficiency of the enzyme trihydroxycholestanoyl-CoA oxidase. This was based on the pattern of accumulating metabolites. METHODS: Measurement of beta-oxidation enzymes, peroxisomal biochemical analysis in body fluids and cultured skin fibroblasts, and DNA analysis of the PEX12 gene were performed. RESULTS: An isolated beta-oxidation defect in this patient was excluded by measurement of the various beta-oxidation enzymes. The authors found that the patient had a peroxisome biogenesis disorder caused by mutations in the PEX12 gene, although all peroxisomal functions in cultured skin fibroblasts were normal. CONCLUSIONS: The absence of clear peroxisomal abnormalities in the patient's fibroblasts, including a normal peroxisomal localization of catalase, implies that even when all peroxisomal functions in fibroblasts are normal, a peroxisome biogenesis disorder cannot be fully excluded, and further studies may be needed. In addition, the authors' findings imply that there is no longer evidence for the existence of trihydroxycholestanoyl-CoA oxidase deficiency as a distinct disease entity.
https://doi.org/10.1212/01.wnl.0000127576.26352.d1Biochemical Society Transactions · 1989 · 2 citations
Separate peroxisomal oxidases for long-chain acyl-CoA and trihydroxycoprostanoyl-CoA
AbstractConference Article| December 01 1989 Separate peroxisomal oxidases for long-chain acyl-CoA and trihydroxycoprostanoyl-CoA LINDA SCHEPERS; LINDA SCHEPERS *Campus Gasthuisberg-Afdeling Farmakologie, Katolieke Universiteit Leuven, Fakulteit Geneeskunde, Herestraat, B-3000 Leuven Search for other works by this author on: This Site PubMed Google Scholar PAUL P. VAN VELDHOVEN; PAUL P. VAN VELDHOVEN *Campus Gasthuisberg-Afdeling Farmakologie, Katolieke Universiteit Leuven, Fakulteit Geneeskunde, Herestraat, B-3000 Leuven Search for other works by this author on: This Site PubMed Google Scholar HENDRIK J. EYSSEN; HENDRIK J. EYSSEN †Rega Instituut, Afdeling Microbiologie, Minderbroederstraat, B-3000 Leuven, Belgium Search for other works by this author on: This Site PubMed Google Scholar GUY P. MANNAERTS GUY P. MANNAERTS *Campus Gasthuisberg-Afdeling Farmakologie, Katolieke Universiteit Leuven, Fakulteit Geneeskunde, Herestraat, B-3000 Leuven Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (1989) 17 (6): 1076. https://doi.org/10.1042/bst0171076 Article history Received: June 12 1989 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Cite Icon Cite Get Permissions Citation LINDA SCHEPERS, PAUL P. VAN VELDHOVEN, HENDRIK J. EYSSEN, GUY P. MANNAERTS; Separate peroxisomal oxidases for long-chain acyl-CoA and trihydroxycoprostanoyl-CoA. Biochem Soc Trans 1 December 1989; 17 (6): 1076. doi: https://doi.org/10.1042/bst0171076 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search Keywords: ACox, acyl-CoA oxidase, THCCox, trihydroxycoprostanoyl-CoA oxidase © 1989 Biochemical Society1989 Article PDF first page preview Close Modal You do not currently have access to this content.
https://doi.org/10.1042/bst0171076European Journal of Medical Case Reports · 2021 · 0 citations · open access
Peroxisomal acyl CoA oxidase deficiency: a rare inherited disorder of nervous system
AbstractBackground: Peroxisomal acyl CoA oxidase deficiency is a very rare neurodegenerative disorder characterised by postnatal hypotonia, seizures, and neurological regression in early infancy. Case Presentation: Here, we present a case of two children in a family affected with peroxisomal acyl CoA oxidase deficiency. Early onset of hypotonia, seizures, and psychomotor delay was observed in both the sibs. Plasma levels of very long chain fatty acids showed normal levels of phytanic acid, pristanic acid, C22, C24, C26, C26/C22, and C24/C22 ratios. Here, we describe a case where women in her second trimester and with two affected siblings with peroxisomal acyl CoA oxidase deficiency was referred to institute for genetic counselling. Conclusion: Clinical exome analysis of the couple, two affected sibs and the fetus adds new insight into the clinical, neuroradiological, and molecular aspects of this disorder that represents one of the rarer inherited defects of peroxisomal function.
https://doi.org/10.24911/ejmcr/173-1608540583Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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