RARE DISEASE
Peroxisomal acyl-CoA oxidase deficiency
Peroxisomal acyl-CoA oxidase deficiency
Peroxisomal acyl-CoA oxidase deficiency
Synonyms: Pseudo-NALD, Pseudo-neonatal adrenoleukodystrophy, Pseudoadrenoleukodystrophy
Synonyms: Pseudo-NALD, Pseudo-neonatal adrenoleukodystrophy, Pseudoadrenoleukodystrophy
Synonyms: Pseudo-NALD, Pseudo-neonatal adrenoleukodystrophy, Pseudoadrenoleukodystrophy
Drug discovery
0
drugs
With orphan designations
Overview
Peroxisomal acyl-CoA oxidase deficiency is a rare autosomal recessive neurodegenerative disorder caused by ACOX1 gene mutations, impairing peroxisomal β-oxidation of very-long-chain fatty acids (VLCFAs). Neonatal hypotonia, seizures, and facial dysmorphism are common early signs, followed by neuroregression (1–3 years), hypertonia, seizures, and leukodystrophy. Diagnosis relies on elevated plasma VLCFAs, reduced acyl-CoA oxidase activity, and genetic testing. Prognosis is poor, with most patients succumbing to respiratory failure by ~5 years.
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare transplant-related disorders
Research Papers
100 drug discovery papers about Peroxisomal acyl-CoA oxidase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
100 drug discovery papers about Peroxisomal acyl-CoA oxidase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2025-08-22 | Treatment of Inborn Errors by Product Replacement: The Example of Inborn Errors of Bile Acid Synthesis
Many inborn errors of metabolism affect pathways involved in the synthesis of a metabolite that has an important biochemical or physiological function, and adverse effects of the disorder can be attributed to the lack of this metabolite. Thus, there is the opportunity for treatment by 'product replacement'. One of the disorders in the pathways for the synthesis of bile acids from cholesterol, 3β-hydroxy-Δ5-C27-steroid dehydrogenase deficiency, causes cholestatic liver disease in infancy that can be treated very effectively with chenodeoxycholic acid (CDCA) and/or cholic acid (CA). There are several other enzyme deficiencies that can cause liver disease in infancy that improve with CDCA or CA or both (alongside a reduction of abnormal bile acids or alcohols); however, individuals with the same gene variant(s) may remain asymptomatic or have transient liver dysfunction that resolves spontaneously. In some disorders, the more usual presentation is with neurological disease later in childhood or in adolescence or adult life, for example, cerebrotendinous xanthomatosis (CTX), α-methylacyl-CoA racemase deficiency, and oxysterol 7α-hydroxylase deficiency. Treatment with CDCA has been dramatically effective in the neurological disease of CTX. In the disorders of peroxisome biogenesis, liver disease is a part of the clinical picture although neurological symptoms tend to be predominant. Treatment with CDCA and CA (or CA alone) leads to a reduction in the levels of C27 bile acids. Some trials suggest this treatment leads to significant improvement in clinical status and liver function tests; others do not. Defects in individual peroxisomal enzymes and transporters vary in their clinical presentations. Treatment of acyl-CoA oxidase 2 deficiency with ursodeoxycholic acid is discussed.
2023-11-23 | Efficacy of HDAC Inhibitors in Driving Peroxisomal β-Oxidation and Immune Responses in Human Macrophages: Implications for Neuroinflammatory Disorders
Elevated levels of saturated very long-chain fatty acids (VLCFAs) in cell membranes and secreted lipoparticles have been associated with neurotoxicity and, therefore, require tight regulation. Excessive VLCFAs are imported into peroxisomes for degradation by β-oxidation. Impaired VLCFA catabolism due to primary or secondary peroxisomal alterations is featured in neurodegenerative and neuroinflammatory disorders such as X-linked adrenoleukodystrophy and multiple sclerosis (MS). Here, we identified that healthy human macrophages upregulate the peroxisomal genes involved in β-oxidation during myelin phagocytosis and pro-inflammatory activation, and that this response is impaired in peripheral macrophages and phagocytes in brain white matter lesions in MS patients. The pharmacological targeting of VLCFA metabolism and peroxisomes in innate immune cells could be favorable in the context of neuroinflammation and neurodegeneration. We previously identified the epigenetic histone deacetylase (HDAC) inhibitors entinostat and vorinostat to enhance VLCFA degradation and pro-regenerative macrophage polarization. However, adverse side effects currently limit their use in chronic neuroinflammation. Here, we focused on tefinostat, a monocyte/macrophage-selective HDAC inhibitor that has shown reduced toxicity in clinical trials. By using a gene expression analysis, peroxisomal β-oxidation assay, and live imaging of primary human macrophages, we assessed the efficacy of tefinostat in modulating VLCFA metabolism, phagocytosis, chemotaxis, and immune function. Our results revealed the significant stimulation of VLCFA degradation with the upregulation of genes involved in peroxisomal β-oxidation and interference with immune cell recruitment; however, tefinostat was less potent than the class I HDAC-selective inhibitor entinostat in promoting a regenerative macrophage phenotype. Further research is needed to fully explore the potential of class I HDAC inhibition and downstream targets in the context of neuroinflammation.
2023-05-12 | Peroxisome Deficiency in Cochlear Hair Cells Causes Hearing Loss by Deregulating BK Channels
Abstract The peroxisome is a ubiquitous organelle in rodent cells and plays important roles in a variety of cell types and tissues. It is previously indicated that peroxisomes are associated with auditory function, and patients with peroxisome biogenesis disorders (PBDs) are found to have hearing dysfunction, but the specific role of peroxisomes in hearing remains unclear. In this study, two peroxisome‐deficient mouse models ( Atoh1‐Pex5 −/− and Pax2‐Pex5 −/− ) are established and it is found that peroxisomes mainly function in the hair cells of cochleae. Furthermore, peroxisome deficiency‐mediated negative effects on hearing do not involve mitochondrial dysfunction and oxidative damage. Although the mammalian target of rapamycin complex 1 (mTORC1) signaling is shown to function through peroxisomes, no changes are observed in the mTORC1 signaling in Atoh1‐Pex5 −/‐ mice when compared to wild‐type (WT) mice. However, the expression of large‐conductance, voltage‐, and Ca2 + ‐activated K + (BK) channels is less in Atoh1‐Pex5 −/− mice as compared to the WT mice, and the administration of activators of BK channels (NS‐1619 and NS‐11021) restores the auditory function in knockout mice. These results suggest that peroxisomes play an essential role in cochlear hair cells by regulating BK channels. Hence, BK channels appear as the probable target for treating peroxisome‐related hearing diseases such as PBDs.
2023-01-11 | Two Argan Oil Phytosterols, Schottenol and Spinasterol, Attenuate Oxidative Stress and Restore LPS-Dysregulated Peroxisomal Functions in Acox1−/− and Wild-Type BV-2 Microglial Cells
Oxidative stress and inflammation are the key players in neuroinflammation, in which microglia dysfunction plays a central role. Previous studies suggest that argan oil attenuates oxidative stress, inflammation, and peroxisome dysfunction in mouse brains. In this study, we explored the effects of two major argan oil (AO) phytosterols, Schottenol (Schot) and Spinasterol (Spina), on oxidative stress, inflammation, and peroxisomal dysfunction in two murine microglial BV-2 cell lines, wild-ype (Wt) and Acyl-CoA oxidase 1 (Acox1)-deficient cells challenged with LPS treatment. Herein, we used an MTT test to reveal no cytotoxicity for both phytosterols with concentrations up to 5 µM. In the LPS-activated microglial cells, cotreatment with each of these phytosterols caused a significant decrease in intracellular ROS production and the NO level released in the culture medium. Additionally, Schot and Spina were able to attenuate the LPS-dependent strong induction of Il-1β and Tnf-α mRNA levels, as well as the iNos gene and protein expression in both Wt and Acox1−/− microglial cells. On the other hand, LPS treatment impacted both the peroxisomal antioxidant capacity and the fatty acid oxidation pathway. However, both Schot and Spina treatments enhanced ACOX1 activity in the Wt BV-2 cells and normalized the catalase activity in both Wt and Acox1−/− microglial cells. These data suggest that Schot and Spina can protect cells from oxidative stress and inflammation and their harmful consequences for peroxisomal functions and the homeostasis of microglial cells. Collectively, our work provides a compelling argument for the protective mechanisms of two major argan oil phytosterols against LPS-induced brain neuroinflammation.
2022-12-06 | Catalase-deficient mice induce aging faster through lysosomal dysfunction
Lysosomes are a central hub for cellular metabolism and are involved in the regulation of cell homeostasis through the degradation or recycling of unwanted or dysfunctional organelles through the autophagy pathway. Catalase, a peroxisomal enzyme, plays an important role in cellular antioxidant defense by decomposing hydrogen peroxide into water and oxygen. In accordance with pleiotropic significance, both impaired lysosomes and catalase have been linked to many age-related pathologies with a decline in lifespan. Aging is characterized by progressive accumulation of macromolecular damage and the production of high levels of reactive oxygen species. Although lysosomes degrade the most long-lived proteins and organelles via the autophagic pathway, the role of lysosomes and their effect on catalase during aging is not known. The present study investigated the role of catalase and lysosomal function in catalase-knockout (KO) mice.We performed experiments on WT and catalase KO younger (9 weeks) and mature adult (53 weeks) male mice and Mouse embryonic fibroblasts isolated from WT and KO mice from E13.5 embryos as in vivo and in ex-vivo respectively. Mouse phenotyping studies were performed with controls, and a minimum of two independent experiments were performed with more than five mice in each group.We found that at the age of 53 weeks (mature adult), catalase-KO mice exhibited an aging phenotype faster than wild-type (WT) mice. We also found that mature adult catalase-KO mice induced leaky lysosome by progressive accumulation of lysosomal content, such as cathespin D, into the cytosol. Leaky lysosomes inhibited autophagosome formation and triggered impaired autophagy. The dysregulation of autophagy triggered mTORC1 (mechanistic target of rapamycin complex 1) activation. However, the antioxidant N-acetyl-L-cysteine and mTORC1 inhibitor rapamycin rescued leaky lysosomes and aging phenotypes in catalase-deficient mature adult mice.This study unveils the new role of catalase and its role in lysosomal function during aging. Video abstract.
2025-08-22 | Treatment of Inborn Errors by Product Replacement: The Example of Inborn Errors of Bile Acid Synthesis
Many inborn errors of metabolism affect pathways involved in the synthesis of a metabolite that has an important biochemical or physiological function, and adverse effects of the disorder can be attributed to the lack of this metabolite. Thus, there is the opportunity for treatment by 'product replacement'. One of the disorders in the pathways for the synthesis of bile acids from cholesterol, 3β-hydroxy-Δ5-C27-steroid dehydrogenase deficiency, causes cholestatic liver disease in infancy that can be treated very effectively with chenodeoxycholic acid (CDCA) and/or cholic acid (CA). There are several other enzyme deficiencies that can cause liver disease in infancy that improve with CDCA or CA or both (alongside a reduction of abnormal bile acids or alcohols); however, individuals with the same gene variant(s) may remain asymptomatic or have transient liver dysfunction that resolves spontaneously. In some disorders, the more usual presentation is with neurological disease later in childhood or in adolescence or adult life, for example, cerebrotendinous xanthomatosis (CTX), α-methylacyl-CoA racemase deficiency, and oxysterol 7α-hydroxylase deficiency. Treatment with CDCA has been dramatically effective in the neurological disease of CTX. In the disorders of peroxisome biogenesis, liver disease is a part of the clinical picture although neurological symptoms tend to be predominant. Treatment with CDCA and CA (or CA alone) leads to a reduction in the levels of C27 bile acids. Some trials suggest this treatment leads to significant improvement in clinical status and liver function tests; others do not. Defects in individual peroxisomal enzymes and transporters vary in their clinical presentations. Treatment of acyl-CoA oxidase 2 deficiency with ursodeoxycholic acid is discussed.
2023-11-23 | Efficacy of HDAC Inhibitors in Driving Peroxisomal β-Oxidation and Immune Responses in Human Macrophages: Implications for Neuroinflammatory Disorders
Elevated levels of saturated very long-chain fatty acids (VLCFAs) in cell membranes and secreted lipoparticles have been associated with neurotoxicity and, therefore, require tight regulation. Excessive VLCFAs are imported into peroxisomes for degradation by β-oxidation. Impaired VLCFA catabolism due to primary or secondary peroxisomal alterations is featured in neurodegenerative and neuroinflammatory disorders such as X-linked adrenoleukodystrophy and multiple sclerosis (MS). Here, we identified that healthy human macrophages upregulate the peroxisomal genes involved in β-oxidation during myelin phagocytosis and pro-inflammatory activation, and that this response is impaired in peripheral macrophages and phagocytes in brain white matter lesions in MS patients. The pharmacological targeting of VLCFA metabolism and peroxisomes in innate immune cells could be favorable in the context of neuroinflammation and neurodegeneration. We previously identified the epigenetic histone deacetylase (HDAC) inhibitors entinostat and vorinostat to enhance VLCFA degradation and pro-regenerative macrophage polarization. However, adverse side effects currently limit their use in chronic neuroinflammation. Here, we focused on tefinostat, a monocyte/macrophage-selective HDAC inhibitor that has shown reduced toxicity in clinical trials. By using a gene expression analysis, peroxisomal β-oxidation assay, and live imaging of primary human macrophages, we assessed the efficacy of tefinostat in modulating VLCFA metabolism, phagocytosis, chemotaxis, and immune function. Our results revealed the significant stimulation of VLCFA degradation with the upregulation of genes involved in peroxisomal β-oxidation and interference with immune cell recruitment; however, tefinostat was less potent than the class I HDAC-selective inhibitor entinostat in promoting a regenerative macrophage phenotype. Further research is needed to fully explore the potential of class I HDAC inhibition and downstream targets in the context of neuroinflammation.
2023-05-12 | Peroxisome Deficiency in Cochlear Hair Cells Causes Hearing Loss by Deregulating BK Channels
Abstract The peroxisome is a ubiquitous organelle in rodent cells and plays important roles in a variety of cell types and tissues. It is previously indicated that peroxisomes are associated with auditory function, and patients with peroxisome biogenesis disorders (PBDs) are found to have hearing dysfunction, but the specific role of peroxisomes in hearing remains unclear. In this study, two peroxisome‐deficient mouse models ( Atoh1‐Pex5 −/− and Pax2‐Pex5 −/− ) are established and it is found that peroxisomes mainly function in the hair cells of cochleae. Furthermore, peroxisome deficiency‐mediated negative effects on hearing do not involve mitochondrial dysfunction and oxidative damage. Although the mammalian target of rapamycin complex 1 (mTORC1) signaling is shown to function through peroxisomes, no changes are observed in the mTORC1 signaling in Atoh1‐Pex5 −/‐ mice when compared to wild‐type (WT) mice. However, the expression of large‐conductance, voltage‐, and Ca2 + ‐activated K + (BK) channels is less in Atoh1‐Pex5 −/− mice as compared to the WT mice, and the administration of activators of BK channels (NS‐1619 and NS‐11021) restores the auditory function in knockout mice. These results suggest that peroxisomes play an essential role in cochlear hair cells by regulating BK channels. Hence, BK channels appear as the probable target for treating peroxisome‐related hearing diseases such as PBDs.
2023-01-11 | Two Argan Oil Phytosterols, Schottenol and Spinasterol, Attenuate Oxidative Stress and Restore LPS-Dysregulated Peroxisomal Functions in Acox1−/− and Wild-Type BV-2 Microglial Cells
Oxidative stress and inflammation are the key players in neuroinflammation, in which microglia dysfunction plays a central role. Previous studies suggest that argan oil attenuates oxidative stress, inflammation, and peroxisome dysfunction in mouse brains. In this study, we explored the effects of two major argan oil (AO) phytosterols, Schottenol (Schot) and Spinasterol (Spina), on oxidative stress, inflammation, and peroxisomal dysfunction in two murine microglial BV-2 cell lines, wild-ype (Wt) and Acyl-CoA oxidase 1 (Acox1)-deficient cells challenged with LPS treatment. Herein, we used an MTT test to reveal no cytotoxicity for both phytosterols with concentrations up to 5 µM. In the LPS-activated microglial cells, cotreatment with each of these phytosterols caused a significant decrease in intracellular ROS production and the NO level released in the culture medium. Additionally, Schot and Spina were able to attenuate the LPS-dependent strong induction of Il-1β and Tnf-α mRNA levels, as well as the iNos gene and protein expression in both Wt and Acox1−/− microglial cells. On the other hand, LPS treatment impacted both the peroxisomal antioxidant capacity and the fatty acid oxidation pathway. However, both Schot and Spina treatments enhanced ACOX1 activity in the Wt BV-2 cells and normalized the catalase activity in both Wt and Acox1−/− microglial cells. These data suggest that Schot and Spina can protect cells from oxidative stress and inflammation and their harmful consequences for peroxisomal functions and the homeostasis of microglial cells. Collectively, our work provides a compelling argument for the protective mechanisms of two major argan oil phytosterols against LPS-induced brain neuroinflammation.
2022-12-06 | Catalase-deficient mice induce aging faster through lysosomal dysfunction
Lysosomes are a central hub for cellular metabolism and are involved in the regulation of cell homeostasis through the degradation or recycling of unwanted or dysfunctional organelles through the autophagy pathway. Catalase, a peroxisomal enzyme, plays an important role in cellular antioxidant defense by decomposing hydrogen peroxide into water and oxygen. In accordance with pleiotropic significance, both impaired lysosomes and catalase have been linked to many age-related pathologies with a decline in lifespan. Aging is characterized by progressive accumulation of macromolecular damage and the production of high levels of reactive oxygen species. Although lysosomes degrade the most long-lived proteins and organelles via the autophagic pathway, the role of lysosomes and their effect on catalase during aging is not known. The present study investigated the role of catalase and lysosomal function in catalase-knockout (KO) mice.We performed experiments on WT and catalase KO younger (9 weeks) and mature adult (53 weeks) male mice and Mouse embryonic fibroblasts isolated from WT and KO mice from E13.5 embryos as in vivo and in ex-vivo respectively. Mouse phenotyping studies were performed with controls, and a minimum of two independent experiments were performed with more than five mice in each group.We found that at the age of 53 weeks (mature adult), catalase-KO mice exhibited an aging phenotype faster than wild-type (WT) mice. We also found that mature adult catalase-KO mice induced leaky lysosome by progressive accumulation of lysosomal content, such as cathespin D, into the cytosol. Leaky lysosomes inhibited autophagosome formation and triggered impaired autophagy. The dysregulation of autophagy triggered mTORC1 (mechanistic target of rapamycin complex 1) activation. However, the antioxidant N-acetyl-L-cysteine and mTORC1 inhibitor rapamycin rescued leaky lysosomes and aging phenotypes in catalase-deficient mature adult mice.This study unveils the new role of catalase and its role in lysosomal function during aging. Video abstract.
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