The Inflammatory Response in Acyl-CoA Oxidase 1 Deficiency (Pseudoneonatal Adrenoleukodystrophy)

Hajj, Hammam I. El; Vluggens, Aurore; Andreoletti, Pierre; Ragot, Kévin; Mandard, Stéphane; Kersten, Sander; Waterham, Hans R.; Lizard, Gérard; Wanders, Ronald J. A.; Reddy, Janardan K.; Cherkaoui‐Malki, Mustapha

doi:10.1210/en.2012-1137

Cited by 43 publications

(39 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since we demonstrated that ACOX1-deficient neural stem cells from patient 1 accumulate VLCFA, it is consistent with the observation that VLCFA has toxic and pro-inflammatory effects on neurons, leading to progressive gray matter atrophy and secondary demyelination (Hein et al 2008; El Hajj et al 2012). In summary, each patient reported herein provides unique insight into the nature of ACOX1 deficiency.…”

Section: Discussionsupporting

confidence: 89%

Effects of hematopoietic stem cell transplantation on acyl‐CoA oxidase deficiency: a sibling comparison study

Wang

Monuki

Powers

et al. 2014

J of Inher Metab Disea

View full text Add to dashboard Cite

Objective Acyl-CoA oxidase (ACOX1) deficiency is a rare disorder of peroxisomal very-long chain fatty acid oxidation. No reports detailing attempted treatment, longitudinal imaging, or neuropathology exist. We describe the natural history of clinical symptoms and brain imaging in two siblings with ACOX1 deficiency, including the younger sibling's response to allogeneic unrelated donor hematopoietic stem cell transplantation (HSCT). Methods We conducted retrospective chart review to obtain clinical history, neuro-imaging, and neuropathology data. ACOX1 genotyping were performed to confirm the disease. In vitro fibroblast and neural stem cell fatty acid oxidation assays were also performed. Results Both patients experienced a fatal neurodegenerative course, with late-stage cerebellar and cerebral gray matter atrophy. Serial brain magnetic resonance imaging in the younger sibling indicated demyelination began in the medulla and progressed rostrally to include the white matter of the cerebellum, pons, midbrain, and eventually subcortical white matter. The successfully engrafted younger sibling had less brain inflammation, cortical atrophy, and neuronal loss on neuroimaging and neuropathology compared to the untreated older sister. Fibroblasts and stem cells demonstrated deficient very long chain fatty acid oxidation. Interpretation Although HSCT did not halt the course of ACOX1 deficiency, it reduced the extent of white matter inflammation in the brain. Demyelination continued because of ongoing neuronal loss, which may be due to inability of transplant to prevent progression of gray matter disease, adverse effects of chronic corticosteroid use to control graft-versus-host disease, or intervention occurring beyond a critical point for therapeutic efficacy.

show abstract

Section: Discussionsupporting

confidence: 89%

Effects of hematopoietic stem cell transplantation on acyl‐CoA oxidase deficiency: a sibling comparison study

Wang

Monuki

Powers

et al. 2014

J of Inher Metab Disea

View full text Add to dashboard Cite

show abstract

“…The genes ACOX1 (the acyl-coenzyme A oxidase 1) and UNC13D (Caenorhabditis elegans unc-13 homolog D) play a key role in the metabolism of very long chain fatty acids and vesicle maturation. A deficiency in these genes leads to pseudoneonatal adrenoleukodystrophy, a rare neurological disorder characterized by the accumulation of very long chain fatty acids, neurological deterioration, diffuse leukodystrophy with progressive demyelination, brain atrophy and severe white matter abnormalities (Fournier et al, 1994;El Hajj et al, 2012), and familial hemophagocytic lymphohistiocytosis type 3 (FHLH-3), a rare and genetically heterogeneous disorder with an autosomal recessive inheritance characterized by uncontrolled proliferation, infiltration of activated lymphocytes and macrophages, overproduction of inflammatory cytokines and immune dysregulation from the defective function of cytotoxic lymphocytes, and abnormal imaging of the brain white matter (Fitzgerald and MacClain, 2003;Yoon et al, 2010).…”

Section: Genome-wide Association Studymentioning

confidence: 99%

Genetic associations of leukoaraiosis indicate pathophysiological mechanisms in white matter lesions etiology

Lin¹,

Huang

Tzeng

2015

Reviews in the Neurosciences

View full text Add to dashboard Cite

AbstractLeukoaraiosis (LA), also called white matter lesions (WMLs) and white matter hyperintensities (WMHs), is a frequent neuroimaging finding commonly seen on magnetic resonance imaging brain scans of elderly people with prevalence ranging from 50% to 100%. Although it remains asymptomatic, LA is not considered to be benign, and it is showed to be related to a host of poor clinical outcomes and increases the risk of disability, dementia, depression, stroke, and the overall morbidity and mortality. Pathologically, LA is characterized by loss of myelin and axons, patchy demyelination, and denudation of ependyma in regions of WMH. Age and hypertension are the most importantly established risk factors for LA. However, the precise pathogenic mechanisms remain unclear. Together with the previous findings, our recent genetic results strongly supported that LA is associated with immune response and neuroinflammation. Therefore, we confidently hypothesized that LA was not only a common neuroimaging phenomenon in the elderly but also an emerging neuroinflammatory disorder in the central nervous system. This article focusing on neuroimaging classification, genetics basis, and putative molecular mechanism introduced the basic knowledge and current status of LA and put forward some of our research ideas and results from our molecular genetics research, which may pave the way for deciphering the putative pathogenic mechanism, risk factor, epigenetic index, and its application in diagnostic agents or drug target for prevention and treatment. Thus, it could provide clinicians and researchers with a specific and modern overview of LA to enable the understanding of recent progress and future directions in this illness.

show abstract

“…It has indeed been suggested that VLCFA accumulation, a typical hallmark of peroxisomal β ‐oxidation disorders such as X‐linked ALD, might trigger an inflammatory cascade in immune cells that can subsequently lead to the neuroinflammatory disease seen in disorders such as cerebellar ALD. Several studies have indeed reported that abnormal VLCFA accumulation could increase inflammatory activation of murine astrocytes, peritoneal macrophages, human fibroblasts and mononuclear cells . In murine astrocytes, silencing of Abcd1 and Abcd2 , two peroxisomal transporters involved in shuttling substrates into peroxisomes, leads to a threefold increase of C26:0 together with activation of nuclear factor‐ κ B, activator protein‐1 and CCAAT‐enhancer‐binding protein and increased production of inflammatory cytokines such as TNF‐ α and IL‐1 β .…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have indeed reported that abnormal VLCFA accumulation could increase inflammatory activation of murine astrocytes, peritoneal macrophages, human fibroblasts and mononuclear cells. [37][38][39][40] In murine astrocytes, silencing of Abcd1 and Abcd2, two peroxisomal transporters involved in shuttling substrates into peroxisomes, leads to a threefold increase of C26:0 together with activation of nuclear factor-jB, activator protein-1 and CCAAT-enhancer-binding protein and increased production of inflammatory cytokines such as TNF-a and IL-1b. 38,50,51 Treatment of Abcd1/2 silenced astrocytes with a mixture of oleic acid/erucic acid (Lorenzo's Oil) not only normalizes VLCFA levels but also significantly reduces the production of inflammatory cytokines, suggesting that VLCFA accumulation is indeed underlying the inflammatory activation of peroxisomal boxidation deficient astrocytes.…”

Section: Discussionmentioning

confidence: 99%

“…It has been proposed that accumulation of VLCFA might enhance inflammatory signalling in diverse cell types. [37][38][39][40] To investigate whether the accumulation of VLCFA in different lipid species affects classical and alternative polarization in BMDM Mfp2 À/À macrophages, we first measured gene expression of a panel of inflammatory genes, including cytokines (Tnf, Il1b, Il1a, Il6, Il12a, Il12b) and chemokines (Cxcl1, Cxcl2, Ccl3, Ccl5, Ccl8) after classical activation with LPS/IFN-c. The gene expression of inflammatory cytokines and chemokines as well as their production, was low or below the detection limit in basal state both in control and Mfp2 À/À macrophages (Fig.…”

Section: Mfp2-deficient Bmdm Have Reduced Inflammatory Cytokine Produmentioning

confidence: 99%

See 1 more Smart Citation

Lipid homeostasis and inflammatory activation are disturbed in classically activated macrophages with peroxisomal β‐oxidation deficiency

et al. 2017

View full text Add to dashboard Cite

Macrophage activation is characterized by pronounced metabolic adaptation. Classically activated macrophages show decreased rates of mitochondrial fatty acid oxidation and oxidative phosphorylation and acquire a glycolytic state together with their pro-inflammatory phenotype. In contrast, alternatively activated macrophages require oxidative phosphorylation and mitochondrial fatty acid oxidation for their anti-inflammatory function. Although it is evident that mitochondrial metabolism is regulated during macrophage polarization and essential for macrophage function, little is known on the regulation and role of peroxisomal β-oxidation during macrophage activation. In this study, we show that peroxisomal β-oxidation is strongly decreased in classically activated bone-marrow-derived macrophages (BMDM) and mildly induced in alternatively activated BMDM. To examine the role of peroxisomal β-oxidation in macrophages, we used Mfp2 BMDM lacking the key enzyme of this pathway. Impairment of peroxisomal β-oxidation in Mfp2 BMDM did not cause lipid accumulation but rather an altered distribution of lipid species with very-long-chain fatty acids accumulating in the triglyceride and phospholipid fraction. These lipid alterations in Mfp2 macrophages led to decreased inflammatory activation of Mfp2 BMDM and peritoneal macrophages evidenced by impaired production of several inflammatory cytokines and chemokines, but did not affect anti-inflammatory polarization. The disturbed inflammatory responses of Mfp2 macrophages did not affect immune cell infiltration, as mice with selective elimination of MFP2 from myeloid cells showed normal monocyte and neutrophil influx upon challenge with zymosan. Together, these data demonstrate that peroxisomal β-oxidation is involved in fine-tuning the phenotype of macrophages, probably by influencing the dynamic lipid profile during macrophage polarization.

show abstract

The Inflammatory Response in Acyl-CoA Oxidase 1 Deficiency (Pseudoneonatal Adrenoleukodystrophy)

Cited by 43 publications

References 46 publications

Effects of hematopoietic stem cell transplantation on acyl‐CoA oxidase deficiency: a sibling comparison study

Effects of hematopoietic stem cell transplantation on acyl‐CoA oxidase deficiency: a sibling comparison study

Genetic associations of leukoaraiosis indicate pathophysiological mechanisms in white matter lesions etiology

Lipid homeostasis and inflammatory activation are disturbed in classically activated macrophages with peroxisomal β‐oxidation deficiency

Contact Info

Product

Resources

About