The Role of Oxidative Stress and Inflammation in X-Link Adrenoleukodystrophy

Yu, Jiayu; Chen, Ting; Guo, Xin; Zafar, Mohammad Ishraq; Li, Huiqing; Wang, Zhihua; Zheng, Juan

doi:10.3389/fnut.2022.864358

Cited by 7 publications

(6 citation statements)

References 132 publications

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“…We further analyzed the possible pathological basis of CCALD triggered by infectious factors. VLCFA-associated oxidative stress in the brain leads to inflammatory demyelination in patients with ABCD1 variations [ 8 , 9 ]. Similarly, after infection, given increased body metabolism, hyperactive mitochondrial metabolism produces more ROS, which may increase white matter susceptibility to oxidative stress [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

Easily misdiagnosed X-linked adrenoleukodystrophy

Wang,

Wang

et al. 2024

Ital J Pediatr

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Background Addison’s disease and X-linked adrenoleukodystrophy (X-ALD) (Addison’s-only) are two diseases that need to be identified. Addison’s disease is easy to diagnose clinically when only skin and mucosal pigmentation symptoms are present. However, X-ALD (Addison’s-only) caused by ABCD1 gene variation is ignored, thus losing the opportunity for early treatment. This study described two patients with initial clinical diagnosis of Addison’s disease. However, they rapidly developed neurological symptoms triggered by infection. After further genetic testing, the two patients were diagnosed with X-ALD. Methods We retrospectively analyzed X-ALD patients admitted to our hospital. Clinical features, laboratory test results, and imaging data were collected. Whole-exome sequencing was used in molecular genetics. Results Two patients were included in this study. Both of them had significantly increased adrenocorticotropic hormone level and skin and mucosal pigmentation. They were initially clinically diagnosed with Addison’s disease and received hydrocortisone treatment. However, both patients developed progressive neurological symptoms following infectious disease. Further brain magnetic resonance imaging was completed, and the results suggested demyelinating lesions. Molecular genetics suggested variations in the ABCD1 gene, which were c.109_110insGCCA (p.C39Pfs*156), c.1394–2 A > C (NM_000033), respectively. Therefore, the two patients were finally diagnosed with X-ALD, whose classification had progressed from X-ALD (Addison’s-only) to childhood cerebral adrenoleukodystrophy (CCALD). Moreover, the infection exacerbates the demyelinating lesions and accelerates the onset of neurological symptoms. Neither the two variation sites in this study had been previously reported, which extends the ABCD1 variation spectrum. Conclusions Patients with only symptoms of adrenal insufficiency cannot be simply clinically diagnosed with Addison’s disease. Being alert to the possibility of ABCD1 variation is necessary, and complete genetic testing is needed as soon as possible to identify X-ALD (Addison’s-only) early to achieve regular monitoring of the disease and receive treatment early. In addition, infection, as a hit factor, may aggravate demyelinating lesions of CCALD. Thus, patients should be protected from external environmental factors to delay the progression of cerebral adrenoleukodystrophy.

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Section: Discussionmentioning

confidence: 99%

Easily misdiagnosed X-linked adrenoleukodystrophy

Wang,

Wang

et al. 2024

Ital J Pediatr

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Section: Discussionmentioning

confidence: 99%

“…Furthermore, patients due to mutations in ABCD1, GALC, IDUA, and ARSA are frequently treated by bone marrow transplant. While this may serve as a functional enzyme replacement therapy, it may also point to immune-specific roles for these metabolic enzymes(Yu et al, 2022). Similarly, IEI patients may have previously undescribed metabolic defects that contribute to mechanisms of immune dysfunction or alter the function of other tissues.…”

Section: Discussionmentioning

confidence: 99%

Functional Overlap of Inborn Errors of Immunity and Metabolism Genes Define T Cell Immunometabolic Vulnerabilities

Patterson

Needle

Sugiura

et al. 2023

Preprint

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Inborn Errors of Metabolism (IEM) and Immunity (IEI) are Mendelian diseases in which complex phenotypes and patient rarity can limit clinical annotations. Few genes are assigned to both IEM and IEI, but immunometabolic demands suggest functional overlap is underestimated. We applied CRISPR screens to test IEM genes for immunologic roles and IEI genes for metabolic effects and found considerable crossover. Analysis of IEM showed N-linked glycosylation and thede novohexosamine synthesis enzyme,Gfpt1, are critical for T cell expansion and function. Interestingly,Gfpt1-deficient TH1 cells were more affected than TH17 cells, which had increasedNagkfor salvage UDP-GlcNAc synthesis. Screening IEI genes showed the transcription factorBcl11bpromotes CD4+ T cell mitochondrial activity andMcl1expression necessary to prevent metabolic stress. These data illustrate a high degree of functional overlap of IEM and IEI genes and point to potential immunometabolic mechanisms for a previously unappreciated set of these disorders.

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“…Since oxysterols can arise from cholesterol through both enzymatic and non-enzymatic reactions, oxidative stress, another aspect of X-ALD pathology [ 68 ], could also play a role in the observed dysregulation of cholesterol homeostasis. Notably, oxysterols are strong activators of LXR, which induces the transcription of target genes involved in cholesterol export, such as ABCA1 and APOE [ 69 ], as well as the acyl-CoA desaturase SCD1, probably also contributing to our finding of increased levels of monounsaturated CE-FAs in X-ALD.…”

Section: Discussionmentioning

confidence: 99%

ABCD1 Transporter Deficiency Results in Altered Cholesterol Homeostasis

Buda,

Forss-Petter,

Hua

et al. 2023

Biomolecules

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X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disorder, is caused by mutations in the peroxisomal transporter ABCD1, resulting in the accumulation of very long-chain fatty acids (VLCFA). Strongly affected cell types, such as oligodendrocytes, adrenocortical cells and macrophages, exhibit high cholesterol turnover. Here, we investigated how ABCD1 deficiency affects cholesterol metabolism in human X-ALD patient-derived fibroblasts and CNS tissues of Abcd1-deficient mice. Lipidome analyses revealed increased levels of cholesterol esters (CE), containing both saturated VLCFA and mono/polyunsaturated (V)LCFA. The elevated CE(26:0) and CE(26:1) levels remained unchanged in LXR agonist-treated Abcd1 KO mice despite reduced total C26:0. Under high-cholesterol loading, gene expression of SOAT1, converting cholesterol to CE and lipid droplet formation were increased in human X-ALD fibroblasts versus healthy control fibroblasts. However, the expression of NCEH1, catalysing CE hydrolysis and the cholesterol transporter ABCA1 and cholesterol efflux were also upregulated. Elevated Soat1 and Abca1 expression and lipid droplet content were confirmed in the spinal cord of X-ALD mice, where expression of the CNS cholesterol transporter Apoe was also elevated. The extent of peroxisome-lipid droplet co-localisation appeared low and was not impaired by ABCD1-deficiency in cholesterol-loaded primary fibroblasts. Finally, addressing steroidogenesis, progesterone-induced cortisol release was amplified in X-ALD fibroblasts. These results link VLCFA to cholesterol homeostasis and justify further consideration of therapeutic approaches towards reducing VLCFA and cholesterol levels in X-ALD.

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The Role of Oxidative Stress and Inflammation in X-Link Adrenoleukodystrophy

Cited by 7 publications

References 132 publications

Easily misdiagnosed X-linked adrenoleukodystrophy

Easily misdiagnosed X-linked adrenoleukodystrophy

Functional Overlap of Inborn Errors of Immunity and Metabolism Genes Define T Cell Immunometabolic Vulnerabilities

ABCD1 Transporter Deficiency Results in Altered Cholesterol Homeostasis

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