Metabolic rerouting via SCD1 induction impacts X-linked adrenoleukodystrophy.
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ABSTRACT:
SUBMITTER: Raas Q
PROVIDER: S-EPMC8262477 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:X-linked adrenoleukodystrophy (X-ALD) is an inherited metabolic disorder caused by pathogenic variants in the ABCD1 gene, leading to accumulation of saturated very long chain fatty acids (VLCFA) in body fluids and tissues including brain and spinal cord. In the absence of a clear genotype-phenotype correlation the molecular mechanisms of the fatal cerebral adrenoleukodystrophy (cALD) and the milder adrenomyeloneuropathy (AMN) phenotypes remain unknown. Given our previous evidence of role of astrocytes in the neuroinflammatory response in X-ALD we investigated the metabolic and molecular profiles of astrocytes derived from induced pluripotent stem cells (iPSC). The iPSCs were in turn generated from skin fibroblasts of healthy controls and patients with AMN or cALD. AMN and cALD astrocytes exhibited lack of ABCD1 and accumulation of VLCFA, a biochemical hallmark of X-ALD disease. Accumulation of VLCFA was significantly higher in cALD astrocytes. Mitochondrial function analysis by Seahorse extracellular flux identified increased oxygen consumption and extracellular acidification rates in cALD astrocytes, yet the ATP levels were decreased. Molecular signaling identified increased phosphorylation of STAT3 in cALD astrocytes, and higher proinflammatory cytokine and Toll like receptor (TLR) expression. CRISPR-Cas9 knock-in of functional ABCD1 gene expression differentially affected the expression of key molecular and metabolic targets in AMN and cALD astrocytes. AMN and cALD iPSC-derived astrocytes and their isogenic controls demonstrate differential aspects of X-ALD metabolic and inflammatory response to ABCD1 mutation and can be further utilized for exploring the contribution of iPSC-derived astrocytes to differential X-ALD disease pathology.
| S-EPMC10705002 | biostudies-literature
Project description:X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene and is characterized by impaired beta-oxidation of very-long-chain fatty acids (VLCFA) and subsequent VLCFA accumulation in tissues. In adulthood X-ALD most commonly manifests as a gradually progressive myelopathy, (adrenomyeloneuropathy; AMN) without any curative or disease modifying treatments. We recently showed that bezafibrate (BF), a drug used for the treatment of hyperlipidaemia, reduces VLCFA accumulation in X-ALD fibroblasts by inhibiting ELOVL1, an enzyme involved in the VLCFA synthesis. We therefore designed a proof-of-principal clinical trial to determine whether BF reduces VLCFA levels in plasma and lymphocytes of X-ALD patients. Ten males with AMN were treated with BF for 12 weeks at a dose of 400 mg daily, followed by 12 weeks of 800 mg daily. Every 4 weeks patients were evaluated for side effects and blood samples were taken for analysis. Adherence was good as indicated by a clear reduction in triglycerides. There was no reduction in VLCFA in either plasma or lymphocytes. Plasma levels of BF did not exceed 25 µmol/L. We concluded that BF, at least in the dose given, is unable to lower VLCFA levels in plasma or lymphocytes in X-ALD patients. It is unclear whether this is due to the low levels of BF reached in plasma. Our future work is aimed at the identification of highly-specific inhibitors of ELOVL1 that act at much lower concentrations than BF and are well tolerated. BF appears to have no therapeutic utility in X-ALD.ClinicalTrials.gov NCT01165060.
| S-EPMC3401223 | biostudies-literature
Project description:Currently the molecular basis for the clinical heterogeneity of X-linked adrenoleukodystrophy (X-ALD) is poorly understood. The genetic bases for all different phenotypic variants of X-ALD are mutations in the gene encoding the peroxisomal ATP-binding cassette (ABC) transporter, ABCD1 (formerly adrenoleukodystrophy protein, ALDP). ABCD1 transports CoA-activated very long-chain fatty acids from the cytosol into the peroxisome for degradation. The phenotypic variability is remarkable ranging from cerebral inflammatory demyelination of childhood onset, leading to death within a few years, to adults remaining pre-symptomatic through more than five decades. There is no general genotype-phenotype correlation in X-ALD. The default manifestation of mutations in ABCD1 is adrenomyeloneuropathy, a slowly progressive dying-back axonopathy affecting both ascending and descending spinal cord tracts as well as in some cases, a peripheral neuropathy. In about 60% of male X-ALD patients, either in childhood (35-40%) or in adulthood (20%), an initial, clinically silent, myelin destabilization results in conversion to a devastating, rapidly progressive form of cerebral inflammatory demyelination. Here, ABCD1 remains a susceptibility gene, necessary but not sufficient for inflammatory demyelination to occur. Although the accumulation of very long-chain fatty acids appears to be essential for the pathomechanism of all phenotypes, the molecular mechanisms underlying these phenotypes are fundamentally different. Cell autonomous processes such as oxidative stress and energy shortage in axons as well as non-cell autonomous processes involving axon-glial interactions seem pertinent to the dying-back axonopathy. Various dynamic mechanisms may underlie the initiation of inflammation, the altered immune reactivity, the propagation of inflammation, as well as the mechanisms leading to the arrest of inflammation after hematopoietic stem cell transplantation. An improved understanding of the molecular mechanisms involved in these events is required for the development of urgently needed therapeutics.
| S-EPMC3988840 | biostudies-literature
Project description:X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disorder, is a clinically heterogeneous disease that can manifest as devastating inflammatory cerebral demyelination (CALD) leading to death of affected males. Currently, the only curative treatment is allogeneic hematopoietic stem cell transplantation (HSCT). However, HSCT is only effective when performed at an early stage because the inflammation may progress for eighteen months after HSCT. Thus, alternative treatment options able to immediately halt the progression are urgently needed. X-ALD is caused by mutations in the ABCD1 gene, encoding the peroxisomal membrane protein ABCD1, resulting in impaired very long-chain fatty acid metabolism. The related ABCD2 protein is able to functionally compensate for ABCD1-deficiency both in vitro and in vivo. Recently, we demonstrated that of the cell types derived from CD34+ stem cells, predominantly monocytes but not lymphocytes are metabolically impaired in X-ALD. As ABCD2 is virtually not expressed in these cells, we hypothesize that a pharmacological up-regulation of ABCD2 should compensate metabolically and halt the inflammation in CALD. Retinoids are anti-inflammatory compounds known to act on ABCD2. Here, we investigated the capacity of selected retinoids for ABCD2 induction in human monocytes/macrophages. In THP-1 cells, 13-cis-retinoic acid reached the highest, fivefold, increase in ABCD2 expression. To test the efficacy of retinoids in vivo, we analyzed ABCD2 mRNA levels in blood cells isolated from acne patients receiving 13-cis-retinoic acid therapy. In treated acne patients, ABCD2 mRNA levels were comparable to pre-treatment levels in monocytes and lymphocytes. Nevertheless, when primary monocytes were in vitro differentiated into macrophages and treated with 13-cis-retinoic acid, we observed a fourfold induction of ABCD2. However, the level of ABCD2 induction obtained by retinoids alone is probably not of therapeutic relevance for X-ALD. In conclusion, our results suggest a change in promoter accessibility during macrophage differentiation allowing induction of ABCD2 by retinoids.
| S-EPMC4117577 | biostudies-literature
Project description:X-adrenoleukodystrophy (X-ALD) is a metabolic, peroxisomal disease affecting the nervous system, adrenal cortex and testis resulting from inactivating mutations in ABCD1 gene which encodes a peroxisomal membrane half-adenosine triphosphate (ATP)-binding cassette transporter, ABCD1 (or ALDP), whose defect is associated with impaired peroxisomal beta-oxidation and accumulation of saturated very long-chain fatty acids (VLCFA) in tissues and body fluids. Several phenotypes are recognized in male patients including cerebral ALD in childhood, adolescence or adulthood, adrenomyeloneuropathy (AMN), Addison's disease and, eventually, gonadal insufficiency. Female carriers might present with mild to severe myeloneuropathy that resembles AMN. There is a lack of phenotype-genotype correlations, as the same ABCD1 gene mutation may be associated with different phenotypes in the same family, suggesting that genetic, epigenetic, environmental and stochastic factors are probably contributory to the development and course of the disease. Degenerative changes, like those seen in pure AMN without cerebral demyelination, are characterized by loss of axons and secondary myelin in the long tracts of the spinal cord, possibly related to the impaired lipid metabolism of VLCFAs and the associated alterations (ie, oxidative damage). Similar lesions are encountered following inactivation of ABCD1 in mice (ABCD1(-)). A different and more aggressive phenotype is secondary to cerebral demyelination, very often accompanied by inflammatory changes in the white matter of the brain and associated with activation of T lymphocytes, CD1 presentation and increased levels of cytokines, gamma-interferon, interleukin (IL)-1alpha, IL-2 and IL-6, Granulocyte macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-alpha, chemokines and chemokine receptors.
| S-EPMC8094714 | biostudies-literature
Project description:Males with X-linked adrenoleukodystrophy (ALD) are at high risk for developing adrenal insufficiency and/or progressive leukodystrophy (cerebral ALD) at an early age. Pathogenic variants in ABCD1 result in elevated levels of very long-chain fatty acids (VLCFA), including C26:0-lysophosphatidylcholine (C26:0-LPC). Newborn screening for ALD enables prospective monitoring and timely therapeutic intervention, thereby preventing irreversible damage and saving lives. The Dutch Health Council recommended to screen only male newborns for ALD without identifying untreatable conditions associated with elevated C26:0-LPC, like Zellweger spectrum disorders and single peroxisomal enzyme defects. Here, we present the results of the SCAN (Screening for ALD in the Netherlands) study which is the first sex-specific newborn screening program worldwide. Males with ALD are identified based on elevated C26:0-LPC levels, the presence of one X-chromosome and a variant in ABCD1, in heel prick dried bloodspots. Screening of 71 208 newborns resulted in the identification of four boys with ALD who, following referral to the pediatric neurologist and confirmation of the diagnosis, enrolled in a long-term follow-up program. The results of this pilot show the feasibility of employing a boys-only screening algorithm that identifies males with ALD without identifying untreatable conditions. This approach will be of interest to countries that are considering ALD newborn screening but are reluctant to identify girls with ALD because for girls there is no direct health benefit. We also analyzed whether gestational age, sex, birth weight and age at heel prick blood sampling affect C26:0-LPC concentrations and demonstrate that these covariates have a minimal effect.
| S-EPMC10092852 | biostudies-literature
Project description:ObjectiveWe report a novel presentation of childhood cerebral X-linked adrenoleukodystrophy: status epilepticus followed by abrupt and catastrophic neurologic deterioration.MethodsA description of the clinical presentation, laboratory evaluation, and imaging findings leading to a diagnosis of X-linked adrenoleukodystrophy.ResultsA 3-year-old male with prior history of autism presented with fever, diarrhea, and status epilepticus requiring a pentobarbital coma. Admission labs were notable only for a glucose level of 22 mg/dL, which stabilized after correction. The child never returned to his prior neurologic baseline, with complete loss of gross motor, fine motor, and speech skills. Serial brain magnetic resonance imaging (MRI)/magnetic resonance spectroscopy (MRS) was notable for progressive diffuse cortical signal changes with swelling, diffusion restriction, and ultimately laminar necrosis. Nine months after presentation, CSF (cerebrospinal fluid) protein and MRS lactate were persistently elevated, concerning for a neurodegenerative disorder. This led to testing for mitochondrial disease, followed by lysosomal and peroxisomal disorders. Very long-chain fatty acids were elevated. Identification of a pathogenic ABCD1 mutation confirmed the diagnosis of X-linked adrenoleukodystrophy.ConclusionsBoys with childhood cerebral X-linked adrenoleukodystrophy typically present with gradual behavioral changes. Rare reports of boys presenting with transient altered mental status or status epilepticus describe a recovery to their pre-presentation baseline. To our knowledge this is the first X-ALD patient to present with status epilepticus with abrupt and catastrophic loss of neurologic function. X-linked adrenoleukodystrophy should be suspected in young males presenting with seizures, acute decline in neurologic function, with persistently elevated CSF protein and MRS lactate.
| S-EPMC4582021 | biostudies-literature
Project description:X-linked adrenoleukodystrophy is caused by ATP-binding cassette transporter D1 (ABCD1) mutations and manifests by default as slowly progressive spinal cord axonopathy with associated demyelination (adrenomyloneuropathy). In 60% of male cases, however, X-linked adrenoleukodystrophy converts to devastating cerebral inflammation and demyelination (cerebral adrenoleukodystrophy) with infiltrating blood-derived monocytes and macrophages and cytotoxic T cells that can only be stopped by allogeneic haematopoietic stem cell transplantation or gene therapy at an early stage of the disease. Recently, we identified monocytes/macrophages but not T cells to be severely affected metabolically by ABCD1 deficiency. Here we found by whole transcriptome analysis that, although monocytes of patients with X-linked adrenoleukodystrophy have normal capacity for macrophage differentiation and phagocytosis, they are pro-inflammatory skewed also in patients with adrenomyloneuropathy in the absence of cerebral inflammation. Following lipopolysaccharide activation, the ingestion of myelin debris, normally triggering anti-inflammatory polarization, did not fully reverse the pro-inflammatory status of X-linked adrenoleukodystrophy macrophages. Immunohistochemistry on post-mortem cerebral adrenoleukodystrophy lesions reflected the activation pattern by prominent presence of enlarged lipid-laden macrophages strongly positive for the pro-inflammatory marker co-stimulatory molecule CD86. Comparative analyses of lesions with matching macrophage density in cases of cerebral adrenoleukodystrophy and acute multiple sclerosis showed a similar extent of pro-inflammatory activation but a striking reduction of anti-inflammatory mannose receptor (CD206) and haemoglobin-haptoglobin receptor (CD163) expression on cerebral adrenoleukodystrophy macrophages. Accordingly, ABCD1-deficiency leads to an impaired plasticity of macrophages that is reflected in incomplete establishment of anti-inflammatory responses, thus possibly contributing to the devastating rapidly progressive demyelination in cerebral adrenoleukodystrophy that only in rare cases arrests spontaneously. These findings emphasize monocytes/macrophages as crucial therapeutic targets for preventing or stopping myelin destruction in patients with X-linked adrenoleukodystrophy.
| S-EPMC6061697 | biostudies-literature
Project description:Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder with classical features, which can be also recognised in a low resource setting. It had been described in various populations across the globe, but very few cases have been reported from Africa. In a boy with features of a progressive central nervous system condition and adrenal failure, ABCD1 gene screening was performed based on a clinical history and basic radiological features which were compatible with ALD. A common ABCD1 mutation was identified in this patient, which is the first report of genetically confirmed ALD in Sub-Saharan Africa. ALD is likely under recognised in those areas where there is no neurologist. This genetic confirmation widens geographical distribution of ABCD1-associated disease, and illustrates recognisability of this disorder, even when encountered in a low-resource environment.
| S-EPMC7011349 | biostudies-literature
Project description:Importance:X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal genetic disorder in which an accumulation of very long-chain fatty acids leads to inflammatory demyelination in the central nervous system and to adrenal cortex atrophy. In 2016, X-ALD was added to the US Recommended Uniform Screening Panel. Objective:To evaluate the performance of a single-tier newborn screening assay for X-ALD in North Carolina. Design, Setting, and Participants:This diagnostic screening study was of all newborn dried blood spot specimens received in the North Carolina State Laboratory of Public Health between January 2 and June 1, 2018, excluding specimens of insufficient quantity or quality. A total of 52?301 specimens were screened for X-ALD using negative ionization high-performance liquid chromatography tandem mass spectrometry to measure C24:0- and C26:0-lysophosphatidylcholine concentrations. Sanger sequencing of the adenosine triphosphate-binding cassette subfamily D member 1 (ABCD1) gene was performed on screen-positive specimens. Exposures:A medical and family history, newborn physical examination, sequencing of ABCD1 on dried blood spot samples, and plasma analysis of very long-chain fatty acids were obtained for all infants with screen-positive results. Main Outcomes and Measures:The prevalence of X-ALD in North Carolina and the positive predictive value and false-positive rate for the first-tier assay were determined. Results:Of 52?301 infants tested (47.8% female, 50.6% male, and 1.7% other or unknown sex), 12 received screen-positive results. Of these 12 infants, 8 were confirmed with a genetic disorder: 3 male infants with X-ALD, 3 X-ALD-heterozygous female infants, 1 female infant with a peroxisome biogenesis disorder, and 1 female infant with Aicardi-Goutières syndrome. Four infants were initially classified as having false-positives results, including 3 female infants who were deemed unaffected and 1 male infant with indeterminate results on confirmatory testing. The positive predictive value for X-ALD or other genetic disorders for the first-tier assay was 67%, with a false-positive rate of 0.0057%. Conclusions and Relevance:This newborn screening pilot study reported results on 2 lysophosphatidylcholine analytes, identifying 3 male infants with X-ALD, 3 X-ALD-heterozygous female infants, and 3 infants with other disorders associated with increased very long-chain fatty acids. These results showed successful implementation in a public health program with minimal risk to the population. The findings will support other state laboratories planning to implement newborn screening for X-ALD and related disorders.
| S-EPMC7042889 | biostudies-literature