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X-linked adrenoleukodystrophy (X-ALD), caused by an ABCD1 mutation, is a progressive neurodegenerative disorder associated with the accumulation of very long-chain fatty acids (VLCFA). Cerebral inflammatory demyelination is the major feature of childhood cerebral ALD (CCALD), the most severe form of ALD, but its underlying mechanism remains poorly understood. Here, we identify the aberrant production of cholesterol 25-hydroxylase ( CH25H ) and 25-hydroxycholesterol (25-HC) in the cellular context of CCALD based on the analysis of ALD patient-derived induced pluripotent stem cells and ex vivo fibroblasts. Intriguingly, 25-HC, but not VLCFA, promotes robust NLRP3 inflammasome assembly and activation via potassium efflux-, mitochondrial reactive oxygen species (ROS)- and liver X receptor (LXR)-mediated pathways. Furthermore, stereotaxic injection of 25-HC into the corpus callosum of mouse brains induces microglial recruitment, interleukin-1β production, and oligodendrocyte cell death in an NLRP3 inflammasome-dependent manner. Collectively, our results indicate that 25-HC mediates the neuroinflammation of X-ALD via activation of the NLRP3 inflammasome. The mechanism underlying neuroinflammation in X-linked adrenoleukodystrophy (ALD) is poorly understood. Here authors identify aberrant production of 25-hydroxycholesterol (25-HC) in ALD patient-derived cells, and show that 25-HC mediates neuroinflammation via activating the NLRP3 inflammasome.

X-linked Adrenoleukodystrophy (X-ALD) is the most common leukodystrophy and peroxisomal disease with an incidence ranging from 1:15,000-50,000 males [2,3]. X-ALD results from a variety of mutations of the ABCD1 gene (ATP-binding cassette, D1 subtype) in the Xq28 chromosome. For late-onset rarely presentation in adults such as the previously determined that do not shown typical childhood symptoms, later in life present cognitive problems like dementia and behavioral changes. In the genetic analysis, ABCD1 gene exon 1 c,761C>T and p.T254M homozygous were detected. The 47-year-old male patient had a cognitive performance decline that started 12 years ago. Therefore, he began to experience occupational loss. In the following years, gait disorder and vision problems emerged. In the patient's neurological examination, spasticity was detected in the lower extremities. The DTR response was extensor. Visual acuity was significantly impaired and he could count fingers from 1 meter. In the following years, the patient developed mutism and became bedridden as his neurological condition progressed. No significant disorder was detected in the patient's endocrine tests. In the brain MRI, widespread white matter signal change and significant global cortical atrophy were detected. The X-ALD is rarely presents in adults also with a progressive white matter affection and it could be presented differ clinical manifestations such dementia.

X-linked adrenoleukodystrophy (ALD) is a severe brain demyelinating disease in boys that is caused by a deficiency in ALD protein, an adenosine triphosphate-binding cassette transporter encoded by the ABCD1 gene. ALD progression can be halted by allogeneic hematopoietic cell transplantation (HCT). We initiated a gene therapy trial in two ALD patients for whom there were no matched donors. Autologous CD34⁺ cells were removed from the patients, genetically corrected ex vivo with a lentiviral vector encoding wild-type ABCD1, and then re-infused into the patients after they had received myeloablative treatment. Over a span of 24 to 30 months of follow-up, we detected polyclonal reconstitution, with 9 to 14% of granulocytes, monocytes, and T and B lymphocytes expressing the ALD protein. These results strongly suggest that hematopoietic stem cells were transduced in the patients. Beginning 14 to 16 months after infusion of the genetically corrected cells, progressive cerebral demyelination in the two patients stopped, a clinical outcome comparable to that achieved by allogeneic HCT. Thus, lentiviral-mediated gene therapy of hematopoietic stem cells can provide clinical benefits in ALD.

The secretary of the US Department of Health and Human Services in February 2016 recommended that X-linked adrenoleukodystrophy (X-ALD) be added to the recommended uniform screening panel for state newborn screening programs. This decision was informed by data presented on the accuracy of screening from New York, the only state that currently offers X-ALD newborn screening, and published and unpublished data showing health benefits of earlier treatment (hematopoietic stem cell transplantation and adrenal hormone replacement therapy) for the childhood cerebral form of X-ALD. X-ALD newborn screening also identifies individuals with later-onset disease, but poor genotype–phenotype correlation makes predicting health outcomes difficult and might increase the risk of unnecessary treatment. Few data are available regarding the harms of screening and presymptomatic identification. Significant challenges exist for implementing comprehensive X-ALD newborn screening, including incorporation of the test, coordinating follow-up diagnostic and treatment care, and coordination of extended family testing after case identification.

Background Over 80% of women with X-linked adrenoleukodystrophy (ALD) develop spinal cord disease in adulthood for which treatment is supportive only. For future clinical trials quantitative data on disease progression rates are essential. Moreover, diagnosis can be challenging in ALD women, as the most important diagnostic biomarker is normal in 15–20%. Better biomarkers are needed. The purpose of this single centre cross-sectional follow-up study in women with ALD was to assess whether Expanded Disability Status Scale (EDSS), AMC Linear Disability Scale (ALDS) and Short Form (36) Health Survey (SF-36) can detect disease progression and to model the effect of age and duration of symptoms on the rate of progression. Moreover, we performed a pilot study to assess if a semi-targeted lipidomics approach can identify possible new diagnostic biomarkers. Results In this study 46 women (baseline clinical data published by our group previously) were invited for a follow-up visit. Newly identified women at our center were also recruited. We analysed 65 baseline and 34 follow-up assessments. Median time between baseline and follow-up was 7.8 years (range 6.4–8.7). Mean age at baseline was 49.2 ± 14.2 years, at follow-up 55.4 ± 10.1. EDSS increased significantly (+ 0.08 points/year), but the other outcome measures did not. Increasing age and duration of symptoms were associated with more disability. For the pilot study we analysed plasma of 20 ALD women and 10 controls with ultra-high performance liquid chromatography coupled to high-resolution mass spectrometry, which identified 100 potential biomarker ratios with strong differentiating properties and non-overlapping data distributions between ALD women and controls. Conclusions Progression of spinal cord disease can be detected with EDSS, but not with ALDS or SF-36 after a follow-up period of almost 8 years. Moreover, age and the duration of symptoms seem positively associated with the rate of progression. Although a significant progression was measurable, it was below the rate generally conceived as clinically relevant. Therefore, EDSS, ALDS and SF-36 are not suitable as primary outcome measures in clinical trials for spinal cord disease in ALD women. In addition, a semi-targeted lipidomics approach can identify possible new diagnostic biomarkers for women with ALD.

Purpose X-linked adrenoleukodystrophy (XALD) can affect the eyes. Existing therapies are hampered by early quantitative examination methods. This study used an optical coherence tomography angiography system (OCTA) to investigate retinal microvascular density and perfusion in XALD patients. Methods Fifty-two patients and 47 age-matched controls were included in this cross-sectional study. The patients were divided into three groups (symptomatic, less symptomatic, and controls). We compared the foveal avascular zone area, vascular density and perfusion area at the superficial vascular complex (SVC) and deep vascular complex (DVC) of the peripapillary and macular between the groups. We correlated these measurements with scale scores. Results Compared with the controls, the symptomatic group had significantly lower vascular density in the superior nasal sector of the peripapillary SVC (MD − 4.940884; 95% CI − 9.655061 to − 0.226707; p = 0.036), lower vascular density (MD − 4.259225; 95% CI − 8.248627  to  − 0.269823; p = 0.032) and lower perfusion area (MD − 0.180304; 95% CI − 0.337135  to  − 0.023472; p = 0.018) in the peripheral ring superior quadrant of the macular SVC. Compared with the less symptomatic group, the symptomatic group exhibited a significantly lower vascular density (MD − 5.635483; 95% CI − 10.450009  to  − 0.820957; p = 0.015) and perfusion area (MD − 0.063351; 95% CI − 0.116611  to  − 0.010091; p = 0.013) in the superior nasal sector of the peripapillary SVC; lower vascular density (MD − 4.817846; 95% CI − 8.924294  to  − 0.711399; p = 0.015) and perfusion area (MD − 0.202707; 95% CI − 0.369499  to  − 0.035915; p = 0.011) in the peripheral ring superior quadrant of the macular SVC; and greater vascular density (MD 7.209401; 95% CI 0.818716–13.600086; p = 0.021) and perfusion area (MD 0.047320; 95% CI 0.001685–0.092956; p = 0.039) in the inferior nasal sector of the peripapillary DVC. Among the 52 patients, the expanded disability status score (EDSS) was moderately negatively correlated with the vascular density (p = 0.001) and perfusion area (p = 0.002) in the peripheral ring superior quadrant of the macular SVC. Conclusion Changes in retinal vascular density and perfusion exist in XALD patients and are correlated with disease severity. OCTA has the potential to monitor the progression of XALD.

Background Adrenoleukodystrophy (ALD) is a rare X-linked genetic metabolic disorder characterized by the accumulation of very long chain fatty acids (VLCFA) within the adrenal glands, as well as the central and peripheral nervous systems. Adult-onset ALD is particularly uncommon and easily misdiagnosed. The objective of this study is to facilitate the early diagnosis and treatment of adult-onset ALD. Case presentation Seven adult-onset ALD patients of Chinese descent were enrolled in the study. Detailed clinical characteristics, laboratory results, imaging findings and genetic testing of the patients were collected and analyzed. All seven patients diagnosed with adult-onset ALD were male, including two with adult cerebral ALD (ACALD), one with adrenomyeloneuropathy (AMN), and four presenting with the spinocerebellar variant. The primary clinical manifestations of the two ACALD patients were progressive cognitive dysfunction and psychiatric symptoms. The AMN patient showed chronic progressive spastic paraplegia and displayed non-specific thoracic spinal cord atrophy on MRI. Symptoms observed in the four patients with spinocerebellar variant included cerebellar ataxia, dysarthria, spastic paraplegia, peripheral neuropathy, sphincter dysfunction, and alopecia. These four patients all demonstrated symmetrical white matter hyperintensity (WMH) in the cerebellum on brain magnetic resonance imaging (MRI). Additionally, two of these patients exhibited abnormal MRI signals in the pyramidal tract. All the patients had an elevation of VLCFAs, which is diagnostic for ALD. One patient exhibited elevated adrenocorticotropic hormone (ACTH) and decreased cortisol levels, while six patients displayed slightly elevated ACTH levels and normal cortisol levels without any clinical signs of adrenal insufficiency. Genetic testing identified four known ABCD1 pathogenic variants as well as two novel pathogenic variants. Conclusions Progressive cognitive impairment and behavioral abnormalities are common clinical manifestations of ACALD. AMN and the spinocerebellar variant are prevalent phenotypes of adult-onset ALD. Patients with adult-onset ALD may present with isolated WMH in the cerebellum on brain MRI. Routine screening for ALD should be conducted in male patients diagnosed with Addison’s disease. Subclinical adrenal cortex insufficiency is a common finding in adult-onset ALD. Elevated levels of VLCFA function as a reliable clinical biomarker for ALD. The identification of novel pathogenic variants in ABCD1 broadens the genetic spectrum of ALD.

X-adrenoleukodystrophy (X-ALD) is a peroxisomal metabolic disorder caused by mutations in the ABCD1 gene encoding the peroxisomal ABC transporter adrenoleukodystrophy protein (ALDP). Similar mutations in ABCD1 may result in a spectrum of phenotypes in males with slow progressing adrenomyeloneuropathy (AMN) and fatal cerebral adrenoleukodystrophy (cALD) dominating most cases. Mouse models of X-ALD do not capture the phenotype differences and an appropriate model to investigate the mechanism of disease onset and progress remains a critical need. Here, we generated induced pluripotent stem cell (iPSC) lines from skin fibroblasts of two each of apparently healthy control, AMN, and cALD patients with non-integrating mRNA-based reprogramming. iPSC lines expanded normally and expressed pluripotency markers Oct4, SOX2, NANOG, SSEA, and TRA-1–60. Expression of markers SOX17, Brachyury, Desmin, OXT2, and beta tubulin III demonstrated the ability of the iPSCs to differentiate into all three germ layers. iPSC-derived lines from CTL, AMN, and cALD male patients were differentiated into astrocytes. Differentiated AMN and cALD astrocytes lacked ABCD1 expression and accumulated saturated very long chain fatty acids (VLCFAs), a hallmark of X-ALD, and demonstrated differential mitochondrial bioenergetics, cytokine gene expression, and differences in STAT3 and AMPK signaling between AMN and cALD astrocytes. These patient astrocytes provide disease-relevant tools to investigate the mechanism of differential neuroinflammatory response in X-ALD and will be valuable cell models for testing new therapeutics.

Background: X-ALD is a white matter (WM) disease caused by mutations in the ABCD1 gene encoding the transporter of very-long-chain fatty acids (VLCFAs) into peroxisomes. Strikingly, the same ABCD1 mutation causes either devastating brain inflammatory demyelination during childhood or, more often, progressive spinal cord axonopathy starting in middle-aged adults. The accumulation of undegraded VLCFA in glial cell membranes and myelin has long been thought to be the central mechanism of X-ALD. Methods: This review discusses studies in mouse and drosophila models that have modified our views of X-ALD pathogenesis. Results: In the Abcd1 knockout (KO) mouse that mimics the spinal cord disease, the late manifestations of axonopathy are rapidly reversed by ABCD1 gene transfer into spinal cord oligodendrocytes (OLs). In a peroxin-5 KO mouse model, the selective impairment of peroxisomal biogenesis in OLs achieves an almost perfect phenocopy of cerebral ALD. A drosophila knockout model revealed that VLCFA accumulation in glial myelinating cells causes the production of a toxic lipid able to poison axons and activate inflammatory cells. Other mouse models showed the critical role of OLs in providing energy substrates to axons. In addition, studies on microglial changing substates have improved our understanding of neuroinflammation. Conclusions: Animal models supporting a primary role of OLs and axonal pathology and a secondary role of microglia allow us to revisit of X-ALD mechanisms. Beyond ABCD1 mutations, pathogenesis depends on unidentified contributors, such as genetic background, cell-specific epigenomics, potential environmental triggers, and stochasticity of crosstalk between multiple cell types among billions of glial cells and neurons.

Background Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder. Its cerebral form presents as a learning and behavioral disorder that, if untreated, leads to rapid neurological regression, disability, and death within 10 years of diagnosis. Therefore, the disease significantly impacts patients’ quality of life, making quality of life assessment crucial for effective medical treatment and care. However, no disease-specific quality of life scale exists for ALD. Therefore, we conducted qualitative research to determine the experiences of patients and their families as a preliminary step toward developing one. Results Four mothers of patients with cerebral ALD were interviewed. Based on classification using the qualitative content analysis method, the verbatim transcripts were grouped into four themes: support needs for patients, support needs for families, the impact of treatment, and challenges within support systems. Conclusions Support for patients and family members is required after ALD is diagnosed. In addition to addressing symptoms, daily life support and caregiving burden should be considered. Furthermore, several challenges and opportunities exist for improving treatment and support systems. Therefore, combining appropriate supporters and support systems according to the progressive and hereditary characteristics of ALD is crucial.