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Endocrine Feb 2024X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by the variations in the ATP-binding cassette sub-family D member 1 (ABCD1) gene. This study is...
X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by the variations in the ATP-binding cassette sub-family D member 1 (ABCD1) gene. This study is the first to report central precocious puberty (CPP) in individuals with X-ALD. A 6-year-old boy exhibited mucocutaneous pigmentation, increased plasma adrenocorticotropic hormone levels, and elevated very long-chain fatty acids (VLCFA). We identified a variant, c.1826A>G (p. Glu609Gly), in exon 8 of the ABCD1 gene in the proband. Additionally, he displayed rapid growth, testicular volume of 5-6 mL, the onset of pubic hair, and pubertal levels of luteinizing hormone (LH), all meeting the diagnostic criteria for CPP.
Topics: Male; Humans; Child; Adrenoleukodystrophy; ATP-Binding Cassette Transporters; Puberty, Precocious; Family; Exons; Fatty Acids
PubMed: 37845577
DOI: 10.1007/s12020-023-03562-w -
Cureus Sep 2023Zellweger spectrum disorder (ZSD) is a group of autosomal recessive peroxisomal disorders caused by gene mutations that commonly present with symptoms of severe...
Zellweger spectrum disorder (ZSD) is a group of autosomal recessive peroxisomal disorders caused by gene mutations that commonly present with symptoms of severe hypotonia, epileptic seizures, failure to thrive, hepatomegaly, craniofacial dysmorphisms, and sensorineural hearing loss. This article highlights three patients born with ZSD in Central California. All three patients were born to Mixteco mothers. Patients were genetically analyzed, which revealed mutations that correspond to ZSD. They presented with hypotonia at birth, abnormal hepatic panels, and increased fatty acid levels, findings consistent with Zellweger syndrome (ZS). However, only two of three patients displayed sensorineural hearing loss. Two of the patients failed to survive more than one year of age, which reflects the average life expectancy of an infant presenting with ZS. Observed and recorded cases of ZS in the Mixteco population have been postulated to be related to consanguinity and/or a founder effect. Studies have shown that autosomal recessive diseases are more prevalent in consanguineous populations. Consanguinity has been denied by patient 1 and is unknown for patients 2 and 3. Founder mutations have been implicated in areas with high rates of autosomal recessive diseases. All three of our Mixteco patients share a distinct lineage as well as a mutation at , leading us to believe that they suffered from an inherited founder mutation. The Mixteco population is not studied well enough to come to a definitive conclusion; however, the recognition of the relationship between ZS and Mixteco background is important, as it allows parents to plan accordingly and increases awareness in the community.
PubMed: 37842507
DOI: 10.7759/cureus.45162 -
European Radiology Experimental Oct 2023In adrenoleukodystrophy (ALD), contrast enhancement (CE) is a disease activity marker, but there is uncertainty about the optimal delay, if any, between contrast...
In adrenoleukodystrophy (ALD), contrast enhancement (CE) is a disease activity marker, but there is uncertainty about the optimal delay, if any, between contrast injection and magnetic resonance imaging (MRI) acquisition to avoid false-negative results. We acquired axial two-dimensional (2D) and three-dimensional (3D) T1-weighted gradient-echo every 6 min from 0 to 36 min after contrast administration (gadobutrol 0.1 mmol/kg) in an ALD patient with enlarging white matter lesions and progressive neuropsychological symptoms, using a 3-T magnet. The image signal over time was qualitatively assessed and measured in two regions of interest. On 3D sequences, no definite CE was appreciated, whereas on 2D sequences, CE was noticed after 6 min and definitely evident after 12 min, when 73% of the maximum signal intensity was measured. In ALD subjects, contrast-enhanced 2D T1-weighted gradient-echo sequences acquired at least 10 min after contrast injection may be considered to reduce false negative results.Relevance statementOur report is the first attempt to find an optimal delay between contrast administration and T1-weighted acquisition in cALD patients in order to correctly detect disease activity and avoid false negative results.Key points• The optimal time between contrast injection and image acquisition for MRI of adrenoleukodystrophy is unknown.• Contrast enhancement predicts adrenoleukodystrophy progression and could help patient's selection for the therapy.• We acquired two post-contrast T1-GRE-2D/3D sequences several times to find the best injection-time.• T1-weighted 2D GRE resulted more sensitive than T1-weighted 3D GRE even after long intervals from injection.• A delay of about 10 min may minimize false negatives.
Topics: Humans; Contrast Media; Adrenoleukodystrophy; Magnetic Resonance Imaging
PubMed: 37782421
DOI: 10.1186/s41747-023-00373-6 -
Frontiers in Endocrinology 2023PM can cause adverse health effects via several pathways, such as inducing pulmonary and systemic inflammation, penetration into circulation, and activation of the...
PM can cause adverse health effects via several pathways, such as inducing pulmonary and systemic inflammation, penetration into circulation, and activation of the autonomic nervous system. In particular, the impact of PM exposure on the liver, which plays an important role in metabolism and detoxification to maintain internal environment homeostasis, is getting more attention in recent years. In the present study, C57BL/6J mice were randomly assigned and treated with PM suspension and PBS solution for 8 weeks. Then, hepatic tissue was prepared and identified by metabolomics analysis and transcriptomics analysis. PM exposure can cause extensive metabolic disturbances, particularly in lipid and amino acids metabolic dysregulation.128 differential expression metabolites (DEMs) and 502 differently expressed genes (DEGs) between the PM exposure group and control group were detected. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that DEGs were significantly enriched in two disease pathways, non-alcoholic fatty liver disease (NAFLD) and type II diabetes mellitus (T2DM), and three signaling pathways, which are TGF-beta signaling, AMPK signaling, and mTOR signaling. Besides, further detection of acylcarnitine levels revealed accumulation in liver tissue, which caused restricted lipid consumption. Furthermore, lipid droplet accumulation in the liver was confirmed by Oil Red O staining, suggesting hepatic steatosis. Moreover, the aberrant expression of three key transcription factors revealed the potential regulatory effects in lipid metabolic disorders, the peroxisomal proliferative agent-activated receptors (PPARs) including PPARα and PPARγ is inhibited, and the activated sterol regulator-binding protein 1 (SREBP1) is overexpressed. Our results provide a novel molecular and genetic basis for a better understanding of the mechanisms of PM exposure-induced hepatic metabolic diseases, especially in lipid metabolism.
Topics: Mice; Animals; Diabetes Mellitus, Type 2; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Lipid Metabolism Disorders; Particulate Matter; Lipids
PubMed: 37780625
DOI: 10.3389/fendo.2023.1212291 -
Biomolecules Aug 2023X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disorder, is caused by mutations in the peroxisomal transporter ABCD1, resulting in the accumulation...
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.
Topics: Humans; Mice; Animals; Adrenoleukodystrophy; ATP Binding Cassette Transporter, Subfamily D, Member 1; ATP-Binding Cassette Transporters; Fatty Acids; Homeostasis; Cholesterol
PubMed: 37759733
DOI: 10.3390/biom13091333 -
Nature Communications Sep 2023The double-ring AAA+ ATPase Pex1/Pex6 is required for peroxisomal receptor recycling and is essential for peroxisome formation. Pex1/Pex6 mutations cause severe...
The double-ring AAA+ ATPase Pex1/Pex6 is required for peroxisomal receptor recycling and is essential for peroxisome formation. Pex1/Pex6 mutations cause severe peroxisome associated developmental disorders. Despite its pathophysiological importance, mechanistic details of the heterohexamer are not yet available. Here, we report cryoEM structures of Pex1/Pex6 from Saccharomyces cerevisiae, with an endogenous protein substrate trapped in the central pore of the catalytically active second ring (D2). Pairs of Pex1/Pex6(D2) subdomains engage the substrate via a staircase of pore-1 loops with distinct properties. The first ring (D1) is catalytically inactive but undergoes significant conformational changes resulting in alternate widening and narrowing of its pore. These events are fueled by ATP hydrolysis in the D2 ring and disengagement of a "twin-seam" Pex1/Pex6(D2) heterodimer from the staircase. Mechanical forces are propagated in a unique manner along Pex1/Pex6 interfaces that are not available in homo-oligomeric AAA-ATPases. Our structural analysis reveals the mechanisms of how Pex1 and Pex6 coordinate to achieve substrate translocation.
Topics: ATPases Associated with Diverse Cellular Activities; Cryoelectron Microscopy; Mutation; Peroxisomes; Proton-Translocating ATPases; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Substrate Specificity
PubMed: 37741838
DOI: 10.1038/s41467-023-41640-9 -
Biology Direct Sep 2023Peroxisomes play a central role in tuning metabolic and signaling programs in a tissue- and cell-type-specific manner. However, the mechanisms by which the status of...
Peroxisomes play a central role in tuning metabolic and signaling programs in a tissue- and cell-type-specific manner. However, the mechanisms by which the status of peroxisomes is communicated and integrated into cellular signaling pathways are not yet understood. Herein, we report the cellular responses to peroxisomal proteotoxic stress upon silencing the peroxisomal protease/chaperone LONP2. Depletion of LONP2 triggered the accumulation of its substrate TYSND1 protease, while the overall expression of peroxisomal proteins, as well as TYSND1-dependent ACOX1 processing appeared normal, reflecting early stages of peroxisomal proteotoxic stress. Consequently, the alteration of peroxisome size and numbers, and luminal protein import failure was coupled with induction of cell-specific cellular stress responses. Specific to COS-7 cells was a strong activation of the integrated stress response (ISR) and upregulation of ribosomal biogenesis gene expression levels. Common changes between COS-7 and U2OS cell lines included repression of the retinoic acid signaling pathway and upregulation of sphingolipids. Cholesterol accumulated in the endomembrane compartments in both cell lines, consistent with evidence that peroxisomes are required for cholesterol flux out of late endosomes. These unexpected consequences of peroxisomal stress provide an important insight into our understanding of the tissue-specific responses seen in peroxisomal disorders.
Topics: Signal Transduction; Endosomes; Ribosomes; Peptide Hydrolases; Up-Regulation
PubMed: 37736739
DOI: 10.1186/s13062-023-00416-3 -
JIMD Reports Sep 2023Contiguous / deletion syndrome (CADDS) is a rare deletion syndrome involving two contiguous genes on Xq28, and (formerly known as ). Only nine individuals with this...
Contiguous / deletion syndrome (CADDS) is a rare deletion syndrome involving two contiguous genes on Xq28, and (formerly known as ). Only nine individuals with this diagnosis have been reported in the medical literature to date. Intragenic loss-of-function variants in cause the deafness, dystonia, and cerebral hypomyelination syndrome (DDCH). Isolated pathogenic intragenic variants in are associated with the most common peroxisomal disorder, X-linked adrenoleukodystrophy (X-ALD), a single transporter deficiency, which in its more severe cerebral form is characterised by childhood-onset neurodegeneration and high levels of very-long-chain fatty acids (VLCFA). While increased VLCFA levels also feature in CADDS, the few patients described to date all presented as neonates with a severe phenotype. Here we report a tenth individual with CADDS, a male infant with dysmorphic facial features who was diagnosed through ultra-rapid whole genome sequencing (WGS) in the setting of persistent cholestatic liver disease, sensorineural hearing loss, hypotonia and growth failure and developmental delay. Biochemical studies showed elevated VLCFA and mildly reduced plasmalogens. He died at 7 months having developed pancreatic exocrine deficiency and interstitial lung disease, two features we propose to be possible extensions to the CADDS phenotype. We also review the genetic, phenotypic, and biochemical features in previously reported individuals with CADDS.
PubMed: 37701323
DOI: 10.1002/jmd2.12390 -
Pediatric Rheumatology Online Journal Sep 2023Sweet syndrome (SS), also known as acute febrile neutrophilic dermatosis, is an immunologic syndrome characterized by widespread neutrophilic infiltration. Histiocytoid...
BACKGROUND
Sweet syndrome (SS), also known as acute febrile neutrophilic dermatosis, is an immunologic syndrome characterized by widespread neutrophilic infiltration. Histiocytoid Sweet syndrome (H-SS) is a histopathologic variant of SS. While SS most commonly occurs in adults, this case report discusses an infant patient who presented with H-SS.
CASE PRESENTATION
Through a multidisciplinary approach, this patient was also found to have very early onset inflammatory bowel disease (VEO-IBD) and Mevalonate kinase-associated disease (MKAD). While prior case studies have characterized an association between VEO-IBD and MKAD, there is no literature describing the association of all three diagnoses this case: H-SS, VEO-IBD and MKAD. Initiation of canakinumab in this patient resulted in successful control of the disease.
CONCLUSIONS
This case highlights the importance of a multidisciplinary approach to rare diagnoses, and collaboration during cases with significant diagnostic uncertainty.
Topics: Adult; Humans; Infant, Newborn; Inflammatory Bowel Diseases; Mevalonate Kinase Deficiency; Sweet Syndrome
PubMed: 37700301
DOI: 10.1186/s12969-023-00887-8 -
Bioscience Trends Nov 2023Studies have found that intermittent fasting (IF) can prevent diabetes, cancer, heart disease, and neuropathy, while in humans it has helped to alleviate metabolic...
Studies have found that intermittent fasting (IF) can prevent diabetes, cancer, heart disease, and neuropathy, while in humans it has helped to alleviate metabolic syndrome, asthma, rheumatoid arthritis, Alzheimer's disease, and many other disorders. IF involves a series of coordinated metabolic and hormonal changes to maintain the organism's metabolic balance and cellular homeostasis. More importantly, IF can activate hepatic autophagy, which is important for maintaining cellular homeostasis and energy balance, quality control, cell and tissue remodeling, and defense against extracellular damage and pathogens. IF affects hepatic autophagy through multiple interacting pathways and molecular mechanisms, including adenosine monophosphate (AMP)-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), silent mating-type information regulatory 2 homolog-1 (SIRT1), peroxisomal proliferator-activated receptor alpha (PPARα) and farnesoid X receptor (FXR), as well as signaling pathways and molecular mechanisms such as glucagon and fibroblast growth factor 21 (FGF21). These pathways can stimulate the pro-inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), play a cytoprotective role, downregulate the expression of aging-related molecules, and prevent the development of steatosis-associated liver tumors. By influencing the metabolism of energy and oxygen radicals as well as cellular stress response systems, IF protects hepatocytes from genetic and environmental factors. By activating hepatic autophagy, IF has a potential role in treating a variety of liver diseases, including non-alcoholic fatty liver disease, drug-induced liver injury, viral hepatitis, hepatic fibrosis, and hepatocellular carcinoma. A better understanding of the effects of IF on liver autophagy may lead to new approaches for the prevention and treatment of liver disease.
Topics: Humans; Intermittent Fasting; Liver; Fatty Liver; Hepatocytes; Autophagy
PubMed: 37661370
DOI: 10.5582/bst.2023.01207