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Experimental Gerontology Oct 2023Progressive bone marrow (BM) fat accumulation is a common bone loss characteristic in older populations and glucocorticoid (GC)-induced skeletal destruction that is...
Progressive bone marrow (BM) fat accumulation is a common bone loss characteristic in older populations and glucocorticoid (GC)-induced skeletal destruction that is inversely associated with bone synthesis and directly associated with increased peroxisomal proliferator-activated receptor gamma (PPARγ) expression. PPARγ inhibition is an efficient therapeutic strategy for aged- and GC-related skeletal disorders. This study aimed to evaluate the effect of PPARγ inhibition on aged GC-treated female rats. It was hypothesised that bisphenol A diglycidyl ether (BADGE) could inhibit marrow adiposity and improve osteogenesis by inhibiting PPARγ, thereby preventing GC-induced osteoporosis (GIO). Female Sprague-Dawley rats (n = 32, age = 18 months) were randomly allocated to one of the following groups: (1) control, (2) BADGE (30 mg/kg/day, intraperitoneal), (3) methylprednisolone (MP; 30 mg/kg/day, subcutaneous), and (4) MP + BADGE. After eight weeks of treatment, bone density (BD) and trabecular bone microarchitectures were quantified by micro-computed tomography (CT), and BM adipocytes were quantified by histopathology. Additionally, mRNA and protein expression of adipogenic and osteogenic markers were quantified by reverse transcription-quantitative polymerase chain reaction. Furthermore, serum bone turnover biomarker levels were quantified by enzyme-linked immunosorbent assay. MP treatment led to marrow adipogenesis and bone deterioration. However, rats treated with MP + BADGE showed lower marrow adipogenesis, as indicated by smaller marrow adipocyte diameter, decreased density and area percentages, reduced expression of marrow adipogenic genes and proteins, improved BD and trabecular microarchitectures, increased expression of osteogenic genes and proteins, and higher levels of serum bone formation markers. These results were consistent with the differences observed between control and BADGE mono-treated rats. In conclusion, BADGE treatment attenuates BM adiposity and improves bone formation in aged GC-treated female rats by inhibiting PPARγ. Therefore, PPARγ might be a potential target for treating GIO in older populations.
Topics: Female; Rats; Animals; Bone Marrow; Glucocorticoids; PPAR gamma; X-Ray Microtomography; Rats, Sprague-Dawley; Bone and Bones
PubMed: 37659742
DOI: 10.1016/j.exger.2023.112281 -
Environment International Aug 2023Per- and polyfluoroalkyl substances (PFAS) are persistent and ubiquitous environmental contaminants with well-documented hepatotoxicity. However, the mechanistic linkage...
BACKGROUND
Per- and polyfluoroalkyl substances (PFAS) are persistent and ubiquitous environmental contaminants with well-documented hepatotoxicity. However, the mechanistic linkage between PFAS exposure and non-alcoholic fatty liver disease (NAFLD) remains largely elusive.
OBJECTIVES
This study aimed to explore PFAS-to-NAFLD link and the relevant molecular mechanisms.
METHODS
The cross-sectional analyses using National Health and Nutrition Examination Survey (NHANES) data were conducted to investigate the association between PFAS exposure and NAFLD. A combination of in silico toxicological analyses, bioinformatics approaches, animal experiments, and in vitro assays was used to explore the molecular initiating events (MIEs) and key events (KEs) in PFAS-induced hepatic lipid metabolism disorders.
RESULTS
The cross-sectional analyses with NHANES data revealed the significant association between PFAS exposure and hepatic steatosis/NAFLD. The in silico toxicological analyses showed that PPARα activation induced by perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), prototypical representatives of PFAS, is the critical MIE associated with NAFLD-predominant liver diseases. Transcriptome-based bioinformatic annotation and analyses identified that transcriptional upregulation of hepatic acyl-CoA oxidase 1 (ACOX1) in PPARα-regulated peroxisomal β-oxidation pathway was the KE involved with PFOA/PFOS-perturbed hepatic lipid metabolic pathways in humans, mice and rats. The in vivo and in vitro assays further verified that ACOX1-mediated oxidative stress contributed to mitochondrial compromise and lipid accumulation in PFOA/PFOS-exposed mouse hepatocytes, which could be mitigated by co-treatment with ACOX1 inhibitor and mitochondria ROS scavenger. Additionally, we observed that besides PFOA and PFOS, hepatic ACOX1 exhibited good-fit response to short-term exposures of long-chain (C7-C10) perfluoroalkyl carboxylic acids (PFHpA, PFNA, PFDA) and perfluoroalkyl sulfonic acids (PFHpS, PFDS) in human hepatocyte spheroids through benchmark dose (BMD) modeling.
CONCLUSION
Our study unveils a novel molecular target for PFAS-induced hepatic lipid metabolic disorders, shedding new light on prediction, assessment, and mitigation of PFAS hepatotoxicity.
Topics: Humans; Mice; Rats; Animals; Non-alcoholic Fatty Liver Disease; PPAR alpha; Nutrition Surveys; Lipid Metabolism; Cross-Sectional Studies; Alkanesulfonic Acids; Caprylates; Lipid Metabolism Disorders; Fluorocarbons; Chemical and Drug Induced Liver Injury; Environmental Pollutants
PubMed: 37572494
DOI: 10.1016/j.envint.2023.108138 -
Orphanet Journal of Rare Diseases Aug 2023X-linked adrenoleukodystrophy (ALD) is a rare metabolic and neurodegenerative disorder belonging to the group of leukodystrophies, with an estimated incidence around...
BACKGROUND
X-linked adrenoleukodystrophy (ALD) is a rare metabolic and neurodegenerative disorder belonging to the group of leukodystrophies, with an estimated incidence around 1:25 000 newborns worldwide, mostly among men. Childhood Cerebral ALD (CCALD) is the most severe form with a poor prognosis if not properly treated during the first years of life. Currently, only allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely available for CCALD treatment. To date, there is a lack of data regarding CCALD epidemiology, natural history, and current management in France. This knowledge is crucial for the development of new therapies such as gene therapies. In this context, the French National Health Data System (SNDS) is a particularly indicated database to collect information meeting these needs. A non-interventional, national, real-life, retrospective study was performed using secondary data from the national ALD registry (LEUKOFRANCE) and SNDS. CCALD patients detected between 2009 and 2018 and successfully matched between LEUKOFRANCE and SNDS were included in this study. Index date was defined as the first CCALD event detected during study period. Subgroups of patients with sufficient follow-up (6 months) and history (1 year) available around index date were analyzed to assess CCALD burden and natural history.
RESULTS
52 patients were included into the matched cohort. Median annual incidence of CCALD was estimated at 4 patients. Median age at CCALD diagnosis was 7.0 years. Among patients without allo-HSCT, five-year overall survival was 66.6%, with 93.3% of them presenting at least one CCALD symptom and 62.1% presenting a least one major functional disability (MFD). Among patients with allo-HSCT, five-year overall survival was 94.4%, with only 11.1% of patients presenting CCALD symptoms, and 16.7% of presenting a MFD. Mean annualized costs were almost twice as important among patients without allo-HSCT, with 49,211€, 23,117€, respectively. Costs were almost exclusively represented by hospitalizations.
CONCLUSIONS
To the best of our knowledge, this is the most up to date study analyzing CCALD epidemiology, clinical and economic burden in France. The necessity of a precocious management with HSCT highlight the potential benefits of including an expanded screening program among newborns, coupled with family screenings when a mutation is detected.
Topics: Male; Humans; Child; Infant, Newborn; Adrenoleukodystrophy; Retrospective Studies; Hematopoietic Stem Cell Transplantation; France; Cost of Illness
PubMed: 37563635
DOI: 10.1186/s13023-023-02843-x -
Internal Medicine (Tokyo, Japan) Apr 2024Adrenomyeloneuropathy (AMN)/adrenoleukodystrophy (ALD) is an X-linked genetic disorder caused by pathogenic variants in ABCD1. We treated a 54-year-old man with slowly...
Adrenomyeloneuropathy (AMN)/adrenoleukodystrophy (ALD) is an X-linked genetic disorder caused by pathogenic variants in ABCD1. We treated a 54-year-old man with slowly progressive spastic paraparesis with later development of the cerebral form. A pathogenic splice-site variant of ABCD1 (c.1489-1G>A, p.Val497Alafs*51) and elevated levels of very long-chain fatty acids were found, leading to the diagnosis of AMN. Detailed ABCD1 mRNA expression analyses revealed decreased levels of ABCD1 mRNA accompanied by deletion of the first 31 bp in exon 6. The altered mRNA transcriptional patterns associated with splice site variants are diverse and may provide important insights into ALD pathogenesis.
Topics: Male; Humans; Middle Aged; Adrenoleukodystrophy; Pedigree; RNA, Messenger; ATP Binding Cassette Transporter, Subfamily D, Member 1
PubMed: 37558478
DOI: 10.2169/internalmedicine.2240-23 -
Genetics in Medicine : Official Journal... Nov 2023Zellweger spectrum disorders (ZSDs) are known as autosomal recessive disorders caused by defective peroxisome biogenesis due to bi-allelic pathogenic variants in any of...
PURPOSE
Zellweger spectrum disorders (ZSDs) are known as autosomal recessive disorders caused by defective peroxisome biogenesis due to bi-allelic pathogenic variants in any of at least 13 different PEX genes. Here, we report 2 unrelated patients who present with an autosomal dominant ZSD.
METHODS
We performed biochemical and genetic studies in blood and skin fibroblasts of the patients and demonstrated the pathogenicity of the identified PEX14 variants by functional cell studies.
RESULTS
We identified 2 different single heterozygous de novo variants in the PEX14 genes of 2 patients diagnosed with ZSD. Both variants cause messenger RNA mis-splicing, leading to stable expression of similar C-terminally truncated PEX14 proteins. Functional studies indicated that the truncated PEX14 proteins lost their function in peroxisomal matrix protein import and cause increased degradation of peroxisomes, ie, pexophagy, thus exerting a dominant-negative effect on peroxisome functioning. Inhibition of pexophagy by different autophagy inhibitors or genetic knockdown of the peroxisomal autophagy receptor NBR1 resulted in restoration of peroxisomal functions in the patients' fibroblasts.
CONCLUSION
Our finding of an autosomal dominant ZSD expands the genetic repertoire of ZSDs. Our study underscores that single heterozygous variants should not be ignored as possible genetic cause of diseases with an established autosomal recessive mode of inheritance.
Topics: Humans; Alleles; Peroxisomes; Protein Transport; Proteins; Zellweger Syndrome
PubMed: 37493040
DOI: 10.1016/j.gim.2023.100944 -
Cureus May 2023The cavum vergae cyst (CVC) is an uncommon brain malformation. Most patients with CVC are asymptomatic and do not require neurosurgical intervention. Separately,...
The cavum vergae cyst (CVC) is an uncommon brain malformation. Most patients with CVC are asymptomatic and do not require neurosurgical intervention. Separately, cerebral X-linked adrenoleukodystrophy (X-ALD) is one of the phenotypes of a genetic peroxisomal disorder that is seldom managed by neurosurgeons. We report an unusual case of cerebral X-ALD presenting as an enlarging CVC in a child, and discuss its nuances in corroboration with the literature. A previously well six-year-old male presented with confusion and fever. Urgent neuroimaging demonstrated a large CVC with resultant hydrocephalus. Of note, there were symmetrical areas of signal changes in the periventricular white matter bilaterally involving the corpus callosum, thalami, cerebral peduncles, midbrain, and pons in his MRI. Further investigations performed as part of his medical workup reported high plasma concentrations of very long-chain fatty acids (VLCFA). Put together, a diagnosis of cerebral X-ALD was confirmed. Initially, an external ventricular drain was inserted directly into the CVC under stereotaxy to decompress it. Subsequently, endoscopic fenestration of the CVC was performed as the definitive treatment. He recovered uneventfully from the neurosurgical interventions and proceeded for the treatment of his cerebral X-ALD. To our knowledge, this is the first report of cerebral X-ALD presenting as a CVC in a patient. This case adds to the limited literature for both rare conditions and highlights the importance of a multidisciplinary approach to management.
PubMed: 37351235
DOI: 10.7759/cureus.39353 -
Acta Neuropathologica Communications Jun 2023X-linked adrenoleukodystrophy (X-ALD), the most frequent, inherited peroxisomal disease, is caused by mutations in the ABCD1 gene encoding a peroxisomal lipid...
X-linked adrenoleukodystrophy (X-ALD), the most frequent, inherited peroxisomal disease, is caused by mutations in the ABCD1 gene encoding a peroxisomal lipid transporter importing very long-chain fatty acids (VLCFAs) from the cytosol into peroxisomes for degradation via β-oxidation. ABCD1 deficiency results in accumulation of VLCFAs in tissues and body fluids of X-ALD patients with a wide range of phenotypic manifestations. The most severe variant, cerebral X-ALD (CALD) is characterized by progressive inflammation, loss of the myelin-producing oligodendrocytes and demyelination of the cerebral white matter. Whether the oligodendrocyte loss and demyelination in CALD are caused by a primary cell autonomous defect or injury to oligodendrocytes or by a secondary effect of the inflammatory reaction remains unresolved. To address the role of X-ALD oligodendrocytes in demyelinating pathophysiology, we combined the Abcd1 deficient X-ALD mouse model, in which VLCFAs accumulate without spontaneous demyelination, with the cuprizone model of toxic demyelination. In mice, the copper chelator cuprizone induces reproducible demyelination in the corpus callosum, followed by remyelination upon cuprizone removal. By immunohistochemical analyses of oligodendrocytes, myelin, axonal damage and microglia activation during de-and remyelination, we found that the mature oligodendrocytes of Abcd1 KO mice are more susceptible to cuprizone-induced cell death compared to WT mice in the early demyelinating phase. Furthermore, this effect was mirrored by a greater extent of acute axonal damage during demyelination in the KO mice. Abcd1 deficiency did not affect the function of microglia in either phase of the treatment. Also, the proliferation and differentiation of oligodendrocyte precursor cells and remyelination progressed at similar rates in both genotypes. Taken together, our findings point to an effect of Abcd1 deficiency on mature oligodendrocytes and the oligodendrocyte-axon unit, leading to increased vulnerability in the context of a demyelinating insult.
Topics: Animals; Mice; Adrenoleukodystrophy; ATP-Binding Cassette Transporters; Cuprizone; Oligodendroglia; Myelin Sheath; Disease Models, Animal; Mice, Inbred C57BL; ATP Binding Cassette Transporter, Subfamily D, Member 1
PubMed: 37331971
DOI: 10.1186/s40478-023-01595-w -
Clinical Case Reports Jun 2023Rhizomelic chondrodysplasia punctata (RCDP) is a rare disorder (~1 in 100,000 live births) of faulty plasmalogen biosynthesis and defective peroxisomal metabolism. RCDP...
Rhizomelic chondrodysplasia punctata (RCDP) is a rare disorder (~1 in 100,000 live births) of faulty plasmalogen biosynthesis and defective peroxisomal metabolism. RCDP type 2 is specifically caused by glyceronephosphate O-acyltransferase () gene mutations and is inherited as an autosomal recessive trait. The disorder is characterized by skeletal abnormalities, distinctive facial features, intellectual disability, and respiratory distress. The case report describes a newborn baby with a dysmorphic facial appearance and skeletal abnormalities who was admitted to neonatal intensive care with respiratory distress. His parents were first cousins. The whole exome sequencing for this patient identified an interesting homozygous variant in the gene [GNPAT (NM_014236.4):c.1602+1G>A (p.?), Chr1 (GRCh37):g.231408138G>A]. This case report aims to highlight the patient's clinical presentation with the variant and the whole exome sequencing, indicating the identification of a novel mutation in the gene causing RCDP type 2.
PubMed: 37323250
DOI: 10.1002/ccr3.7504 -
Orphanet Journal of Rare Diseases Jun 2023
Correction: Multivariate analysis and model building for classifying patients in the peroxisomal disorders X-linked adrenoleukodystrophy and Zellweger syndrome in Chinese pediatric patients.
PubMed: 37322480
DOI: 10.1186/s13023-023-02752-z -
Nutrients May 2023Adult Refsum disease (ARD) is a rare peroxisomal biogenesis disorder inherited in an autosomal recessive fashion and is often characterized by retinitis pigmentosa,...
Adult Refsum disease (ARD) is a rare peroxisomal biogenesis disorder inherited in an autosomal recessive fashion and is often characterized by retinitis pigmentosa, cerebellar ataxia, and polyneuropathy. Many patients with ARD require diet modification, psychosocial support, and various specialist visits to manage their symptoms. In this study, we explored the quality of life in individuals with ARD by analyzing retrospective survey data collected by the Coordination of Rare Diseases at Sanford (CoRDS) Registry and Global Defeat Adult Refsum Everywhere (DARE) Foundation. Statistical tests used were frequencies, mean, and median. There were 32 respondents, ranging between 11 and 32 responses for each question. The mean age at diagnosis was 35.5 ± 14.5 years (range 6-64) with 36.4% male and 63.6% female respondents. The average age for retinitis pigmentosa diagnosis was 22.8 ± 15.7 years (range 2-61). Dieticians were the most frequently seen (41.7%) for management of low-phytanic-acid diets. Most participants exercise at least once per week (92.5%). Depression symptoms were reported in 86.2% of the participants. Early diagnosis of ARD is important for managing symptoms and preventing progression of visual impairment due to phytanic acid buildup. Interdisciplinary approach should be used for patients to address physical and psychosocial impairments of ARD.
Topics: Adult; Humans; Male; Female; Child, Preschool; Child; Adolescent; Young Adult; Middle Aged; Refsum Disease; Phytanic Acid; Retrospective Studies; Quality of Life; Retinitis Pigmentosa; Life Style
PubMed: 37299514
DOI: 10.3390/nu15112551