-
Euro Surveillance : Bulletin Europeen... Jan 2024BackgroundWomen are overrepresented among individuals with post-acute sequelae of SARS-CoV-2 infection (PASC). Biological (sex) as well as sociocultural (gender)...
BackgroundWomen are overrepresented among individuals with post-acute sequelae of SARS-CoV-2 infection (PASC). Biological (sex) as well as sociocultural (gender) differences between women and men might account for this imbalance, yet their impact on PASC is unknown.AimWe assessed the impact of sex and gender on PASC in a Swiss population.MethodOur multicentre prospective cohort study included 2,856 (46% women, mean age 44.2 ± 16.8 years) outpatients and hospitalised patients with PCR-confirmed SARS-CoV-2 infection.ResultsAmong those who remained outpatients during their first infection, women reported persisting symptoms more often than men (40.5% vs 25.5% of men; p < 0.001). This sex difference was absent in hospitalised patients. In a crude analysis, both female biological sex (RR = 1.59; 95% CI: 1.41-1.79; p < 0.001) and a score summarising gendered sociocultural variables (RR = 1.05; 95% CI: 1.03-1.07; p < 0.001) were significantly associated with PASC. Following multivariable adjustment, biological female sex (RR = 0.96; 95% CI: 0.74-1.25; p = 0.763) was outperformed by feminine gender-related factors such as a higher stress level (RR = 1.04; 95% CI: 1.01-1.06; p = 0.003), lower education (RR = 1.16; 95% CI: 1.03-1.30; p = 0.011), being female and living alone (RR = 1.91; 95% CI: 1.29-2.83; p = 0.001) or being male and earning the highest income in the household (RR = 0.76; 95% CI: 0.60-0.97; p = 0.030).ConclusionSpecific sociocultural parameters that differ in prevalence between women and men, or imply a unique risk for women, are predictors of PASC and may explain, at least in part, the higher incidence of PASC in women. Once patients are hospitalised during acute infection, sex differences in PASC are no longer evident.
Topics: Female; Humans; Male; Adult; Middle Aged; COVID-19; Post-Acute COVID-19 Syndrome; Switzerland; Prospective Studies; SARS-CoV-2; Disease Progression
PubMed: 38214079
DOI: 10.2807/1560-7917.ES.2024.29.2.2300200 -
International Journal of Pediatrics &... Dec 2019
PubMed: 31890844
DOI: 10.1016/j.ijpam.2019.11.002 -
Orphanet Journal of Rare Diseases May 2023The peroxisome is a ubiquitous single membrane-enclosed organelle with an important metabolic role. Peroxisomal disorders represent a class of medical conditions caused...
Multivariate analysis and model building for classifying patients in the peroxisomal disorders X-linked adrenoleukodystrophy and Zellweger syndrome in Chinese pediatric patients.
BACKGROUND
The peroxisome is a ubiquitous single membrane-enclosed organelle with an important metabolic role. Peroxisomal disorders represent a class of medical conditions caused by deficiencies in peroxisome function and are segmented into enzyme-and-transporter defects (defects in single peroxisomal proteins) and peroxisome biogenesis disorders (defects in the peroxin proteins, critical for normal peroxisome assembly and biogenesis). In this study, we employed multivariate supervised and non-supervised statistical methods and utilized mass spectrometry data of neurological patients, peroxisomal disorder patients (X-linked adrenoleukodystrophy and Zellweger syndrome), and healthy controls to analyze the role of common metabolites in peroxisomal disorders, to develop and refine a classification models of X-linked adrenoleukodystrophy and Zellweger syndrome, and to explore analytes with utility in rapid screening and diagnostics.
RESULTS
T-SNE, PCA, and (sparse) PLS-DA, operated on mass spectrometry data of patients and healthy controls were utilized in this study. The performance of exploratory PLS-DA models was assessed to determine a suitable number of latent components and variables to retain for sparse PLS-DA models. Reduced-features (sparse) PLS-DA models achieved excellent classification performance of X-linked adrenoleukodystrophy and Zellweger syndrome patients.
CONCLUSIONS
Our study demonstrated metabolic differences between healthy controls, neurological patients, and peroxisomal disorder (X-linked adrenoleukodystrophy and Zellweger syndrome) patients, refined classification models and showed the potential utility of hexacosanoylcarnitine (C26:0-carnitine) as a screening analyte for Chinese patients in the context of a multivariate discriminant model predictive of peroxisomal disorders.
Topics: Child; Humans; Adrenoleukodystrophy; East Asian People; Multivariate Analysis; Peroxisomal Disorders; Zellweger Syndrome; China
PubMed: 37189159
DOI: 10.1186/s13023-023-02673-x -
Advances in Experimental Medicine and... 2020Peroxisomes are multifunctional organelles best known for their role in cellular lipid and hydrogen peroxide metabolism. In this chapter, we review and discuss the... (Review)
Review
Peroxisomes are multifunctional organelles best known for their role in cellular lipid and hydrogen peroxide metabolism. In this chapter, we review and discuss the diverse functions of this organelle in brain physiology and neurodegeneration, with a particular focus on oxidative stress. We first briefly summarize what is known about the various nexuses among peroxisomes, the central nervous system, oxidative stress, and neurodegenerative disease. Next, we provide a comprehensive overview of the complex interplay among peroxisomes, oxidative stress, and neurodegeneration in patients suffering from primary peroxisomal disorders. Particular examples that are discussed include the prototypic Zellweger spectrum disorders and X-linked adrenoleukodystrophy, the most prevalent peroxisomal disorder. Thereafter, we elaborate on secondary peroxisome dysfunction in more common neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Finally, we highlight some issues and challenges that need to be addressed to progress towards therapies and prevention strategies preserving, normalizing, or improving peroxisome activity in patients suffering from neurodegenerative conditions.
Topics: Adrenoleukodystrophy; Alzheimer Disease; Humans; Multiple Sclerosis; Neurodegenerative Diseases; Oxidative Stress; Parkinson Disease; Peroxisomes; Zellweger Syndrome
PubMed: 33417204
DOI: 10.1007/978-3-030-60204-8_2 -
Ophthalmology Dec 2023Individuals with Zellweger spectrum disorder (ZSD) manifest a spectrum of clinical phenotypes but almost all have retinal degeneration leading to blindness. The onset,... (Review)
Review
PURPOSE
Individuals with Zellweger spectrum disorder (ZSD) manifest a spectrum of clinical phenotypes but almost all have retinal degeneration leading to blindness. The onset, extent, and progression of retinal findings have not been well described. It is crucial to understand the natural history of vision loss in ZSD to define reliable endpoints for future interventional trials. Herein, we describe ophthalmic findings in the largest number of ZSD patients to date.
DESIGN
Retrospective review of longitudinal data from medical charts and review of cross-sectional data from the literature.
PARTICIPANTS
Sixty-six patients with ZSD in the retrospective cohort and 119 patients reported in the literature, divided into 4 disease phenotypes based on genotype or clinical severity.
METHODS
We reviewed ophthalmology records collected from the retrospective cohort (Clinicaltrials.gov NCT01668186) and performed a scoping review of the literature for ophthalmic findings in patients with ZSD. We extracted available ophthalmic data and analyzed by age and disease severity.
MAIN OUTCOME MEASURES
Visual acuity (VA), posterior and anterior segment descriptions, nystagmus, refraction, electroretinography findings, visual evoked potentials, and OCT results and images.
RESULTS
Visual acuity was worse at younger ages in those with severe disease compared with older patients with intermediate to mild disease for all 78 participants analyzed, with a median VA of 0.93 logarithm of the minimum angle of resolution (Snellen 20/320). Longitudinal VA data revealed slow loss over time and legal blindness onset at an average age of 7.8 years. Funduscopy showed retinal pigmentation, macular abnormalities, small or pale optic discs, and attenuated vessels with higher prevalence in milder severity groups and did not change with age. Electroretinography waveforms were diminished in 91% of patients, 46% of which were extinguished and did not change with age. OCT in milder patients revealed schitic changes in 18 of 23 individuals (age range 1.8 to 30 years), with evolution or stable macular edema.
CONCLUSIONS
In ZSD, VA slowly deteriorates and is associated with disease severity, serial electroretinography is not useful for documenting vision loss progression, and intraretinal schitic changes may be common. Multiple systematic measures are required to assess retinal dystrophy accurately in ZSD, including functional vision measures.
FINANCIAL DISCLOSURE(S)
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Topics: Humans; Child; Infant; Child, Preschool; Adolescent; Young Adult; Adult; Cross-Sectional Studies; Evoked Potentials, Visual; Retrospective Studies; Zellweger Syndrome; Blindness; Retina
PubMed: 37541626
DOI: 10.1016/j.ophtha.2023.07.026 -
Digestive and Liver Disease : Official... Jan 2020Several rare pediatric liver disorders are accompanied by ophthalmic signs whose awareness and early identification may be of value in confirming/accelerating their... (Review)
Review
Several rare pediatric liver disorders are accompanied by ophthalmic signs whose awareness and early identification may be of value in confirming/accelerating their diagnosis. Many of these signs are asymptomatic and can only be detected with an ophthalmological examination. Corneal signs are described in patients with Wilson's disease, Alagille's syndrome and some liver storage diseases. Cataract plays an important role to diagnose galactosemia. Retinal involvement is seen in some peroxisomal disorders (e.g. Zellweger's syndrome), in mucopolysaccharidoses (pigmentary retinopathy), and in Niemann-Pick disease (macular cherry red spot). In mucopolysaccharidoses optic nerve can be involved as optic atrophy secondary to pigmentary retinopathy or to chronic papilledema. Children with neonatal cholestasis due to hypopituitarism may present septo-optic dysplasia. Several infectious agents have an ophthalmological/hepatic involvement in the fetal life and/or thereafter. Some mitochondrial liver diseases, such as Pearson's syndrome, present pigmentary retinopathy and a chronic progressive external ophthalmoplegia. Finally, some drugs while protecting the liver may damage the ocular system as seen with long-term glucocorticoids and Nitisinone administration. This review provides a synopsis of those conditions that hepatologists and ophthalmologists should share among themselves to better take care of patients. Synoptic tables are presented to facilitate the mutual understanding of the issues.
Topics: Child; Cyclohexanones; Eye Diseases; Gastroenterologists; Glucocorticoids; Humans; Liver Diseases; Nitrobenzoates; Ophthalmologists; Pediatrics
PubMed: 31843253
DOI: 10.1016/j.dld.2019.11.009 -
European Heart Journal. Cardiovascular... May 2023
Topics: Humans; Pheochromocytoma; Takotsubo Cardiomyopathy; Syndrome; Adrenal Gland Neoplasms
PubMed: 37014047
DOI: 10.1093/ehjci/jead053 -
Journal of Cellular Biochemistry May 2021The peroxisome is responsible for a variety of vital pathways in primary metabolism, including the very long-chain fatty-acid oxidation and plasmalogen lipid...
The peroxisome is responsible for a variety of vital pathways in primary metabolism, including the very long-chain fatty-acid oxidation and plasmalogen lipid biosynthesis. Autosomal recessive disorder of the Zellweger spectrum (ZSD) is a major subset of peroxisome biogenesis disorders (PBDs) that can be caused by mutations in any of the 14 PEX genes. Zellweger syndrome (ZS) is the foremost common and severe phenotype within the heterogeneous ZSD. However, missense mutations encode proteins with residual functions, which are associated with phenotypes that are milder than ZS. Mutations in the PEX1 gene are among the most prevalent. PEX1 and PEX6 proteins, belonging to the AAA family of ATPases, form a hexameric complex, which is associated with peroxisome membranes and essential for peroxisome biology. In this study, a two-month-old Iranian boy with hypotonia, poor feeding, and difficulty in breathing was diagnosed with Zellweger syndrome. The parents of the patient were second cousins and healthy and no similar cases were observed in the parents' family. The PEX1 gene was sequenced in the patient and his parents. The compound heterozygous mutations, p. Arg949Trp and p. Gly970Ala, were identified in the patient, while the parents were heterozygous for these alleles. Sequence analysis of the mutant PEX1 D2 domain revealed that mutation p. Arg949Trp precisely occurred in a conserved arginine residue (P4 Arg), which hinders the substrate processing of the complex. Several database records have reported mutation p. Arg949Trp(R949W) but its clinical significance is given as uncertain. We report here a novel mutation, p. Gly970Ala, which is not recorded before and may prevent proper interaction of PEX1 and PEX6 proteins. In summary, the clinical findings and peroxisome profile of the patient suggested that compound heterozygosity for these two missense mutations resulted in a nonfunctional PEX1/PEX6 complex causing the severe ZS phenotype.
PubMed: 33955040
DOI: 10.1002/jcb.29945 -
Orphanet Journal of Rare Diseases Jul 2022Pathogenic variants in PEX-genes can affect peroxisome assembly and function and cause Zellweger spectrum disorders (ZSDs), characterized by variable phenotypes in terms...
BACKGROUND
Pathogenic variants in PEX-genes can affect peroxisome assembly and function and cause Zellweger spectrum disorders (ZSDs), characterized by variable phenotypes in terms of disease severity, age of onset and clinical presentations. So far, defects in at least 15 PEX-genes have been implicated in Mendelian diseases, but in some of the ultra-rare ZSD subtypes genotype-phenotype correlations and disease mechanisms remain elusive.
METHODS
We report five families carrying biallelic variants in PEX13. The identified variants were initially evaluated by using a combination of computational approaches. Immunofluorescence and complementation studies on patient-derived fibroblasts were performed in two patients to investigate the cellular impact of the identified mutations.
RESULTS
Three out of five families carried a recurrent p.Arg294Trp non-synonymous variant. Individuals affected with PEX13-related ZSD presented heterogeneous clinical features, including hypotonia, developmental regression, hearing/vision impairment, progressive spasticity and brain leukodystrophy. Computational predictions highlighted the involvement of the Arg294 residue in PEX13 homodimerization, and the analysis of blind docking predicted that the p.Arg294Trp variant alters the formation of dimers, impairing the stability of the PEX13/PEX14 translocation module. Studies on muscle tissues and patient-derived fibroblasts revealed biochemical alterations of mitochondrial function and identified mislocalized mitochondria and a reduced number of peroxisomes with abnormal PEX13 concentration.
CONCLUSIONS
This study expands the phenotypic and mutational spectrum of PEX13-related ZSDs and also highlight a variety of disease mechanisms contributing to PEX13-related clinical phenotypes, including the emerging contribution of secondary mitochondrial dysfunction to the pathophysiology of ZSDs.
Topics: Genetic Association Studies; Humans; Membrane Proteins; Mutation; Peroxisomes; Zellweger Syndrome
PubMed: 35854306
DOI: 10.1186/s13023-022-02415-5 -
Molecular Genetics and Metabolism Jul 2021In Zellweger syndrome (ZS), lack of peroxisome function causes physiological and developmental abnormalities in many organs such as the brain, liver, muscles, and...
In Zellweger syndrome (ZS), lack of peroxisome function causes physiological and developmental abnormalities in many organs such as the brain, liver, muscles, and kidneys, but little is known about the exact pathogenic mechanism. By disrupting the zebrafish pex2 gene, we established a disease model for ZS and found that it exhibits pathological features and metabolic changes similar to those observed in human patients. By comprehensive analysis of the fatty acid profile, we found organ-specific accumulation and reduction of distinct fatty acid species, such as an accumulation of ultra-very-long-chain polyunsaturated fatty acids (ultra-VLC-PUFAs) in the brains of pex2 mutant fish. Transcriptome analysis using microarray also revealed mutant-specific gene expression changes that might lead to the symptoms, including reduction of crystallin, troponin, parvalbumin, and fatty acid metabolic genes. Our data indicated that the loss of peroxisomes results in widespread metabolic and gene expression changes beyond the causative peroxisomal function. These results suggest the genetic and metabolic basis of the pathology of this devastating human disease.
Topics: Animals; Disease Models, Animal; Fatty Acids; Female; Gene Expression; Gene Expression Profiling; Humans; Liver; Male; Peroxins; Peroxisomes; Zebrafish; Zellweger Syndrome
PubMed: 34016526
DOI: 10.1016/j.ymgme.2021.05.002