Search Results (167)

Background/Objectives: Wilson’s disease (WD) is a rare autosomal recessive disorder of copper metabolism that results in hepatic, neurological, and psychiatric manifestations. Despite being described globally, data from the Middle East remains limited. This study presents the first comprehensive national cohort analysis of WD in Oman, examining clinical features, diagnostic challenges, treatment patterns, and long-term outcomes. Methods: A retrospective cohort study was conducted on 36 Omani patients diagnosed with WD between 2013 and 2020 at Sultan Qaboos University Hospital using AASLD diagnostic criteria. Clinical presentation, biochemical parameters, treatment regimens, and progression-free survival were analyzed. Results: The median age at diagnosis was 14.5 years, with a slight female predominance (55.6%). Clinical presentation varied: 25% had hepatic symptoms, 22.2% had mixed hepatic-neurological features, and 16.7% presented with neurological symptoms alone. Asymptomatic cases identified via family screening accounted for 33.3%. Diagnostic delays were most pronounced among patients presenting with neurological symptoms. A positive family history was reported in 88.9% of cases, suggesting strong familial clustering despite a low rate of consanguinity (5.6%). Regional distribution was concentrated in Ash Sharqiyah North and Muscat. Chelation therapy with trientine or penicillamine, often combined with zinc, was the mainstay of treatment. Treatment adherence was significantly associated with improved progression-free survival (p = 0.012). Conclusions: WD in Oman is marked by heterogeneous presentations, frequent diagnostic delays, and strong familial clustering. Early detection through cascade screening and sustained treatment adherence are critical for favorable outcomes. These findings support the need for national screening policies and structured long-term care models for WD in the region. Full article

Biographies of Max Wilson and Gunnar Jungner were published in 2017 and 2020. An in-depth appreciation of the Wilson and Jungner principles, and the publication they were presented in, ‘Principles and Practice of Screening for Disease’, published as nr. 34 in the Public Health Paper-series of the World Health Organisation (W.H.O), called PHP-34 hereafter, was not published as yet. Here an analysis is given of PHP-34 and the ten screening principles, focusing on three subjects. First, by careful analysis of PHP-34, the literature published in the peer reviewed scientific literature, and other sources, the historical background and origin of the ten principles is determined. Second, the precise composition of PHP-34 is described, as parts of the monograph were derived from other seminal works published between roughly 1950 and 1965. Third, it is determined what the contributions of both authors of the monograph were. Results together are discussed in relation to the time PHP-34 was conceptualized and the importance of PHP-34 and the ten principles in the current era. Results show that in the 15 years preceding the publication of PHP-34, many principles of screening were published by authors in the United States of America, a selection of which ended up in PHP-34. Secondly, about 33% of the 145 pages of PHP-34 are drawn from other publications and studies on screening. Thirdly, the case can be made that the actual writing of PHP-34 was done (almost) entirely by Wilson. Regardless, Wilson and Jungner to this day should be applauded for their work. It is a testimony to the value of PHP-34 that we are still reflecting upon, discussing and seeking to intelligently apply the screening principles almost 60 years after their original publication. Full article

Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene. While hepatic manifestations are frequent, psychiatric symptoms occur in up to 30% of patients and may precede neurological signs. This study was the first to assess the relationship between oxidative stress, selected genetic polymorphisms, and psychiatric symptoms in WD. A total of 464 patients under the care of the Institute of Psychiatry and Neurology in Warsaw were studied. Genotyping for GPX1 (rs1050450), SOD2 (rs4880), and CAT (rs1001179) was performed, along with biochemical analyses of copper metabolism, oxidative DNA, lipid and protein damage, and systemic antioxidant capacity. Among the most important observations are the following: the homozygous GPX1 rs1050450 TT and SOD2 rs4880 CC genotypes were associated with the lowest prevalence of psychiatric symptoms. The CAT rs1001179 TT genotype was linked to a delayed onset of psychiatric symptoms by 6.0–8.5 years. Patients with or without psychiatric symptoms did not differ significantly in saliva 8-OHdG, total antioxidant capacity, serum glutathione (GSH), catalase, and MnSOD; however, patients reporting psychiatric symptoms had significantly higher prostaglandin F2α 8-epimer (8-iso-PGF2α) concentrations and tended to have lower serum glutathione peroxidase (Gpx) concentrations compared to those without such symptoms. Our data firstly provide consistent evidence that oxidative stress balance associated with copper overload in the CNS may be associated with CNS damage and the development of psychiatric symptoms of WD. In particular, our findings of increased oxidative lipid damage together with decreased Gpx activity indirectly suggest that damage to neuronal membrane lipids, which may be potentially related to abnormalities in GSH metabolism, may have an etiological role in CNS damage and related symptoms. Full article

Wilson’s disease is a rare autosomal recessive disorder of copper metabolism characterized by excessive copper accumulation in the liver, brain, and other tissues. This paper provides an overview of the primary pharmacological agents used in its treatment, including penicillamine, trientine, tetrathiomolybdate, and zinc. Their mechanisms of action, therapeutic applications, and side-effect profiles are examined, emphasizing how each agent helps reduce copper overload. Additionally, brief information is given on novel therapies such as gene therapy and artificial intelligence applications. Furthermore, information about the structural and chemical properties of these compounds is provided, highlighting the molecular features that enable them to chelate copper or reduce its intestinal absorption. By integrating pathophysiological insights with chemical and mechanistic perspectives, this paper offers a comprehensive review of existing treatment strategies for Wilson’s disease and stresses the importance of careful, patient-specific management to optimize long-term outcomes. Full article

Background: Copper dyshomeostasis has been implicated in a subset of Alzheimer’s disease (AD) patients, characterized by elevated non-ceruloplasmin-bound copper (non-Cp Cu). However, traditional methods for estimating non-Cp Cu are indirect and analytically imprecise. This study introduces and validates a direct assay for exchangeable copper (ExcCu) by inductively coupled plasma-mass spectrometry (ICP-MS), compliant with Clinical and Laboratory Standards Institute (CLSI) guidelines. Methods: We performed analytical validation of the ExcCu assay following CLSI protocols (EP5, EP6, EP7, EP9, EP15, and EP28). ExcCu and other copper-related biomarkers were quantified in serum samples from 154 healthy controls, 82 AD patients, and 10 patients with Wilson disease (WD). Diagnostic performance was evaluated via receiver operating characteristic (ROC) curve analysis, and inter-method agreement was assessed using Bland–Altman plots. Results: The ExcCu assay demonstrated excellent linearity, precision (CV < 6%), and inter-laboratory reproducibility. Among AD patients, ExcCu levels were significantly elevated compared to controls (p < 0.001). ExcCu distinguished AD from controls with an AUC of 0.80 and a specificity of 95%. Compared to non-Cp Cu, ExcCu yielded no negative values and showed reduced bias. The relative exchangeable copper (REC) index was more effective in differentiating AD from WD (AUC = 0.88). Conclusions: The validated ExcCu assay overcomes the limitations of the traditional non-Cp Cu calculation, offering a reliable biomarker for copper-related AD subtypes. Its high specificity supports its use in patient stratification, potentially contributing to personalized approaches in AD diagnosis and therapy. Full article

This study identified an oxidase-positive protein in the plasma membrane fraction of the C. elegans N2 strain. The protein with a molecular weight of approximately 85 kDa reacted with antibodies against human and mouse, but not rat, ceruloplasmin and exhibited oxidase activity. Bioinformatic analysis revealed that the F21D5.3 protein possesses four copper-binding sites, similar to those in other multicopper oxidases (MCOs), and plastocyanin-like domains characteristic of MCOs. However, neither an iron-binding domain nor ferroxidase activity, typical features of MCOs, were detected through in silico analysis and or in-gel assays. Despite the absence of ferroxidase activity, these findings suggest that the protein may be the product of the F21D5.3 gene, an ortholog of MCOs in C. elegans. Heat map analysis indicated F21D5.3 expression in the entero-rectal valve cells and both the anterior and posterior intestines. Among the genes associated with copper transport, only cua-1 exhibited a similar expression pattern. In the C. elegans cua-1^H828Q strain, which mimics a mutation in human ATP7B linked to Wilson’s disease (WD), oxidase activity was also observed. Notably, both strains showed reduced oxidase activity when cultured with silver nanoparticles (AgNPs). These findings highlight the potential of the cua-1^H828Q strain as a model for studying copper and iron metabolism and for developing therapeutic strategies for WD. Full article

Wilson’s disease (WD) is an inherited disorder characterized by abnormal copper metabolism with complex pathological features. Currently, the mechanism of copper overload-induced hepatic injury is unclear. Green tea is a natural chelator, and its main ingredients, green tea polyphenol (GTP) and L-theanine (L-TA) are good at binding to heavy metals like iron and copper. There have been no reports on green tea extracts (GTE) for the treatment of Wilson’s disease. This study investigated the hepatoprotective effect of GTE on WD model mice. Initially, we examined the impact of green tea extract on copper metabolism, excretion, and hepatoprotective effects in WD model toxic milk mice. Then, Ultra performance liquid chromatography (UPLC-DAD) was established to analyze GTP and L-TA in green tea extract. Further screening of eight active components and copper complex active components in green tea extract was carried out by ion analyzer. Finally, we verified the pharmacodynamic effects of these active ingredients at the animal level. The results showed that GTE improves liver function and attenuates liver injury in TX mice by promoting tissue copper excretion and inhibiting oxidative stress, which provides a theoretical basis for green tea’s potential to improve the clinical symptoms of WD. Full article

Introduction: Obesity is a chronic disease associated with increased risk for several cancers, including colorectal cancer (CRC), a leading cause of cancer-related mortality. The majority of CRC cases are associated with modifiable risk factors. Metabolic and bariatric surgery (MBS) is a proven, durable, and successful intervention for obesity. This study aimed to evaluate the impact of MBS on CRC risk through measures of association, such as relative risk (RR) and odds ratio (OR). Methods: A systematic search of PubMed, Scopus, Web of Science, ScienceDirect, and Embase was conducted to identify systematic reviews (SR) and meta-analyses examining the relationship between obesity treated with MBS and CRC incidence. The PICO framework guided inclusion criteria, and three independent reviewers screened articles using Rayyan software. Quality assessment was performed using AMSTAR2. Results: Of 1336 screened articles, 10 SR met inclusion criteria, encompassing 53,452,658 patients. Meta-analyses consistently showed a significant reduction in CRC risk following MBS in patients with severe obesity. Risk reductions were reported by Liu et al. (RR: 0.46, 95% CI: 0.32–0.67, p < 0.01), Chierici et al. (RR: 0.46, 95% CI: 0.28–0.75, p = 0.018), Wilson et al. (RR: 0.69, 95% CI: 0.53–0.88, p = 0.003), and Pararas et al. (RR: 0.56, 95% CI: 0.40–0.80, p < 0.001). Sensitivity analyses supported these findings. For colon cancer, Liu and Chierici both reported an RR of 0.75 (95% CI: 0.46–1.21, p = 0.2444) with significant heterogeneity (I² = 89%). A trend towards reduced rectal cancer risk (RR: 0.74, 95% CI: 0.40–1.39, p = 0.3523) was noted but limited by fewer studies. Sex-specific analyses revealed protective effects in both sexes, with a more pronounced impact in females (RR: 0.54, 95% CI: 0.37–0.79, p = 0.0014). Conclusions: This umbrella review synthesizes current evidence on the impact of MBS on CRC risk, highlighting a consistent protective association. The findings also indicate a potential risk reduction for both colon and rectal cancer, with a more pronounced effect observed among females compared to males. Given the profound implications of MBS on cancer incidence, morbidity, and mortality, further high-quality, long-term studies are essential to deepen our understanding and optimize its role in cancer prevention and patient care. Full article

Copper accumulation in neurons induces oxidative stress, disrupts mitochondrial activity, and accelerates neuronal death, which is central to the pathophysiology of neurodegenerative diseases like Wilson disease. Standard treatments for copper toxicity, such as D-penicillamine, trientine, and chloroquine, are frequently associated with severe side effects, creating a need for safer therapeutic alternatives. To address this, we developed a curcumin-loaded nanoemulsion (CUR-NE) using the spontaneous emulsification technique, aimed at enhancing the bioavailability and therapeutic efficacy of curcumin. The optimized nanoemulsion displayed a particle size of 76.42 nm, a zeta potential of −20.4 mV, and a high encapsulation efficiency of 93.69%, with a stable and uniform structure. The in vitro tests on SH-SY5Y neuroblastoma cells demonstrated that CUR-NE effectively protected against copper-induced toxicity, promoting significant cellular uptake. Pharmacokinetic studies revealed that CUR-NE exhibited a longer half-life and extended circulation time compared to free curcumin. Additionally, pharmacodynamic evaluations, including biochemical assays and histopathological analysis, confirmed that CUR-NE provided superior neuroprotection in copper overload conditions. These results emphasize the ability of CUR-NE to augment the therapeutic effects of curcumin, presenting a novel approach for managing copper-induced neurodegeneration. The study highlights the effectiveness of nanoemulsion-based delivery platforms in improving chelation treatments for neurological diseases. Full article

Autophagy and mitophagy are critical cellular processes that maintain homeostasis by removing damaged organelles and promoting cellular survival under stress conditions. In the context of diabetic kidney disease, these mechanisms play essential roles in mitigating cellular damage. This review provides an in-depth analysis of the recent literature on the relationship between autophagy, mitophagy, and diabetic kidney disease, highlighting the current state of knowledge, existing research gaps, and potential areas for future investigations. Diabetic nephropathy (DN) is traditionally defined as a specific form of kidney disease caused by long-standing diabetes, characterized by the classic histological lesions in the kidney, including mesangial expansion, glomerular basement membrane thickening, nodular glomerulosclerosis (Kimmelstiel–Wilson nodules), and podocyte injury. Clinical markers for DN are albuminuria and the gradual decline in glomerular filtration rate (GFR). Diabetic kidney disease (DKD) is a broader and more inclusive term, for all forms of chronic kidney disease (CKD) in individuals with diabetes, regardless of the underlying pathology. This includes patients who may have diabetes-associated kidney damage without the typical histological findings of diabetic nephropathy. It also accounts for patients with other coexisting kidney diseases (e.g., hypertensive nephrosclerosis, ischemic nephropathy, tubulointerstitial nephropathies), even in the absence of albuminuria, such as a reduction in GFR. Full article

As a structural and catalytic cofactor, copper is involved in many biological pathways and is required for the biochemistry of all living organisms. However, excess intracellular copper can induce cell death due to its potential to catalyze the generation of reactive oxygen species, thus copper homeostasis is strictly regulated. And the deficiency or accumulation of intracellular copper is connected with various pathological conditions. Since the success of platinum-based compounds in the clinical treatment of various types of neoplasias, metal-based drugs have shown encouraging perspectives for drug development. Compared to platinum, copper is an essential intracellular trace element that may have better prospects for drug development than platinum. Recently, the potential therapeutic role of copper-induced autophagy in chronic diseases such as Parkinson’s, Wilson’s, and cardiovascular disease has already been demonstrated. In brief, copper ions, numerous copper complexes, and copper-based nano-preparations could induce autophagy, a lysosome-dependent process that plays an important role in various human diseases. In this review, we not only focus on the current advances in elucidating the mechanisms of copper or copper-based compounds/preparations on the regulation of autophagy but also outline the association between copper-induced autophagy and human diseases. Full article

For many genetic disorders, there are no specific metabolic biomarkers nor analytical methods suitable for newborn population screening, even where highly effective preemptive treatments are available. The direct measurement of signature peptides as a surrogate marker for the protein in dried blood spots (DBSs) has been shown to successfully identify patients with Wilson Disease (WD) and three life-threatening inborn errors of immunity, X-linked agammaglobulinemia (XLA), Wiskott–Aldrich syndrome (WAS), and adenosine deaminase deficiency (ADAD). A novel proteomic-based multiplex assay to detect these four conditions from DBS using high-throughput LC-MS/MS was developed and validated. The clinical validation results showed that the assay can accurately identify patients of targeted disorders from controls. Additionally, 30,024 newborn DBS samples from the Washington State Department of Health Newborn Screening Laboratory have been screened from 2022 to 2024. One true presumptive positive case of WD was found along with three false positive cases. Five false positives for WAS were detected, but all of them were premature and/or low-birth-weight babies and four of them had insufficient DNA for confirmation. The pilot study demonstrates the feasibility and effectiveness of utilizing this multiplexed proteomic assay for newborn screening. Full article

An intriguing aspect of restrictive cardiomyopathies (RCM) is the microbiome role in the natural history of the disease. These cardiomyopathies are often difficult to diagnose and so result in significant morbidity and mortality. The human microbiome, composed of billions of microorganisms, influences various physiological and pathological processes, including cardiovascular health. Studies have shown that gut dysbiosis, an imbalance in the composition of intestinal bacteria, can contribute to systemic inflammation, a key factor in many cardiovascular conditions. An increase in gut permeability, frequently caused by dysbiosis, allows bacterial endotoxins to enter the bloodstream, activating inflammatory pathways that exacerbate cardiac dysfunction. Recent reports highlight the potential role of microbiome in amyloidogenesis, as certain bacteria produce proteins that accelerate the formation of amyloid fibrils. Concurrently, advancements in amyloidosis treatments have sparked renewed hopes, marking a promising era for managing these kinds of diseases. These findings suggest that the gut–heart axis may be a potential factor in the development and progression of cardiovascular disease like RCM, opening new paths for therapeutic intervention. The aim of this review is to provide a detailed overview of the gut–heart axis, focusing on RCM. Full article

The biomarker-based Dutch Newborn Screening (NBS) panel (as of 2024) comprises 19 inherited metabolic disorders (IMDs). With the use of next-generation sequencing (NGS) as a first-tier screen, NBS could expand to include IMDs that lack a reliable biochemical footprint in dried blood spots, while also reducing secondary findings. To be eligible for inclusion in NBS, an IMD needs to fulfill the Wilson and Jungner criteria, with treatability being one of the most important criteria. In this study, we aimed to identify IMDs eligible for DNA-first NBS when considering only treatability in the context of NBS as a prerequisite. First, three independent reviewers performed a systematic literature review of the 1459 genotypic IMDs and their causative gene(s), as described in the International Classification of Inherited Metabolic Disorders (dated 1 February 2021), applying 16 criteria to exclude non-treatable disorders. Eligible disorders were then discussed in three online meetings with a project group of clinical laboratory geneticists, medical laboratory specialists specialized in IMD, and pediatricians with expertise in IMDs. Based on treatability, we identified 100 genes, causing 95 IMDs, as eligible for NBS, including 42 causal genes for the IMDs in the current biomarker-based NBS. The other 58 genes are primarily associated with treatable defects in amino acid metabolism and fatty acid oxidation. Other IMDs were excluded, most often because of insufficient literature. As the evaluation of treatability was not straightforward, we recommend the development of standardized treatability scores for the inclusion of IMDs in NBS. Full article

Background/Objectives: Wilson’s disease (WD) (OMIM 277900) or hepatolenticular degeneration is an autosomal recessive disorder caused by impaired copper excretion with subsequent accumulation in the liver, brain, and other tissues of the body. The defects in copper metabolism are based on various pathogenic variants of the ATP7B gene encoding copper-transporting P-type ATPase. The aim of this work is to search for pathogenic variants of the ATP7B gene among Eastern Eurasian patient cohorts and to pick correlations between pathogenic variants, gender, age of onset of the disease, and the course of the disease. Methods: The material for the study was the biomaterial of 100 people. The search for mutations was carried out by Sanger sequencing. Multiple alignment of nucleotide sequences and their analysis was performed using the MEGA-X software. To study the genotype-phenotypic correlation, an analysis of the medical records of each patient was carried out. Results: Most common pathogenic variant (48%) in the sample is p.His1069Gln (c.3207C>A), located in exon 14 of the ATP7B gene. Pathogenic variants of p.Glu1064Lys (c.3190G>A)—20%—and p.Met769HisfsTer26 (c.2304insC)—8%—of exons 14 and 8 were also common. For patients with pathogenic alleles p.His1069Gln (c.3207C>A) and p.Glu1064Lys (c.3190G>A), typical deviations are mental and neurological manifestations of WD. In patients with the pathogenic allele p.Met769HisfsTer26 (c.2304insC), deviations are more characteristic of the liver and a combination of various symptoms that are atypical for WD. Conclusions: In this study, we were able to obtain differences in symptoms in patients with different pathogenic alleles of the ATP7B gene. Full article