Zebrafish (Danio rerio) have become indispensable models for advancing our understanding of multiple metabolic disorders such as obesity, diabetes mellitus, dyslipidemia, and metabolic syndrome. This review provides a comprehensive analysis of zebrafish as a powerful tool for dissecting the genetic and molecular mechanisms of these diseases, focusing on key genes, like pparγ, lepr, ins, and srebp. Zebrafish offer distinct advantages, including genetic tractability, optical transparency in early development, and the conservation of key metabolic pathways with humans. Studies have successfully used zebrafish to uncover conserved metabolic mechanisms, identify novel disease pathways, and facilitate high-throughput screening of potential therapeutic compounds. The review also highlights the novelty of using zebrafish to model multifactorial metabolic disorders, addressing challenges such as interspecies differences in metabolism and the complexity of human metabolic disease etiology. Moving forward, future research will benefit from integrating advanced omics technologies to map disease-specific molecular signatures, applying personalized medicine approaches to optimize treatments, and utilizing computational models to predict therapeutic outcomes. By embracing these innovative strategies, zebrafish research has the potential to revolutionize the diagnosis, treatment, and prevention of metabolic disorders, offering new avenues for translational applications. Continued interdisciplinary collaboration and investment in zebrafish-based studies will be crucial to fully harnessing their potential for advancing therapeutic development.

Wilson's disease (WD) is a rare autosomal recessive inherited disorder characterized by dysregulated copper metabolism, amenable to treatment with chelating agents. It manifests with hepatic and neurological symptoms, often precipitating the development of liver cirrhosis as a prominent complication. This study aims to elucidate the factors, biomarker alterations, and therapeutic modalities influencing the progression of cirrhosis in WD patients.

This retrospective cohort study utilized WD patient data from West China Fourth Hospital (May 2018-September 2023). The primary outcome was the development of cirrhosis in initially cirrhosis-free WD patients. LASSO-COX regression identified predictive factors. The 1:1 propensity score matching generated a matched subgroup for robust Cox regression validation.

Among 133 initially cirrhosis-free WD patients, 47 developed cirrhosis during 35.98 (22.04-49.21) months. Significant differences were observed between the cirrhosis and non-cirrhosis groups in age at enrollment, age at WD diagnosis, clinical symptoms, educational levels, and administration of dimercaptosuccinic acid, compound glycyrrhizin polyene, and phosphatidylcholine. Multivariate Cox regression identified age at enrollment (hazard ratio [HR]: 1.038, 95% CI: 1.002-1.075), the use of glycyrrhizin (HR: 0.421, 95% CI: 0.192-0.926), erythrocyte (HR: 0.748, 95% CI: 0.626-0.895), and platelet counts (HR: 0.993, 95% CI: 0.988-0.998) associated with cirrhosis. Robust Cox analysis on the matched subgroup confirmed these findings.

Glycyrrhizic acid emerges as a potential hepatoprotective agent for WD patients. Furthermore, the progression of cirrhosis in WD patients is characterized by advanced age and decreased baseline levels of erythrocytes and platelets, suggesting their potential utility as prognostic indicators.

Wilson disease (WD) is a genetic disorder of copper metabolism caused by mutations in the ATP7B gene resulting in toxic copper accumulation in several organs. WD can manifest as liver disease, a progressive neurological disorder, a psychiatric illness, or a combination of these. Other clinical manifestations can also occur. Diagnosis is challenging and typically requires a range of biochemical tests, imaging, genetic testing for ATP7B, and/or liver biopsy. WD is treatable with chelating agents, such as d-penicillamine and trientine, and/or zinc salts alongside with dietary copper restriction. Liver transplantation may be indicated in WD patients with severe hepatic disease, and cautiously considered in patients with neurological WD. Treatment success highly depends on patient adherence and treatment persistence. Therefore, effective interventions for improving patient adherence and close monitoring are key for preventing WD progression. In Portugal, there are no reference centers for WD, and patients are dispersed across numerous medical specialists. This review aimed to summarize the most recent and relevant information for the diagnosis, treatment, and monitoring of WD in Portugal, as well as possible interventions for stimulating adherence to treatment.

We aimed to analyze the clinical features, treatment, and prognosis of Wilson disease (WD) combined with polycystic ovary syndrome (PCOS), and to explore the correlation between endocrine abnormalities and liver damage.

The clinical data of 40 female patients of WD combined with PCOS (PCOS-WD) were retrospectively analyzed. 43 age- and BMI-matched patients of PCOS with non-WD (PCOS-NWD) were performed as the control group. The patients of PCOS-WD were assigned to adolescent group (n = 18) and reproductive age group (n = 22) according to the age onset of PCOS, and also assigned to normal testosterone group (n = 18) and elevated testosterone group (n = 22) according to the testosterone level. The clinical features, laboratory tests, imaging examinations, treatment, and outcome of all patients were analyzed, and correlation analysis was processed between gonadal hormone and liver damage parameters.

The testosterone level was significantly higher in the PCOS-NWD than in the PCOS-WD patients (Z=-2.306, P = 0.021). The clinical hyperandrogenism was significantly more prevalent in adolescent group within PCOS-WD patients (P = 0.025), while the serum alanine aminotransferase was significantly higher in reproductive age group (Z=-2.572, P = 0.010). The hepatic fibrosis index was significantly higher in elevated testosterone group than in normal testosterone group (Z = -2.190, P = 0.029), while the progesterone level was lower in elevated testosterone group (Z = 2.394, P = 0.017). The testosterone level was positively correlated with the hepatic fibrosis index (P = 0.039, R = 0.328). In followed-up observations, no significant difference was found in menstrual cycle and pregnancy outcomes between progesterone combined with copper chelation therapy and copper chelation therapy alone.

PCOS is an important endocrine comorbidity of female WD patients. The extent of liver damage in WD patients may be related to the hormonal imbalance of PCOS. The study recommends routine screening for PCOS in adolescent WD patients. Testosterone levels may serve as a valuable reference for informing treatment decisions. Copper chelation therapy with or without progesterone is beneficial to the recovery of patients with PCOS-WD.

Wilson's disease (WD) is an autosomal recessive inherited disease caused by ATP7B gene mutations. Some mutations in ATP7B are presumed to be pathogenic by altering pre-mRNA splicing, while most have not been functionally verified. This study aimed to perform functional studies to verify the pathogenicity of variants that may affect pre-mRNA splicing.

We recruited 42 pediatric patients who were clinically diagnosed with WD (Leipzig score ≥ 4) and underwent ATP7B gene sequencing. We leveraged in silico analysis and prioritized seven splice genic variants in ATP7B. Minigene assays were used to evaluate the effects of the selected variants on transcript splicing. Total RNA was extracted from peripheral blood mononuclear cells (PBMCs), and Reverse Transcription-Polymerase Chain Reaction (RT-PCR) was performed on samples from several patients to verify the splicing alterations.

This study screened 42 distinct mutations for their potential effects on splicing based on in silico analysis and functional verification. Five intronic variants (c.1286-1delG, c.1543 + 1G > T, c.1708-1G > C, c.1870-8A > G, and c.2121 + 3A > T) and one missense variant (c.2120A > G) were proved to alter the splicing of ATP7B transcription by minigene assays. The transcript assays demonstrated splicing changes in vivo in patient PBMCs for c.3993 T > G. The altered transcription products resulting from c.2570_2572del were confirmed by sequencing.

This study adds experimental evidence to genetic diagnosis based on assessing the genetic defects of 42 pediatric WD patients and provides new insights into the pathogenicity of the splicing variants.

Wilson disease (WD) is an autosomal-recessive disorder that disrupts copper homeostasis. ATPase copper transporting beta (ATP7B) gene is implicated as the disease-causing gene in WD. The common symptoms associated with WD include hepatic, neurological, psychiatric, and ophthalmic manifestations. The genetic landscape of WD is under-investigated in the Middle East and has never been studied in Jordan. We aimed to investigate the genetic profile of several unrelated Jordanian families with one or more patients affected by WD.

Twenty-four Jordanian families with WD underwent clinical evaluation and genetic profiling by whole-exome and Sanger sequencing.

Surprisingly, the same variant (ATP7B:c.3551C>T;p.Ile1184Thr) was identified, for the first time, exclusively in the homozygous state, in eight consanguineous unrelated families. Before our study, the previous classification of this variant was either of uncertain significance (VUS) or likely pathogenic (LP). Interestingly, the patients harboring this variant displayed variable clinical manifestations on both the intra- and interfamilial levels, as previously described in cases with WD. The age of diagnosis, hepatic manifestations, neuropsychiatric involvements, and Kayser-Fleischer ring occurrence varied significantly in terms of existence and severity among the recruited individuals. Following our investigation, based on clinical data and co-segregation analysis, we re-classified the variant ATP7B:c.3551C>T;p.Ile1184Thr from VUS/LP to pathogenic, for the first time. Besides, our genetic analysis helped in resolving diagnostic ambiguity by either establishing or ruling out the diagnosis of WD.

Since the identified variant (ATP7B:p.Ile1184Thr) was discovered in multiple unrelated families, we create an avenue for the potential consideration of this variant as a recurrent, or possibly a founder variant, in the Jordanian population. Our work sheds light, for the first time, on the molecular underpinnings of WD in Jordan and compiles the WD-causing variants in the Middle East. Ultimately, the findings of our work can guide designing region-specific targeted genetic testing of WD in Jordan and provide valuable insights to direct clinical decisions for atypical WD presentations.

Wilson disease is an inherited disorder of copper metabolism affecting mainly the liver and brain. Trientine dihydrochloride (TETA-2HCl) is approved for the treatment of Wilson disease in patients (≥ 5 years) intolerant to D-penicillamine therapy. This study assessed the long-term outcomes of treatment with TETA-2HCl in Wilson disease patients.

In this Phase 2, prospective study, patients continued their treatment of TETA-2HCl 300 mg (200 mg trientine base) for 12 months (July 2015-April 2017) at one center in Germany. Primary outcomes were the safety and efficacy of TETA-2HCl treatment; Biomarkers of copper metabolism; and the course of hepatic and neurologic disease.

Overall, 51 patients contributed data. Almost all patients (50 [98.0%]) were considered responders (rating of ≤ 4 at the 12-month visit); Unified Wilson Disease Rating Scale scores improved throughout the study from a mean (standard deviation) of 11.3 (24.31) at Baseline to 8.8 (22.86) at Month 12. Biochemical assessments of liver parameters (transaminases, liver synthesis) as well as markers of copper metabolism (24-h urinary copper, non-ceruloplasmin bound copper (NCC)) showed improved or stable disease throughout the study. Treatment-emergent adverse events were reported in five (9.6%) patients. No patients withdrew from treatment due to adverse events, and no serious adverse events were considered to be treatment-related.

This study demonstrated that treatment with TETA-2HCl was effective and well tolerated in hepatic and neurologic disease manifestations. Additionally, improvement in neurological symptoms was reported throughout the trial, suggesting that improvements may be reported for an extended period after initiation of therapy. Trial Registration: NCT02426905.

Wilson's disease is an autosomal recessive disorder of copper metabolism which affects the liver, brain and other organs. Diagnosis is based on: clinical features; biochemical tests, including plasma ceruloplasmin concentration, 24-h urinary copper excretion, copper content in the liver; and molecular analysis. Leipzig score and additionally relative exchangeable copper determination are recommended for diagnosis. Pharmacological therapy comprises chelating agents (penicillamine, trientine) and zinc salts, while only chelators are recommended for significant liver disease. Monitoring is based on clinical symptoms, liver tests and copper metabolism (urinary copper excretion, exchangeable copper) to detect poor compliance and over/under-treatment. Acute liver failure is challenging as making a diagnosis is difficult and pharmacological therapy may not be sufficient to save life. Liver transplantation has a well-defined role in Wilsonian acute hepatic failure but may also be considered in neurological disease.

As a highly complex organ with digestive, endocrine, and immune-regulatory functions, the liver is pivotal in maintaining physiological homeostasis through its roles in metabolism, detoxification, and immune response. Various factors including viruses, alcohol, metabolites, toxins, and other pathogenic agents can compromise liver function, leading to acute or chronic injury that may progress to end-stage liver diseases. While sharing common features, liver diseases exhibit distinct pathophysiological, clinical, and therapeutic profiles. Currently, liver diseases contribute to approximately 2 million deaths globally each year, imposing significant economic and social burdens worldwide. However, there is no cure for many kinds of liver diseases, partly due to a lack of thorough understanding of the development of these liver diseases. Therefore, this review provides a comprehensive examination of the epidemiology and characteristics of liver diseases, covering a spectrum from acute and chronic conditions to end-stage manifestations. We also highlight the multifaceted mechanisms underlying the initiation and progression of liver diseases, spanning molecular and cellular levels to organ networks. Additionally, this review offers updates on innovative diagnostic techniques, current treatments, and potential therapeutic targets presently under clinical evaluation. Recent advances in understanding the pathogenesis of liver diseases hold critical implications and translational value for the development of novel therapeutic strategies.

A 19-year-old Japanese man was referred for a further evaluation of liver dysfunction. Despite the absence of symptoms or obesity, the liver biopsy results were consistent with non-alcoholic steatohepatitis. Subsequent investigations revealed low serum ceruloplasmin, increased urinary copper excretion, and a known mutation c.3809A>G (p.Asn1270Ser) in the copper-transporting enzyme P-type ATPase (ATP7B) gene, leading to a diagnosis of Wilson's disease. A previously unreported variant, i.e., c.3866A>T (p.Asp1289Val) was detected on the patient's other allele and was considered a novel mutation, classified as 'likely pathogenic' according to the American College of Medical Genetics guidelines.

Wilson disease (WD) is a genetic disorder of copper metabolism. Early diagnosis of WD is inherently challenging due to the absence of typical symptoms. This study aimed to identify urinary protein biomarkers for WD using targeted and nontargeted mass spectrometry-based approaches.

Exploratory urinary proteomic research on WD patients was initially conducted and revealed some potential biomarkers (alpha-2-macroglobulin, alpha-1-antitrypsin, complement C3, prothrombin, and complement factor B). A multiple reaction monitoring (MRM) assay was subsequently developed and applied to an independent WD cohort for protein candidate validation. Finally, a Random Forest (RF) model constructed with five proteins was evaluated for its diagnostic capacity.

The linear range of the MRM assay extended from 0.025 ng/L to 155 ng/L and the limit of quantification (LOQ) ranged from 0.0095 ng/L to 9.2308 ng/L. Alpha-2-macroglobulin, alpha-1-antitrypsin, and complement C3 exhibited significant increases (p < 0.05) in WD patients compared to the controls, whereas prothrombin and complement factor B only showed variations in concentration. The physiology reference intervals (RIs) for alpha-2-macroglobulin, alpha-1-antitrypsin, complement C3, prothrombin, and complement factor B were estimated as 0-12.50, 0-123.08, 0-5.20, 0-16.59, 0-4.85 ng/mol Cr, while the pathology RIs were 0-114.86, 0-600.98, 0-12.62, 0-22.16, and 0-10.83 ng/mol Cr, respectively. The RF model demonstrated an area under the curve (AUC) of 0.99 for the training data and 0.83 for the testing data.

Based on the proteomic results, the quantitative method was successfully applied for the validation of protein candidates in WD. Using supervised machine learning, the five-protein panel exhibited excellent accuracy in non-invasive diagnosis of WD.

Wilson's disease (WD) is a rare metabolic disorder of copper accumulation in organs such as liver, brain, and cornea. Diagnoses and treatments are challenging in settings, where advanced diagnostic tests are unavailable, copper chelating agents are frequently scarce, healthcare professionals lack disease awareness, and medical follow-ups are limited. Prompt diagnoses and treatments help prevent complications, improve patients' quality of life, and ensure a normal life expectancy. The clinical presentations and outcomes of WD can vary within a single family.

We present the cases of two siblings (19 and 27 years) from a consanguineous family in rural Ecuador, diagnosed as having WD during a family screening. The male patient, diagnosed at age 19 after his brother's death from acute liver failure, presented with compensated cirrhosis, neurological symptoms, and bilateral Kayser-Fleischer rings. He developed progressive neurological deterioration during an irregular treatment with D-penicillamine due to medication shortages. His condition improved upon switching to trientine tetrahydrochloride, and his neurological symptoms improved over an 8-year period of follow-ups. The female patient, diagnosed at age 10, exhibited only biochemical alterations. Her treatment history was similar; however, she remained asymptomatic without disease progression over the same follow-up period. We discuss the potential influence of epigenetic mechanisms and modifier genes on the various phenotypes, emphasizing the need for research in these areas to optimize therapeutic strategies.

Our patients' medical histories show how early diagnosis and treatment can prevent disease progression; and, how suboptimal treatments impact disease outcomes.

Wilson disease (WD) is a rare inherited copper metabolism disorder characterized by progressive pathological deposition of copper, primarily in the liver and brain. This longitudinal retrospective study conducted using the French national claims (Système National des Données de Santé [SNDS]) database assessed WD prevalence in France, described patients' characterizations and healthcare resource use and associated costs. Patients with WD were identified from SNDS using the International Classification of Diseases, 10th Revision code E83.0 for copper metabolism disorder or a long-term disease (affection de longue durée [ALD]) associated with this code between 2010 and 2019. Patients were categorized into hepatic, neurological, and psychiatric sub-cohorts. We identified 2287 patients with WD yielding a crude prevalence of 1 case per 33 898 individuals in 2019. The mean age at inclusion was 39.9 (standard deviation [SD] 22.8) years, 11 years more than that of the incident cohort (28.6, SD 20.3) identified via ALD, and 1180 (51.6%) patients were male. The crude mortality was 3.2% (in total 370 patients died). Overall, 1011 (44.2%), 754 (33.0%), and 414 (18.1%) patients experienced hepatic, neurological, and psychiatric manifestations, respectively. In total, 922 (40.3%) patients were reimbursed for WD-specific treatment, the most common being D-penicillamine (74.8%), and 201 (8.8%) underwent liver transplantation. The average annual hospitalization cost per patient was 4273.7€ (SD 11916.0). At least one sick leave was reported for 533 (23.3%) patients, with an annual average cost of 788.7€ (SD 1328.6). Our findings provide an updated understanding of the prevalence of WD, and indicate a considerable level of morbidity in this population, as well as a high level of direct/indirect costs associated with WD.

Wilson's disease (WD) is a rare metabolic disorder caused by variations in the ATP7B gene. It usually manifests hepatic, neurologic, and psychiatric symptoms due to excessive copper accumulation. The prevalence of WD and its common variants differ across populations. This study aimed to examine these aspects of WD within the Thai population, where information has been limited. We reviewed ClinVar and the Wilson Disease Mutation Database, organizing variants classified as pathogenic or likely pathogenic in one or both databases as "relaxed" and "strict" lists. Allele frequencies were estimated from genotyping array data (Asian Screening Array: ASA; Illumina Corp, CA) of 6291 Thai subjects, which also underwent genotype imputation. The prevalence of WD in the Thai population was estimated assuming Hardy-Weinberg Equilibrium. The strict list yielded a prevalence of 1/24,128 (carrier frequency=1/78), while the relaxed list yielded a prevalence of 1/9971 (carrier frequency=1/50). The most common WD variants in Thai subjects were c.2333 G > T, c.3443 T > C, and c.813 C > A from the strict list, and c.3316 G > A and c.2605 G > A from the relaxed list. The ASA chip covered approximately 59 and 24% of WD variants from the strict and relaxed lists, respectively. Based on the estimated prevalence, a carrier screening program for WD is not currently required in Thailand. However, as genotyping services become more affordable and accessible, such a program would facilitate early identification, treatment, and prevention of WD.

Wilson's disease (WD) typically manifests in children and young adults, with little knowledge of its late-onset forms. In this study, we performed a retrospective cohort study of 105 WD patients (99 index cases, 6 siblings) with an onset age ≥35 years. We compared 99 index late-onset patients with 1237 early-onset patients and analyzed the ATP7B variant penetrance referring to the Genome Aggregation Database (gnomAD). Sixty-two ATP7B variants were identified in the late-onset patients, among which A874V, V1106I, R919G, and T935M were correlated with late presentation of WD. Regarding gnomAD, V1106I and T935M exhibited significantly low penetrance, and there is a lack of patients carrying a genotype of V1106I/V1106I, R919G/R919G, T935M/T935M, V1106I/T935M, V1106I/R919G, or T935M/R919G. Our data revealed that patients carrying a combination of two late-onset variants may be overlooked due to atypical or lack of WD symptoms, which may provide valuable insights into the genetic basis and diagnosis of WD.

To describe the epidemiology, patient characteristics and comorbidities in patients with Wilson disease (WD) in the USA.

Retrospective, population-based study.

The study used the US Komodo claims database containing records regarding medical claims for over 120 million individuals.

Patients with WD were identified via ICD-10 (10th revision of the International Classification of Diseases) code during the study period 2016-2019 and no age restriction was applied. A further stratification by disease subtype ('hepatic', 'neurologic' and 'psychiatric') was performed.

WD prevalence was reported by age, sex and US census regions/divisions. Adjusted prevalence was calculated using age-specific prevalence standardised to the USA (2010 US census) and to the world (WHO 2000-2025) to enable comparisons across countries, using direct standardisation of prevalence estimates by age group.

Overall, 2115 patients with WD were identified during the study period. Among them, 56.8% had hepatic symptoms, 57.0% neurologic symptoms and 47.4% psychiatric symptoms. The most frequent manifestations in hepatic patients were liver signs and symptoms (90.8%), in neurologic patients cognitive defects (50.7%) and in psychiatric patients mood disorders (86.4%). The mean age in the overall cohort was 39.9 years. Prevalence estimation was based on 1481 patients with WD between 2017 and 2019. The 2017-2019 crude period prevalence was 21.2 patients per million (95% CI: 20.1 to 22.3), with similar prevalence observed for both sexes.

This study provides important real-world data on the diagnosed prevalence of WD in the USA and revealed the comorbidities associated with various disease subtypes, thereby providing a comprehensive basis for guiding physicians and policy makers in the management of this chronic disease.

Wilson's disease (WD) is a hereditary condition marked by abnormalities in copper metabolism, which precipitate a spectrum of neurological symptoms and cognitive impairments. Emerging research has highlighted ferroptosis (FPT) as a distinct type of programmed cell death, potentially linked to various cognitive dysfunctions. Nevertheless, the connection between FPT and cognitive impairment in Wilson's disease (WDCI) remains largely enigmatic. In our study, we utilized a multifaceted approach, combining reverse network pharmacology, data mining, and molecular docking techniques to explore the potential for treating WDCI via FPT-related pathways. This thorough analysis revealed a series of proteins, including P38[Formula: see text], GSK3[Formula: see text], P53, GPX4, and PTGS2, as pivotal targets for WDCI treatment. Notably, Diosgenin (DG) has been identified as a prospective core component in this therapeutic framework. In the WD copper-loaded rat model, evaluations using the Morris water maze (MWM), Y maze, hematoxylin and eosin staining, transmission electron microscopy (TEM), and immunofluorescence (IF) detection showed that DG significantly enhanced cognitive function recovery, reduced structural damage to hippocampal neurons, and protected mitochondrial integrity. In addition, Western blot (WB) and quantitative reverse transcription PCR (qRT-PCR) analysis showed that DG significantly upregulated the expression levels of proteins and mRNA such as P38[Formula: see text], GSK3[Formula: see text], P53, GPX4, and PTGS2 in animal and cell models. Furthermore, DG effectively reversed the dysregulated expression of oxidative stress markers, including [Formula: see text], malondialdehyde (MDA), superoxide dismutase (SOD), and reactive oxygen species (ROS). This study elucidates the neuroprotective effect of DG on hippocampal neurons by activating the P38[Formula: see text]-mediated FPT pathway, highlighting its efficacy as a potent monomer in traditional Chinese medicine and illuminating its potential role in the clinical treatment of WDCI.

Population-based biobanks enable genomic screening to support initiatives that prevent disease onset or slow its progression and to estimate the prevalence of genetic diseases in the population. Wilson's disease (WD) is a rare genetic copper-accumulation disorder for which timely intervention is crucial, as treatment is readily available. We studied WD in the Estonian Biobank population to advance patient screening, swift diagnosis, and subsequent treatment. Combined analysis of genotype and phenotype data from electronic health records (EHRs) consolidated at the Estonian biobank led to the identification of 17 individuals at high risk of developing WD, who were recalled for further examination and deep phenotyping. All recall study participants, regardless of phenotype, age, and prior WD diagnosis, had low serum ceruloplasmin and copper levels, and 87% also exhibited signs of early to late neurodegeneration. The p.His1069Gln variant in ATP7B, a prevalent pathogenic mutation, showed a striking four- to five-fold enrichment in Estonians compared with other populations. Based on our analysis of genetic and nationwide health registry data, we estimate that WD remains underdiagnosed and undertreated in Estonia. Our study demonstrates that personalized medicine, implemented with the collaboration of medical professionals, has the potential to reduce the healthcare burden by facilitating the accurate diagnosis of rare genetic diseases. To our knowledge, this report is the first to describe a large-scale national biobank-based study of WD.

Liver transplantation currently represents a therapeutic option for patients with Wilson disease presenting with end-stage liver disease or acute liver failure. Indeed, it has been associated with excellent postoperative survival curves in view of young age at transplant and absence of recurrence. Attention has shifted over the past decades to a wise expansion of indications for liver transplantation. Evidence has emerged supporting the transplantation of carefully selected patients with primarily neuropsychiatric symptoms and compensated cirrhosis. The rationale behind this approach is the potential for surgery to improve copper homeostasis and consequently ameliorate neuropsychiatric symptoms. However, several questions remain unanswered, such as how to establish thresholds for assessing pretransplant neuropsychiatric impairment, how to standardize preoperative neurological assessments, and how to define postoperative outcomes for patients meeting these specific criteria. Furthermore, a disease-specific approach will be proposed both for the liver transplant evaluation of candidates with Wilson disease and for patient care during the transplant waiting period, highlighting the peculiarities of this systemic disease.

It has been found that various heavy metals can initiate different types of regulated cell deaths. Among these metals, copper, an essential trace micronutrient that plays a major role in a lot of physiological processes, also can initiate cell death. It can act as a constituent of metalloenzymes, and can act as a mediator for signaling pathways to regulate proliferation and metastasis of tumor. It is also an integral part of some metal-based anticancer drugs. Recent studies have revealed that excessive intracellular copper accumulation leads to the aggregation of mitochondrial lipoylated proteins, causing proteotoxic stress and ultimately resulting in cell death. This newly discovered copper-induced cell death is termed as cuproptosis. In the last few years, a lot of research has been done to understand the mechanism of copper-mediated cell death, and attempts have also been made to identify the relationship between cuproptosis and the development of cancer. In this review, we have provided a comprehensive overview on the significance of copper, its regulation inside the body, the possible mechanism of cuproptosis, and how this cuproptosis can be employed as a therapeutic tool for cancer ablation.

The need for sleep is universal, and the ability to meet this need impacts the quality of life for patients, families, and caregivers. Although substantial progress has been made in treating rare diseases, many patients have unmet medical sleep needs, and current regulatory policy makes it prohibitively difficult to address those needs medically. This opinion reviews the rare disease experience with sleep disorders and explores potential solutions. First, we provide case profiles for the rare diseases Wilson's Disease, Angelman Syndrome, and Prader-Willi Syndrome. These profiles highlight challenges in rare disease diagnosis and barriers to pinpointing disease pathophysiology, including biomarkers that intersect with sleep disorders. Second, we transition to a bird's eye view of sleep disorders and rare diseases by reporting input from a stakeholder discussion with the U.S. Food and Drug Administration regarding abnormal sleep patterns in various rare diseases. Last, in response to the profound unmet medical needs of patients with rare diseases and sleep disorders, we propose adapting and using the clinical trial design known as a "basket trial". In this case, a basket trial would include patients with different rare diseases but the same debilitating symptoms. This research approach has the potential to benefit many rare disease patients who are otherwise left with profound unmet medical needs.

Wilson's disease (WD) is a rare autosomal recessive disorder causing excessive copper deposition and a spectrum of manifestations, particularly neurological and hepatic symptoms. We analysed the clinical characteristics of patients with WD admitted to the country's only reference centre, which provided long-term care to most adult patients in Poland over seven decades (pre-1959 to 2019).

Electronic prospective data collection began in the 2000s and, for prior years, medical records were analysed retrospectively. Demographic and clinical characteristics, treatment and outcomes were analysed by decade of diagnosis. Life-years lost were estimated in patients with WD compared with the general population. Kaplan-Meier curves were used for a time-to-death analysis using 2000-2009 as a reference.

In total, 929 patients were analysed. The number of patients increased from 21 before 1959 to 315 for 2000 to 2009 period. Mostly males were diagnosed before the 1990s, but the numbers of female patients diagnosed increased thereafter. Initially, most patients presented with neurological manifestations; however, the incidence of hepatic manifestations and asymptomatic presentations increased over time as patients were diagnosed early and consequently were more independent at diagnosis. Fewer Kayser-Fleischer rings were detected recently. Prior to 1970, patients were treated with D-penicillamine (DP); however, since the introduction of zinc, both therapies have been used as often. Since the 1990s, switches between DP and zinc were recorded in 6%-7% of patients. Consistent improvement in survival has been observed over the years.

This is the largest cohort of patients with WD reported in Poland, with the longest follow-up. Earlier diagnosis and prognosis have improved over seven decades.

Copper serves as an indispensable cofactor for all living organisms, and its excessive accumulation has been associated with a variety of diseases. Wilson's disease (WD) serves as an illustrative example of copper toxicity in humans, frequently presenting with liver and/or neuropsychiatric symptoms. The current therapeutic drugs, penicillamine (PA) and zinc gluconate (ZnG), have constraints, and research on their combination efficacy remains insufficient. It has been reported that melatonin (MLT) plays a vital role in binding to transition metals and exhibits strong antioxidant capacity. To investigate the therapeutic efficacy of MLT and combined treatment, rats were randomly divided into the following seven groups: the control (Con) group, copper-laden model rat (Mod) group, PA-treated group, ZnG-treated group, MLT- treated group, PA-ZnG-treated group, and PA-MLT-treated group. Then potential mechanisms and targets were investigated using a combination of metabolomics and network pharmacology and verified by molecular docking and qPCR. The findings revealed that MLT and the combination significantly improved behavior, pathology and copper levels in copper-laden rats. The results of the metabolomics study showed that profoundly altered metabolites were identified, and alanine, aspartate and glutamate metabolism, pyruvate metabolism, citrate cycle (TCA cycle), and glycolysis/gluconeogenesis were explored. In addition, molecular docking showed that MLT had high binding affinity with key targets, and qPCR results revealed that MLT could reverse the mRNA expression of targets GOT2 and PKM2. It was concluded that MLT effectively improves brain injury in copper-laden rats, and this effect was linked with the altered features of the metabolite profiles.

Wilson disease (WD) is a rare disorder of copper metabolism, leading to liver and neurological disease. Existing literature on WD in pregnancy is scarce, limiting preconception and obstetrical counselling. In this systematic review with meta-analysis, we determine the prevalence of various adverse pregnancy and neonatal outcomes in WD, as well as evaluate the impact of WD treatment on these outcomes.

Scopus, MEDLINE and EMBASE were searched until 12 May 2023, for studies of pregnant individuals with WD and at least one pregnancy or neonatal outcome of interest. Meta-analysis of single proportions was conducted to pool prevalence data for each outcome. Outcome rates were compared between treated and untreated groups in a meta-analysis of dichotomous events.

Sixteen studies, published from 1975 to 2022, were included in the systematic review. Thirty-seven percent of pregnancies reported at least one adverse pregnancy outcome. Spontaneous abortions (20%), liver diseases of pregnancy (4.5%) and preterm births (2%) were the most frequent adverse pregnancy outcomes in patients with WD. The prevalence of spontaneous abortions was significantly lower in pregnant individuals with WD who received treatment during pregnancy (OR: .47, 95% CI: 35%-63%). The prevalence of any adverse pregnancy outcome was also significantly lower with treatment (OR: .53, 95% CI: .37-.76), which appears to be mostly driven by the reduction of spontaneous abortions.

There is low to moderate quality evidence to suggest that preconception and obstetrical counselling for patients with WD should include a discussion on the potentially high frequency of adverse pregnancy outcomes in this population, as well as the importance of continuing WD treatment during pregnancy to ensure satisfactory pregnancy course and potentially minimize the risk of spontaneous abortions.

The pathophysiology of dystonia in Wilson disease (WD) is complex and poorly understood. Copper accumulation in the basal ganglia, disrupts dopaminergic pathways, contributing to dystonia's development via neurotransmitter imbalance. Despite advances in diagnosis and management, WD with dystonia remains a challenging condition to treat. We aim to report the unprecedented co-occurrence of pathogenic genetic variants in both the ATP7B and KMT2B genes in a patient with WD. A 13-year-old male presented at 12 with dysarthria and bilateral Kayser-Fleischer rings. Over months, dystonia spread to his left foot, upper limb, and trunk, accompanied by slowed daily activities. Diagnostic tests included MRI for brain structure, abdominal ultrasound for liver function, serum ceruloplasmin and copper levels to assess copper metabolism, and 24-hour urine copper tests for excretion levels. Whole exome sequencing was conducted using genomic DNA from peripheral blood samples. Variant classification followed guidelines from the American College of Medical Genetics and Genomics. The sequencing revealed compound heterozygous pathogenic variants in the ATP7B gene: NM_000053.4:c.2165dupT and NM_000053.4:c.813C>A. A pathogenic variant in the KMT2B gene, NM_014727:c.3052delA, was identified. This case highlights WD co-occurrence with ATP7B and KMT2B mutations, suggesting KMT2B as a potential genetic modifier.

Introduction Wilson disease (WD) is a rare inherited autosomal recessive disorder caused by a mutation in the ATP7B gene. This mutation affects copper metabolism, leading to the accumulation of copper in the liver, brain, cornea, and other tissues. If not treated, WD can lead to significant morbidities. This study aimed to display the prevalence, clinical presentations, diagnosis, treatment, and outcome of WD in Bahrain. Methods This is a retrospective cohort study of patients diagnosed with WD in the Department of Pediatrics, Salmaniya Medical Complex, Manama, Kingdom of Bahrain, from March 2002 to July 2024. The diagnosis of WD was based on clinical presentations, laboratory markers, radiological imaging, and genetic testing. Results Up to July 2024, eight patients from four families were diagnosed with WD in Bahrain. Accordingly, the prevalence of WD was 1.7 patients per 100,000 (0.002%). Parental consanguinity was noted in all families. Males were equal to females (n=4, 50% each). The mean age at presentation was 13 ± 3.6 years, ranging from 9 to 21 years. Three patients (37.5%) presented with hepatic manifestations, two (25%) with neurological manifestations, and three (37.5%) were detected upon family screening. Kayser Fleischer (KF) rings were found in two (25%) patients via slit lamp examination. Of the seven patients with available data, five (71.4%) had low serum copper, six (85.7%) had low serum ceruloplasmin, and six (85.7%) had high 24-hour urinary copper. Genetic testing was positive for the ATP7B gene variants in all patients, of which four members of one family had a novel mutation. Abdominal ultrasound revealed hepatic cirrhosis in four (50%) patients, increased hepatic echogenicity in five (62.5%), splenomegaly in three (37.5%) patients, and ascites in one (12.5%) patient. Brain magnetic resonance imaging (MRI) was positive in three (50%) out of six patients. All patients received copper chelating therapy. Six (75%) patients survived; one of them underwent living-related liver transplantation due to rapidly progressive neurological symptoms. Two (25%) patients died due to hepatic failure and encephalopathy. Conclusion WD is a rare disorder in Bahrain. This study presents eight patients with WD from four families. Five patients were symptomatic at presentation, while three were diagnosed upon genetic family screening. Hepatic manifestations were the most common presentation, followed by behavioral changes and neurological symptoms. Two patients had KF rings, while three had classical brain MRI findings. Genetic testing served as a confirmatory diagnostic tool that revealed a diversity of variants causing the disease, of which one variant was a novel mutation. Despite oral chelating therapy, morbidity and mortality remain high in patients with WD.

Low serum ceruloplasmin concentration is considered robust marker for Wilson disease (WD) screening, measuring serum ceruloplasmin oxidase activity might be an even more valuable diagnostic tool, but it has not been sufficiently studied.

All patients who were assessed for serum ceruloplasmin oxidase activity between January 1, 2016, and September 2, 2019, were enrolled in this study. The diagnostic performance of serum ceruloplasmin oxidase activity was analyzed using receiver operating characteristic curve analysis (ROC), Spearman's rank correlation, and Mann-Whitney U test.

Serum ceruloplasmin oxidase activity was significantly decreased in WD patients (0.87 U/L, IQR 0.61-1.54). The optimal cut-off of serum ceruloplasmin oxidase activity to identified WD is 7 U/L, with sensitivity and specificity of 97.03 % and 98.19 %, respectively. Furthermore, this study revealed a positive correlation between enzymatic and immunoreactive serum ceruloplasmin tests. As primary diagnostic methods, serum ceruloplasmin levels below the diagnostic cut-offs for either the enzymatic or immunoreactive tests were observed in 818 out of 842 WD patients (97.15 %). Compared with the presence of K-F rings in asymptomatic patients, the accuracy of serum ceruloplasmin tests was significantly higher (56.12 % VS 95.08 %). Moreover, the positive rate of cranial MRI in neurological patients was similar to the tests of serum ceruloplasmin (92.91 % VS 97.40 %). Moreover, 71 patients had ambiguous genetic results, complicating the diagnosis. However, serum ceruloplasmin tests successfully identified 65 out of these 71 patients (91.55 %).

Serum ceruloplasmin oxidase activity has excellent performance in diagnosing WD, which should be widely used as preferred test in WD patients.

Wilson disease (WD) is a rare disorder of copper metabolism, causing copper accumulation mainly in the liver and the brain. The prevalence of WD was previously estimated around 20 to 33.3 patients per million for the United States, Europe, and Asia, but data on the prevalence of WD in Germany are limited.

To describe patient characteristics and to assess prevalence of WD in Germany using a representative claims database.

WD patients were identified in the WIG2 (Wissenschaftliches Institut für Gesundheitsökonomie und Gesundheitssystemforschung; Scientific Institute for Health Economics and Health Systems Research) benchmark database of 4.5 million insured Germans by combining ICD-10-coding with WD-specific lab tests and treatments. The study period ranged from 2013 to 2016 for assessing patient characteristics, and to 2018 for prevalence, respectively.

Seventy unique patients were identified. Most patients (86%) were between 18 and 64 years of age and more often male (60%) than female. Two patients (3%) younger than 18 years were included, as well as 8 patients (11%) older than 64 years. Most common WD subtypes were hepatic (57%), psychiatric (49%), and neurologic (44%). Average prevalence was 20.3 patients per million (range: 17.8-24.4), with similar results for two-year prevalence. Generally, prevalence increased steadily over the study period. Observed mortality was low, with only one death during the study period.

This study adds valuable real-world data on the prevalence and patient characteristics of WD in Germany. Generally, our findings align with other reports and contribute to the global understanding of WD epidemiology. Still, regional and temporal trends remain to be investigated more thoroughly to further the understanding of the natural history and epidemiology of this rare disease.

Few studies have focused on the outcomes of Wilson's disease (WD) diagnosed before age of 5 years. This study aimed to summarize the clinical features of early diagnosed WD and analyse treatment outcomes and the risk factors associated with treatment failure.

A total of 139 children confirmed with WD before 5 years were enrolled in this study. Only patients with follow-up over 1 year were analysed with Kaplan-Meier survival analysis. The composite outcomes included death, progression to liver failure or acute hepatitis, development of renal or neurological symptoms and persistent elevation of alanine aminotransferase (ALT). The treatment failure was defined as occurrence of at least one of above outcomes.

Among 139 WD patients at diagnosis, two (1.4%) WD patients presented with symptomatic liver disease, whereas 137 (98.6%) were phenotypically asymptomatic, including 135 with elevated ALT and 2 with normal liver function. Median serum ceruloplasmin (Cp) was 3.1 mg/dL, and urinary copper excretion was 87.4 μg/24-h. There were 71 variants identified in the the copper-transporting ATPase beta gene, and 29 were loss of function (LOF). 51 patients with LOF variant were younger at diagnosis and had lower Cp than 88 patients without LOF. Among 93 patients with over 1 year of follow-up, 19 (20.4%) received zinc monotherapy, and 74 (79.6%) received a zinc/D-penicillamine combination therapy. 14 (15.1%) patients underwent treatment failure, and its occurrence was associated with poor compliance (p < .01).

Cp is a reliable biomarker for early diagnosis, and zinc monotherapy is an effective treatment for WD during early childhood. Good treatment compliance is critical to achieve a favourable outcome.

Cuproptosis is a novel form of regulated cell death, which plays an important role in the physiological and pathological processes of the human body. Despite the increasing research on cuproptosis-related genes (CRGs) and their correlation with diseases, the pathogenesis of cuproptosis-related diseases remains unclear. Furthermore, there is a lack of reviews on the emerging technologies for regulating cuproptosis in disease treatment. This study delves into the copper-induced cell death mechanism, distinguishing cuproptosis from mechanisms like oxidative stress, glutathione synthesis inhibition, and ubiquitin-proteasome system inhibition. Several long-standing mysteries of diseases such as Wilson's disease and Menkes disease may be attributed to the occurrence of cuproptosis. In addition, we also review the detection indicators related to cuproptosis, providing targets for the diagnosis of cuproptosis-related diseases, and summarize the application value of cuproptosis in tumor therapy to better elucidate the impact of copper in cell death and diseases, and thus to promote the application prospects and possible strategies of cuproptosis-related substances, such as copper ion chelators, copper ion carriers, and copper nanomaterials, in disease therapy.

Acute liver failure (ALF) may be the first and most dramatic presentation of Wilson's disease (WD). ALF due to WD (WD-ALF) is difficult to distinguish from other causes of liver disease and is a clear indication for liver transplantation. There is no firm recommendation on specific and supportive medical treatment for this condition.

To critically evaluate the diagnostic and therapeutic management of WD-ALF patients in order to improve their survival with native liver.

A retrospective analysis of patients with WD-ALF was conducted in two pediatric liver units from 2018 to 2023.

During the study period, 16 children (9 males) received a diagnosis of WD and 2 of them presented with ALF. The first was successfully treated with an unconventional combination of low doses of D-penicillamine and zinc plus steroids, and survived without liver transplant. The second, exclusively treated with supportive therapy, needed a hepatotransplant to overcome ALF.

Successful treatment of 1 WD-ALF patient with low-dose D-penicillamine and zinc plus steroids may provide new perspectives for management of this condition, which is currently only treated with liver transplantation.

Wilson's disease is an autosomal recessive disorder related to copper metabolism which mostly patients occurs in adolescents, fertility has become a problem that WD needs to face.

A 21 years retrospective follow up study was conducted and a total of 220 female patients were included to identify patients with outcomes of pregnancy.

Untreated female patients with WD had a spontaneous abortion rate of 44%. During the study period, 146 female patients with WD from multicenter, 75 patients (51.4%) had successful outcomes of pregnancy. Notably, urinary copper levels below 616 μg/24 h were strongly associated with successful pregnancy. The nomogram built on these variables were age, urinary copper, haemoglobin and Child-Pugh classification, internally validated and showed good performance.

The spontaneous abortion rate was 44% in untreated females with WD and developed a four-variable risk prediction model to accurately predict the likelihood of a successful pregnancy.

Nonalcoholic fatty liver disease (NAFLD) is considered an independent risk factor for cardiovascular disease (CVD). The overall morbidity and mortality of CVD increase with higher fibrosis stage in NAFLD. Carotid atherosclerosis (CAS) is an important predictor of cardiovascular events. However, the relationship between liver fibrosis degree and the risk of CAS in NAFLD patients remains uncertain. We aimed to investigate the relationship between noninvasive liver fibrosis markers and CAS risk in patients with NAFLD.

This study included 3,302 participants with NAFLD. Participants were divided into a CAS group and a non-CAS group based on carotid artery ultrasound results. They were then stratified into quartiles using various noninvasive liver fibrosis markers (fibrosis-4 (FIB-4), modified FIB-4 (mFIB-4), aminotransferase to platelet ratio index (APRI), aminotransferase to alanine aminotransferase ratio (AAR), AAR-to-platelet ratio index (AARPRI), and Forns index) to assess the associations between these markers and the risk of CAS.

In the NAFLD population, individuals with CAS exhibited elevated levels of blood pressure, glucose, lipids, and noninvasive liver fibrosis markers (p < 0.001). The higher quartiles of noninvasive liver fibrosis markers, including FIB-4, mFIB-4, AAR, AARPRI, and Forns index, were significantly associated with increased risks of CAS, even after adjusting for multiple CVD risk factors.

In individuals with NAFLD, increased noninvasive liver fibrosis markers were independently associated with elevated CAS risk, which may be beneficial in assessing the risk of CVD in individuals with NAFLD.

Assessment of Wilson disease is complicated, with neither ceruloplasmin, nor serum or urine copper, being reliable. Two new indices, accurate non-ceruloplasmin copper (ANCC) and relative ANCC were developed and applied to a cohort of 71 patients, as part of a Wilson Disease Registry Study.

Elemental copper-protein speciation was developed for holo-ceruloplasmin quantitation using strong anion exchange chromatography coupled to triple quadrupole inductively coupled plasma mass spectrometry. The serum proteins were separated using gradient elution and measured at m/z 63 (63Cu+) and 48 (32S16O+) using oxygen reaction mode and Cu-EDTA as calibration standard. The ANCC was calculated by subtraction of the ceruloplasmin bound copper from the total serum copper and the RelANCC was the percentage of total copper present as the ANCC.

The accuracy of the holo-ceruloplasmin measurement was established using two certified reference materials, giving a mean recovery of 94.2 %. Regression analysis between the sum of the copper containing species and total copper concentration in the patient samples was acceptable (slope=0.964, intercept=0, r=0.987) and a difference plot, gave a mean difference for copper of 0.38 μmol/L. Intra-day precision for holo-ceruloplasmin at serum copper concentrations of 0.48 and 3.20 μmol/L were 5.2 and 5.6 % CV and the intermediate precision at concentrations of 0.80 and 5.99 μmol/L were 6.4 and 6.4 % CV, respectively. The limit of detection (LOD) and lower limit of quantification (LLOQ) for holo-ceruloplasmin were 0.08 and 0.27 μmol/L as copper, respectively.

ANCC and Relative ANCC are important new diagnostic and monitoring biomarker indices for Wilson disease (WD).

In this study, we used a national cohort of patients with Wilson's disease (WD) to investigate the admissions, mortality rates, and costs over the captured period to assess specific subpopulations at higher burden.

Patients with WD were selected using 2016-2019 National Inpatient Sample (NIS). The weighted estimates and patient data were stratified using demographics and medical characteristics. Regression curves were graphed to derive goodness-of-fit for each trend from which R2 and P values were calculated.

Annual total admissions per 100 000 hospitalizations due to WD were 1075, 1180, 1140, and 1330 ( R2  = 0.75; P  = 0.13) from 2016 to 2019. Within the demographics, there was an increase in admissions among patients greater than 65 years of age ( R2  = 0.90; P  = 0.05) and White patients ( R2  = 0.97; P  = 0.02). Assessing WD-related mortality rates, there was an increase in the mortality rate among those in the first quartile of income ( R2  = 1.00; P  < 0.001). The total cost for WD-related hospitalizations was $20.90, $27.23, $24.20, and $27.25 million US dollars for the years 2016, 2017, 2018, and 2019, respectively ( R2  = 0.47; P  = 0.32). There was an increasing total cost trend for Asian or Pacific Islander patients ( R2  = 0.90; P  = 0.05). Interestingly, patients with cirrhosis demonstrated a decreased trend in the total costs ( R2  = 0.97; P  = 0.02).

Our study demonstrated that certain ethnicity groups, income classes and comorbidities had increased admissions or costs among patients admitted with WD.

Humans are continuously exposed to various heavy metals including copper, iron, cadmium, and arsenic, which were specifically selected for the current analysis because they are among the most frequently encountered environmental mankind and industrial pollutants potentially causing human health hazards and liver injury. So far, these issues were poorly assessed and remained a matter of debate, also due to inconsistent results. The aim of the actual report is to thoroughly analyze the positive as well as negative effects of these four heavy metals on human health. Copper and iron are correctly viewed as pollutant elements essential for maintaining human health because they are part of important enzymes and metabolic pathways. Healthy individuals are prepared through various genetically based mechanisms to maintain cellular copper and iron homeostasis, thereby circumventing or reducing hazardous liver and organ injury due to excessive amounts of these metals continuously entering the human body. In a few humans with gene aberration, however, liver and organ injury may develop because excessively accumulated copper can lead to Wilson disease and substantial iron deposition to hemochromatosis. At the molecular level, toxicities of some heavy metals are traced back to the Haber Weiss and Fenton reactions involving reactive oxygen species formed in the course of oxidative stress. On the other hand, cellular homeostasis for cadmium and arsenic cannot be provided, causing their life-long excessive deposition in the liver and other organs. Consequently, cadmium and arsenic represent health hazards leading to higher disability-adjusted life years and increased mortality rates due to cancer and non-cancer diseases. For unknown reasons, however, liver injury in humans exposed to cadmium and arsenic is rarely observed. In sum, copper and iron are good for the human health of most individuals except for those with Wilson disease or hemochromatosis at risk of liver injury through radical formation, while cadmium and arsenic lack any beneficial effects but rather are potentially hazardous to human health with a focus on increased disability potential and risk for cancer. Primary efforts should focus on reducing the industrial emission of hazardous heavy metals.

The aggregation of amyloid-beta peptide and tau protein dysregulation are implicated to play key roles in Alzheimer's disease pathogenesis and are considered the main pathological hallmarks of this devastating disease. Physiologically, these two proteins are produced and expressed within the normal human body. However, under pathological conditions, abnormal expression, post-translational modifications, conformational changes, and truncation can make these proteins prone to aggregation, triggering specific disease-related cascades. Recent studies have indicated associations between aberrant behavior of amyloid-beta and tau proteins and various neurological diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as retinal neurodegenerative diseases like Glaucoma and age-related macular degeneration. Additionally, these proteins have been linked to cardiovascular disease, cancer, traumatic brain injury, and diabetes, which are all leading causes of morbidity and mortality. In this comprehensive review, we provide an overview of the connections between amyloid-beta and tau proteins and a spectrum of disorders.

Epidemiological data on rare diseases in China are currently limited. The objective of this study was to provide a comprehensive understanding of the prevalence and incidence of rare diseases by systematically analyzing the available epidemiological data. We conducted a comprehensive search of English and Chinese databases, the Incidence and Prevalence Database, the Chinese Rare Disease Guideline, and the Taiwan Health Promotion Administration from 2010 to 2023. We identified the top diseases and regions based on epidemiological data and present the maximum, minimum, and median prevalence and incidence values in tables and forest plots. 1,264 prevalence and incidence data were retrieved from 277 studies, guidelines and official websites, covering 110 rare diseases (53.1%) and 32 regions (94.1%). In terms of geographical regions, incidence or prevalence data were available for 32 regions (94.1%), excluding Tibet Hui Autonomous Region and Macao Special Administrative Region. In terms of rate, 60 and 77 out of 207 diseases (29.0% and 37.2%) had available incidence and prevalence data, respectively. Eight diseases had an incidence rate equal to or greater than that of 1,000 patients per million. The present study provides a comprehensive epidemiological analysis and valuable insights into the prevalence and incidence of rare diseases in China. Our findings underscore the pressing need for sustained drug research and medical support for individuals and families impacted by rare diseases.

Wilson disease (WD) is a progressive, potentially fatal degenerative disease affecting the liver and central nervous system. Given its low prevalence, collecting data on large cohorts of patients with WD is challenging. Comprehensive insurance claims databases provide powerful tools to collect retrospective data on large numbers of patients with rare diseases.

To describe patients with WD in the United States, their treatment and clinical outcome, using a large insurance claims database.

This retrospective, longitudinal study was performed in the Clarivate Real-World Data Product database. All patients with ≥ 2 claims associated with an International Classification of Diseases 10 (ICD-10) diagnostic code for WD (E83.01) between 2016 and 2021 were included and followed until death or study end. Patients were divided into two groups by whether or not they were documented to have received a specific treatment for WD. Clinical manifestations, hospitalisations, liver transplantation and death were documented.

Overall, 5376 patients with an ICD-10 diagnostic code for WD were identified. The mean age at inclusion was 41.2 years and 52.0% were men. A specific WD treatment was documented for 885 patients (15.1%), although the number of patients taking zinc salts may be underestimated due to over the counter purchase. At inclusion, the mean age of patients with a documented treatment was 36.6 ± 17.8 years vs 42.2 ± 19.6 years in those without a documented treatment. During follow-up, 273 patients (5.1%) died. Compared with the American general population, the standardised mortality ratio was 2.19. The proportion of patients with a documented WD-specific treatment who died during follow-up was 4.0% and the mean age at death 52.7 years.

Patients treated for WD in the United States had an excess early mortality compared with the American population. These findings indicate that there is a significant unmet need for effective treatment for WD in the United States.