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Hepatic inflammation is commonly identified in Wilson disease (WD), a genetic disease of hepatic and brain copper accumulation. Copper accumulation is associated with increased oxidative stress and reactive oxygen species generation which may result in non-enzymatic oxidation of membrane-bound polyunsaturated fatty acids (PUFA). PUFA can be oxidized enzymatically via lipoxygenases (LOX), cyclooxygenases (COX), and cytochrome P450 monooxygenases (CYP). Products of PUFA oxidation are collectively known as oxylipins (OXL) and are bioactive lipids that modulate hepatic inflammation. We examined hepatic OXL profiles at early stages of WD in two mouse models, the toxic milk mouse from The Jackson Laboratory (tx-j) and the Atp7b knockout on a C57Bl/6 background (Atp7b-/-B6). Targeted lipidomic analysis performed by ultra-high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry showed that in both tx-j and Atp7b-/-B6 mice, hepatic OXL profiles were altered with higher thromboxane and prostaglandins levels. The levels of oxidative stress marker, 9-HETE were increased more markedly in tx-j mice. However, both genotypes showed upregulated transcript levels of many genes related to oxidative stress and inflammation. Both genotypes showed higher prostaglandins, thromboxin along with higher PUFA-derived alcohols, diols, and ketones with altered epoxides; the expression of Alox5 was upregulated and many CYP-related genes were dysregulated. Pathway analyses show dysregulation in arachidonic acid and linoleic acid metabolism characterizes mice with WD. Our findings indicate alterations in hepatic PUFA metabolism in early-stage WD and suggest the upregulation of both, non-enzymatic ROS-dependent and enzymatic PUFA oxidation, which could have implications for hepatic manifestations in WD and represent potential targets for future therapies.

Background: In the autosomal recessive disorder of copper metabolism, Wilson's disease (WD), patients present hepatic, neurological, and psychiatric symptoms combined in different and unpredictable ways. Brain pathology primarily affects the basal ganglia and may cause movement, cognitive, affective, and behavioral disturbances. Personality traits have been rarely studied in the neurological form of the disease. Objective: To investigate whether patients with the neurological form of WD (WDn) have specific personality traits, especially those typical of frontobasal loop dysfunction. Methods: The personality of 29 adult WDn patients (without significant cognitive and psychiatric disorders) and 29 matched healthy controls was assessed using the Minnesota Multiphasic Personality Inventory (MMPI‐2). Results: Compared to healthy individuals, patients with WDn scored higher on the following MMPI‐2 scales: hypochondriasis, physical malfunctioning, bizarre sensory experiences, health concerns, and general health concerns, with no differentiation between patients and controls on the remaining MMPI‐2 scales. Conclusions: Long‐term treated patients with WDn did not appear to have any specific personality traits reflecting unambiguously frontobasal psychopathology, if self‐report measurement is used. The more strongly exhibited features concerning their actual physical ailments and health anxiety, such as hypochondria, chronic fatigue, and poor psychophysical well‐being, could result from psychological reactions to a chronic disabling brain disease. Further study of personality traits and personality disorders is warranted in patients with clearly defined forms of WD, using various measurement tools. Psychopathological disorders in different forms of WD warrant further studies. [ABSTRACT FROM AUTHOR]

Metabolic abnormalities associated with liver disease have a significant impact on the risk and prognosis of cholecystitis. However, the underlying mechanism remains to be elucidated. Here, we investigated this issue using Wilson's disease (WD) as a model, which is a genetic disorder characterized by impaired mitochondrial function and copper metabolism. Our retrospective clinical study found that WD patients have a significantly higher incidence of cholecystitis and a poorer prognosis. The hepatic immune cell landscape using single-cell RNA sequencing showed that the tissue immune microenvironment is altered in WD, mainly a major change in the constitution and function of the innate immune system. Exhaustion of natural killer (NK) cells is the fundamental factor, supported by the upregulated expression of inhibitory receptors and the downregulated expression of cytotoxic molecules, which was verified in clinical samples. Further bioinformatic analysis confirmed a positive correlation between NK cell exhaustion and poor prognosis in cholecystitis and other inflammatory diseases. The study demonstrated dysfunction of liver immune cells triggered by specific metabolic abnormalities in WD, with a focus on the correlation between NK cell exhaustion and poor healing of cholecystitis, providing new insights into the improvement of inflammatory diseases by assessing immune cell function. [ABSTRACT FROM AUTHOR]

Wilson's disease (WD) is an inherited autosomal recessive disorder of copper metabolism, that affects the liver, the brain, and the musculoskeletal system. The symptoms, clinical course, and outcome of WD are highly variable. The main features—the hepatic and the neurologic forms—can be distinguished, but many patients present with a mixture of both. Diagnosis is based on the combination of clinical signs, biochemical features, histologic findings, and molecular analysis of ATP7B gene, when available. The diagnosis of WD is suggested biochemically by the association of increase serum transaminase concentrations, low serum ceruloplasmin, and high urinary copper concentration. The relative lack of sensitive and specific criteria for the rapid diagnosis of WD has made it difficult to diagnose. It is imperative to consider the differential diagnoses including MEDNIK disease, CDG, and MDRIII deficiency, where copper levels are altered. Making the correct diagnosis is imperative since there are no beneficial effects to chelation in MDRIII, CDG, or other non-WD conditions. These diagnostic difficulties illustrate the importance of metabolic screening and molecular genetics tests in the exact diagnosis of these disorders. Untreated, WD invariably leads to death from liver disease or severe neurological disability, and early and rapid diagnosis remains paramount for optimal patient management. [ABSTRACT FROM AUTHOR]

Programmable and modular systems capable of orthogonal genomic and transcriptomic perturbations are crucial for biological research and treating human genetic diseases. Here, we present the minimal versatile genetic perturbation technology (mvGPT), a flexible toolkit designed for simultaneous and orthogonal gene editing, activation, and repression in human cells. The mvGPT combines an engineered compact prime editor (PE), a fusion activator MS2–p65–HSF1 (MPH), and a drive-and-process multiplex array that produces RNAs tailored to different types of genetic perturbation. mvGPT can precisely edit human genome via PE coupled with a prime editing guide RNA and a nicking guide RNA, activate endogenous gene expression using PE with a truncated single guide RNA containing MPH-recruiting MS2 aptamers, and silence endogenous gene expression via RNA interference with a short-hairpin RNA. We showcase the versatility of mvGPT by simultaneously correcting a c.3207C>A mutation in the ATP7B gene linked to Wilson's disease, upregulating the PDX1 gene expression to potentially treat Type I diabetes, and suppressing the TTR gene to manage transthyretin amyloidosis. In addition to plasmid delivery, we successfully utilize various methods to deliver the mvGPT payload, demonstrating its potential for future in vivo applications. Molecular tools enabling precise DNA mutations and targeted modulation of gene expression have significant potential in medicine and biology. Here, the authors develop a compact system for simultaneous and independent gene editing, activation, and repression in mammalian cells. [ABSTRACT FROM AUTHOR]

Synaptic efficacy is critical for memory formation and consolidation. Accumulating evidence suggest that synapses are impaired during Wilson's disease (WD), contributing to neuronal dysfunction and cognitive decline. WD is a prototypical condition among the copper metabolism disorders. Cognitive impairment is a common feature of affected patients with neurological symptoms, presenting as memory deficits, decreased cognitive flexibility, and impaired learning capabilities. These cognitive deficits can significantly impact the quality of life, affecting work and academic performance. However, the mechanisms mediating the inhibitory synaptic dysfunction in WD are incompletely understood. We investigated the effects of the double-stranded RNA-dependent protein kinase/eukaryotic initiation factor 2α (PKR/eIF2α) pathway on synaptic structure and function in WD using a murine model, toxic milk (TX mice). During mouse open-field tests, we noted a substantial rise in the mobility/immobility ratio among WD model animals compared to that in WT mice. Additionally, WD mice exhibited diminished central area exploration, as evidenced by reduced travel distance. Moreover, they displayed prolonged escape latency in the Barnes maze, suggesting that chronic copper accumulation is associated with neuropsychiatric alterations and cognitive impairment. We also found a decrease in the expression of synapse-associated proteins (synapsin 1, synaptophysin, postsynaptic density protein-93 [PSD93], postsynaptic density protein-95 [PSD95]), and vesicle-associated membrane protein2 [VAMP2]) besides abnormal neurotransmitter levels (including glutamate and GABA), indicating the presence of synaptic dysfunction in TX mice. Inhibiting PKR via C16 prevented these changes, suggesting that dysfunctional cognition is associated with the PKR/eIF2α pathway. We also observed changes in synapses, vesicles, dendritic spine density, and dendritic length that were associated with the presence of cognitive dysfunction. Further investigation revealed that C16 treatment decreased the TUNEL-positive cell numbers in the hippocampus of TX mice and prevented 8-OHdG-induced synaptic dysfunction. Results suggest that PKR downregulation prevents copper-induced synaptic dysfunction in the murine WD model. Therefore, targeting PKR pharmacologically may be a potential therapeutic strategy for treating the copper-induced neuropathology of patients with WD. [ABSTRACT FROM AUTHOR]

Objective: This study aims to analyze the lipid metabolism patterns and identify risk factors for dyslipidemia in Wilson's Disease (WD), offering novel insights into diagnosis and treatment strategies for unexplained dyslipidemia. Methods: Data from Wilson's disease patients hospitalized at the First People's Hospital of Shanghai from December 2008 to February 2015 were collected. Patients were categorized into normal lipid (46 cases) and dyslipidemia (42 cases) groups based on lipid levels. Group analyzes were conducted using t-tests, chi-square analysis, and rank sum tests. Spearman correlation, multiple linear regression, or Logistic regression were employed to identify relevant influencing factors. Results: 1. The incidence of abnormal blood lipids in a series of Wilson's disease patients was 47.73% (25.12 ± 1.29 years old), and the incidence of control healthy group was 27.40%, with proportions of hypercholesterolemia, hypertriglyceridemia, and low-density lipoprotein cholesterol being 14.77, 30.68, and 29.63%, respectively; 2. Significant differences were observed between the dyslipidemia and normal WD groups in AST/ALT ratio, liver parenchymal echo, liver surface, spleen area, and ultrasound total score.3. Low-and high-density lipoprotein cholesterols (LDL-c and HDL-c) showed no significant correlation with these indicators. Triglyceride (TG) exhibited moderately negative correlation with AST/ALT, liver parenchymal echo, spleen area, and ultrasound score. Total cholesterol (TC) displayed low negative correlation with these factors. Conclusion: 1. Dyslipidemia incidence in Wilson's disease patients may exceed that of the normal population, especially in adolescents with unexplained abnormal lipid metabolism; 2. Patients with mild to moderate liver damage are predisposed to elevated triglycerides and total cholesterol, reflecting liver damage impact on lipid metabolism; 3. Glucose metabolism is not implicated in WD-related dyslipidemia; 4. No significant correlation was found between abnormal lipid metabolism and blood concentration of trace elements in WD patients. [ABSTRACT FROM AUTHOR]

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 α , GSK3 β , 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 α , GSK3 β , P53, GPX4, and PTGS2 in animal and cell models. Furthermore, DG effectively reversed the dysregulated expression of oxidative stress markers, including Fe 2 + , 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 α -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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Trientine tetrahydrochloride (TETA-4HCl, Cuvrior®) is a copper chelating agent with the active moiety triethylenetetramine (trientine), developed by Orphalan, Inc. to address the unmet needs in the treatment of Wilson disease. The journey from bench to bedside builds upon the documented safety profile of trientine hydrochloride capsules developed initially to meet the needs of individuals intolerant to d-penicillamine (DPA). Trientine hydrochloride capsules are inherently unstable requiring strict cold chain storage conditions from production, transportation, and use at home by the patient. Trientine tetrahydrochloride has a distinctive, patent-protected unique polymorphic form, which permits the production at scale of film-coated scored tablets deemed room temperature stable for 36 months. Trientine tetrahydrochloride is supported by a well-characterized pharmacodynamic, pharmacokinetic, and metabolic profile demonstrating reliable and predictable dose linearity and dose proportionality kinetics. Trientine tetrahydrochloride is the only trientine formulation that has been compared with DPA in a prospective randomized clinical trial, demonstrating non-inferiority to DPA in adults with stable Wilson disease. On 28 April, 2022, the US Food and Drug Administration approved TETA-4HCl for use in adult patients with Wilson disease who are de-coppered and tolerant to DPA. Health authorities in multiple countries worldwide have approved TETA-4HCl for the treatment of adults and children aged 5 years or more who are intolerant to DPA including the European Union, UK, Saudi Arabia, Switzerland, Colombia, Australia, New Zealand, and China. This article aims to provide a comprehensive narrative review of the key milestones in the development of TETA-4HCl. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Wilson's disease (WD) is a rare autosomal recessive disorder caused by mutations in the ATP7B gene, resulting in copper accumulation. Symptoms rarely appear before the age of 5, almost never before 3. The phenotypic variability of WD suggests the presence of modifying factors, making early diagnosis challenging. We present a case of symptomatic WD in a toddler, emphasizing the importance of considering WD in differential diagnoses and exploring genetic modifiers influencing disease onset. Clinical and laboratory assessments, including liver biopsy, were performed on a 4.2‐year‐old boy presenting with hypertransaminasemia and mild hepatomegaly. Histological evaluation revealed chronic hepatitis with fibrosis and severe steatosis, indicating long‐standing active disease. Genetic analysis identified a missense variant and a 15‐nucleotide deletion in the 5′ UTR promoter region of the ATP7B gene, confirming the WD diagnosis. Additionally, homozygosity for the HFE H63D variant was detected, with transferrin saturations at the upper limit of normal. The patient's clinical management included a trial of D‐penicillamine, discontinued due to side effects, followed by successful zinc acetate therapy. This case underscores the consideration of WD in the differential diagnosis of toddlers. The Ferenci‐Leipzig score remains a valid diagnostic tool for WD even in the presence of a single ATP7B variant, although extended genetic analysis should still be considered. Normal ceruloplasmin levels do not rule out WD. Environmental, epigenetic, and genetic factors appear to influence the WD phenotype; HFE variants may act as modifiers given the link between iron and copper homeostasis, possibly explaining the early symptomatic onset in our patient. [ABSTRACT FROM AUTHOR]

Background: Variants in a gene encoding sodium voltage-gated channel alpha subunit 1 (SCN1A) are known to cause a broad clinical spectrum of epilepsy and associated features, including Dravet syndrome (MIM 607208), non-Dravet developmental and epileptic encephalopathy (MIM 619317), familial febrile seizures (MIM 604403), familial hemiplegic migraine (MIM 609634), and generalized epilepsy with febrile seizures (MIM 604403). Methods: In this study, we examined a patient with Parkinson's disease (PD) without any clinical manifestations of epilepsy and associated features. Genomic nucleic acid was extracted, and a complete coding sequence of the human genome (whole-exome sequencing) was sequenced. Moreover, Sanger sequencing of variants of interest was performed to validate the exome-discovered variants. Results: We identified a heterozygous pathogenic missense mutation (c.1498C>T; p.Arg500Trp) in the SCN1A gene in the patient using the whole-exome sequencing approach. The onset of PD features in our patient occurred at the age of 30 years. Biochemical investigations were carried out to rule out any secondary cause of the disease, including Wilson's disease or another metabolic disorder. MRI of the brain and spinal images were unremarkable. Moreover, a dramatic response to carbidopa–levodopa treatment was also observed in the patient. Conclusion: Our results suggest that the pathogenic variant in SCN1A may lead to PD features without epilepsy. [ABSTRACT FROM AUTHOR]

Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism. The genetic defect in WD affects the ATP7B gene, which encodes the ATP7B transmembrane protein, which is essential for maintaining normal copper homeostasis in the body. It is primarily expressed in the liver and acts by incorporating copper into ceruloplasmin (Cp), the major copper transport protein in the blood. In conditions of excess copper, ATP7B transports it to bile for excretion. Mutations in ATP7B lead to impaired ATP7B function, resulting in copper accumulation in hepatocytes leading to their damage. The toxic "free"—unbound to Cp—copper released from hepatocytes then accumulates in various organs, contributing to their damage and clinical manifestations of WD, including hepatic, neurological, hematological, renal, musculoskeletal, ophthalmological, psychiatric, and other effects. While most clinical manifestations of WD correspond to identifiable organic or cellular damage, the pathophysiology underlying its psychiatric manifestations remains less clearly understood. A search for relevant articles was conducted in PubMed/Medline, Science Direct, Scopus, Willy Online Library, and Google Scholar, combining free text and MeSH terms using a wide range of synonyms and related terms, including "Wilson's disease", "hepatolenticular degeneration", "psychiatric manifestations", "molecular mechanisms", "pathomechanism", and others, as well as their combinations. Psychiatric symptoms of WD include cognitive disorders, personality and behavioral disorders, mood disorders, psychosis, and other mental disorders. They are not strictly related to the location of brain damage, therefore, the question arises whether these symptoms are caused by WD or are simply a coincidence or a reaction to the diagnosis of a genetic disease. Hypotheses regarding the etiology of psychiatric symptoms of WD suggest a variety of molecular mechanisms, including copper-induced CNS toxicity, oxidative stress, mitochondrial dysfunction, mitophagy, cuproptosis, ferroptosis, dysregulation of neurotransmission, deficiencies of neurotrophic factors, or immune dysregulation. New studies on the expression of noncoding RNA in WD are beginning to shed light on potential molecular pathways involved in psychiatric symptomatology. However, current evidence is still insufficient to definitively establish the cause of psychiatric symptoms in WD. It is possible that the etiology of psychiatric symptoms varies among individuals, with multiple biological and psychological mechanisms contributing to them simultaneously. Future studies with larger samples and comprehensive analyses are necessary to elucidate the mechanisms underlying the psychiatric manifestations of WD and to optimize diagnostics and therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background Objectives Methods Results Conclusions Wilson's disease (WD) results from pathogenic ATP7B gene variations, causing copper accumulation mainly in the liver, brain, and kidneys.In India, despite studies on ATP7B variants, WD often goes undiagnosed, with the prevalence, carrier rate, and mutation spectrum remaining unknown.A multicenter study examined genetic variations in WD among individuals of Indian origin via whole exome sequencing. The study used the InDelible structural variants calling pipeline and conducted molecular dynamic simulations on variants of uncertain significance (VUS) in ATP7B AlphaFold protein structures. Additionally, a high‐throughput gene screening panel for WD was developed.This study examined 128 clinically diagnosed cases of WD, revealing 74 genetically confirmed cases, 22 with ATP7B variants, and 32 without. Twenty‐two novel ATP7B gene variants were identified, including a 322 bp deletion classified as a structural variant. Molecular dynamics simulations highlighted the potential deleterious effects of 11 ATP7B VUS. Gene burden analysis suggested associations with ANO8, LGR4, and CDC7. ATP7B gene hotspots for pathogenic variants were identified. Prevalence and carrier rates were determined as one in 18,678 and one in 67, respectively. A multiplex sequencing panel showed promise for accurate WD diagnosis.This study offers crucial insights into WD's genetic variations and prevalence in India, addressing its underdiagnosis. It highlights the novel genetic variants in the ATP7B gene, the involvement of other genes, a scalable, cost‐effective multiplex sequencing panel for WD diagnosis and management and promising advancements in WD care. [ABSTRACT FROM AUTHOR]

Specific recognition and detoxification for copper is the key step for the early diagnosis and treatment of various diseases such as neurodegenerative disease and Wilson's disease. Herein, a Chlorella vulgaris‐inspired versatile theranostic nanoparticles is facilely and greenly prepared by assembling quercetin into poly(beta‐cyclodextrin) (PQNPs), which is further employed in the specific recognition and detoxification for Cu2+ in vitro and in vivo. PQNPs can be used in the detection of Cu2+ in aqueous solutions with fast response time (<5 s) and low detection limit (6.499 nM). The detection for Cu2+ in water and serum can be achieved by naked eye instantaneously on a PQNPs‐based paper sensor, and PQNPs can also act as a biological diagnostic agent for the Cu2+ imaging. Remarkably, PQNPs significantly enhance cell viability of the cell models induced by Cu2+ through the synergistic capacities of chelating Cu2+ and antioxidation. The detoxification of PQNPs for copper poisoning model is further ascertained in vivo, and it found that poly‐β‐cyclodextrin is capable of crossing the blood–brain barrier. Taken together, the as‐prepared versatile theranostic nanoparticles possess advantages of simple composition, significant theranostic efficacy, and novel treatment pattern, presenting an intriguing avenue to develop therapeutics for tackling abnormal copper metabolism in the clinic. [ABSTRACT FROM AUTHOR]

Background and Aims: 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. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Background and purpose: 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). Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Background: Wilson's disease (WD) is a hereditary disorder characterized by an abnormality in copper metabolism. Liver fibrosis, and potentially cirrhosis, induced by copper accumulation are critical factors in the pathogenesis of WD. CircRNAs exhibit high stability and play crucial roles in numerous biological processes. Methods: RNA-seq technology was employed to conduct transcriptome sequencing of the liver from 12 homozygous (TX) mice in the model group (NL group) and 12 wild-type (WT) mice in the control group (N group). Differentially expressed circular RNAs (DE-circRNAs) were identified, and following GO and KEGG analysis, a competitive endogenous RNA (ceRNA) regulatory network was constructed. The identified DE-circRNAs were then randomly validated using RT-qPCR. Results: Utilizing RNA sequencing (RNA-seq), the study identified 54 DE-circRNAs in TX-j mice with WD-induced liver fibrosis model, among which 19 were up-regulated and 35 were down-regulated. GO analysis revealed multiple biological processes, including single-organism process, cellular process, and metabolic process. Further pathway identification using KEGG implicated several pathways, including the HIF-1, PI3K-Akt, AMPK, FoxO, signaling pathway regulating pluripotency of stem cells, phospholipase D, mTOR, Ras, cGMP-PKG, and MAPK signaling pathway, among others. A ceRNA regulatory network was constructed with 20 circRNAs, 7 miRNAs, and 75 mRNAs as crucial core components. Additionally, RT-qPCR validation was performed on randomly selected DE-circRNAs, yielding consistent results (P< 0.05). Conclusion: The findings provide a significant molecular biology foundation for understanding the pathogenesis of liver fibrosis in WD and offer new insights for exploring potential diagnostic and therapeutic targets. [ABSTRACT FROM AUTHOR]

Abstract To investigates the current status of mindfulness in patients with Wilson’s disease (WD) and to explore the effects of psychological resilience, perceived social support, and acceptance of illness on their mindfulness. By using the convenient sampling method, 136 patients with WD were selected from May 2019 to January 2023 in 12 tertiary hospitals in Chengdu. General information questionnaire, five facet mindfulness scale, resilience scale, acceptance of illness and perceived social support scale were used to conduct the investigation. Structural equation model was used to analyze the data. The score of mindfulness of patients with WD was (128.63 ± 22.62), and there were statistically significant differences in different courses of disease, clinical classification, and hospitalization times (P

Abstract Hepatolenticular degeneration (HLD), also known as Wilson's disease (WD), is a rare autosomal recessive disorder regarding copper metabolism. Whether gut microbiota imbalance is involved in developing HLD remains unknown. A comprehensive 16S rRNA amplicon sequencing, metagenomic sequencing, and metabonomic analysis were undertaken in patients with WD to analyze the composition and function profiles of gut microbiota in patients with WD. The data demonstrated differences in gut microbiota and metabolic pathways between WD patients and normal individuals, significantly decreasing bacterial richness and diversity. The levels of Selenomonaceae and Megamonas in WD patients are significantly higher than those in healthy individuals. The relative abundances of Roseburia inulinivorans in patients with WD are lower than in healthy individuals. Compared with healthy people, the level of metabolites in patients with WD is abnormal. Leucylproline, 5-Phenylvaleric Acid and N-Desmethylclobazam, which have nutritional and protective effects, are significantly reduced fecal metabolites in patients with WD. D-Gluconic acid, which can chelate metal ions, may be a potential treatment for WD. The positive correlation it demonstrates with Alistipes indistinctus and Prevotella stercora indicates potential bacteria able to treat WD. These metabolites are mainly related to the biosynthesis of antibiotics, alpha-linolenic acid metabolism, one carbon pool by folate, nicotinate and nicotinamide metabolism. In conclusion, the data from this study elucidate novel mechanisms describing how abnormal gut miccrobiota contribute to the pathogenesis of WD and outlines new molecules for the treatment of WD.

Nuri Mehmet Basan,1 Mohamed Sheikh Hassan,2 Zeynep Gökhan,1 Sena Nur Alper,1 Sümeyye &Scedil;evval Ya&scedil;ar,1 Tu&gbreve;çe Gür,1 Ayhan Köksal1 1Department of Neurology, University of Health Science, Ba&scedil;ak&scedil;ehir Çam and Sakura City Hospital, Istanbul, Turkey; 2Department of Neurology, Mogadishu Somalia Turkey Training and Research Hospital, Mogadishu, SomaliaCorrespondence: Mohamed Sheikh Hassan, Mogadishu Somalia Turkiye Training and Research Hospital, Mogadishu, Somalia, Email dr.m.qalaf@gmail.comAbstract: Wilson’s disease (WD) is a genetic disorder of copper metabolism that is inherited as an autosomal recessive (AR) due to mutations in the ATP7B gene, which is involved in intracellular copper transport. Approximately 40% to 50% of the patients present with neurological symptoms as their first symptom. The most common neurological symptoms are dysarthria, gait abnormalities, ataxia, dystonia, tremor, parkinsonism, and drooling. This case report aims to present a diagnostically challenging case of WD presenting with neurological symptoms. The 38-year-old male patient was admitted with complaints of imbalance, gait disturbance, weakness in the legs, speech impairment, tremors in the hands, syncope, and drooling. The MRI primarily revealed FLAIR, T1, and T hyperintensities in the bilateral globus pallidus of the basal ganglias. At first, the patient was evaluated according to the Leipzig scoring and received one point from the serum ceruloplasmin level and two points from the neurological symptoms and was evaluated as “possible WD” with a total of three points. 24-hour urine copper was collected during and after the D-Penicillamine challenge. After the test, there was an increase of more than 5 times the upper limit. The Leipzig score was recalculated, and a diagnosis of WD was made with a score of five. Even cases without important diagnostic findings such as Kayser-Fleischer ring or high 24-hour urine copper should be evaluated according to the Leipzig score. It is vital to distinguish WD in patients with young-onset movement disorder and neurological symptoms.Keywords: hepatolenticular degeneration, magnetic resonance imaging, hepato-neurologic, Wilson’s disease, neuroradiology

Background and purpose Methods Results Conclusions Disabling dystonia despite optimal medical treatment is common in Wilson disease (WD). No controlled study has evaluated the effect of deep brain stimulation (DBS) on dystonia related to WD. This study was undertaken to evaluate the efficacy of DBS on dystonia related to WD.A meta‐analysis of an N‐of‐1 prospective, randomized, double‐blind, multicenter DBS study was conducted at two French WD reference centers. Main inclusion criteria were patients with WD, stabilized for at least 6 months with significant disability due to dystonia despite optimized medical treatment. The subthalamic nucleus (STN) was targeted for bradykinetic patients with tonic dystonia, and the internal globus pallidus (GPi) was chosen for patients with hyperkinetic dystonia. Each patient underwent two periods of DBS “on” and two periods of DBS “off,” each lasting 4 months. The order of stimulation conditions was randomized. The primary outcome was the change in the Canadian Occupational Performance Measure Performance (COPM‐P) and Satisfaction scores after each 4‐month period. Secondary outcomes were changes in the Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS) severity and disability scores and Unified Wilson's Disease Rating Scale (UWDRS) scores.Between 12 May 2016 and 7 October 2022, three patients were included. Two patients received bilateral GPi DBS, and one received bilateral STN DBS. There was no change of COPM‐P (p = 0.956), BFMDRS, and UWDRS scores. No serious adverse events were reported.STN or GPi DBS are ineffective on dystonia related to WD. [ABSTRACT FROM AUTHOR]