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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 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 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]

The article discusses a case study of a 73-year-old man with choreiform movements attributed to CADASIL type II, a rare hereditary cerebral arteriopathy. The patient exhibited involuntary facial grimacing, tongue persistence, and choreiform movements of the arms, trunk, and legs. Genetic analysis revealed a heterozygous HTRA1 variant, leading to the diagnosis of CADASIL type II. The article highlights the novel presentation of CADASIL type II and the importance of genetic analysis in diagnosing such conditions. [Extracted from the article]

Background/Objectives: Data regarding the outcomes of liver transplantation in disabled, highly dependent, and legally incapacitated adults are scarce, likely due to the infrequency of these procedures in such populations. Multicenter studies in adult transplant centers have shown that patients with coexisting intellectual and developmental disabilities (IDDs) may be denied transplantation because of their expected low longevity and the complexities associated with managing post-transplant care. We examined the long-term patient and graft outcomes in highly dependent, incapacitated patients with IDDs who underwent elective transplantation for chronic liver disease. Methods: Six adult patients who underwent liver transplantation for primary biliary cholangitis (n = 2), hepatitis C cirrhosis (n = 2), Wilson's disease (n = 1), and autoimmune hepatitis (n = 1) were included. The main causes of their disability were infantile cerebral palsy, myotonia, and Niemann–Pick disease. Results: Four of the six patients were women, with a median age of 26 (range: 23–36) years. Only one patient died during follow-up. Their 1- and 5-year survival rates were 100 and 75%, respectively, which were not statistically different from those of the general cohort of electively transplanted patients (95.8 and 90.1%, respectively) (p = 0.35). Conclusions: Adult patients who are highly dependent, disabled, or legally incapable should not be denied liver transplantation because of poor long-term survival rates. Physiological disorders and psychiatric comorbidities should not prevent patients from receiving life-saving surgeries due to poor postoperative compliance or low quality of life. [ABSTRACT FROM AUTHOR]

Background and Aims: Distinctive gut microbial profiles have been observed between patients with Wilson disease (WD) and healthy individuals. Despite this, the exact relationship and influence of gut microbiota on the advancement of WD‐related liver damage remain ambiguous. This research seeks to clarify the gut microbiota characteristics in both human patients and mouse models of WD, as well as their impact on liver injury. Methods: Gut microbial features in healthy individuals, patients with WD, healthy mice and mice with early‐ and late‐stage WD were analysed using 16S rRNA gene sequencing. Additionally, WD‐afflicted mice underwent treatment with either an antibiotic cocktail (with normal saline as a control) or healthy microbiota (using disease microbiota as a control). The study assessed gut microbiota composition, hepatic transcriptome profiles, liver copper concentrations and hepatic pathological injuries. Results: Patients with hepatic WD and mice with WD‐related liver injury displayed altered gut microbiota composition, notably with a significant reduction in Lactobacillus abundance. Additionally, the abundances of several gut genera, including Lactobacillus, Veillonella and Eubacterium coprostanoligenes, showed significant correlations with the severity of liver injury in patients with WD. In WD mice, antibiotic treatment or transplantation of healthy microbiota altered the gut microbial structure, increased Lactobacillus abundance and modified the hepatic transcriptional profile. These interventions resulted in reduced hepatic copper concentration and alleviation of WD‐related liver injury. Conclusions: Individuals and mice with pronounced WD‐related liver injury exhibited shifts in gut microbial composition. Regulating gut microbiota through healthy microbiota transplantation emerges as a promising therapeutic approach for treating WD‐related liver injury. [ABSTRACT FROM AUTHOR]

This article discusses a case study of a patient with cirrhosis who presented with weakness, dysarthria, insomnia, and depression. Initially, his cirrhosis was attributed to alcohol use, but further investigation led to the diagnosis of Wilson's disease, a rare genetic disorder that affects copper metabolism. The article highlights the challenges of diagnosing Wilson's disease, which can mimic other diseases, and emphasizes the importance of obtaining a detailed family history. It also discusses the barriers to diagnosis and care that can occur in underserved populations, such as language barriers and low health literacy. Early identification and treatment of Wilson's disease can reverse symptoms and improve outcomes. [Extracted from the article]

Background: Wilson's disease (WD) is a rare condition resulting from autosomal recessive mutations in ATP7B, a copper transporter, manifesting with hepatic, neurological, and psychiatric symptoms. Timely diagnosis and appropriate treatment yield a positive prognosis, while delayed identification and/or insufficient therapy lead to a poor outcome. Our aim was to establish a prognostic method for WD by characterising biomarkers based on circulating microRNAs. Methods: We conducted investigations across three cohorts: discovery, validation (comprising unrelated patients), and follow-up (revisiting the discovery cohort 3 years later). All groups were compared to age- and gender-matched controls. Plasma microRNAs were analysed via RNA sequencing in the discovery cohort and subsequently validated using quantitative PCR in all three cohorts. To assess disease progression, we examined the microRNA profile in Atp7b−/− mice, analysing serum samples from 6 to 44 weeks of age and liver samples at three time points: 20, 30, and 40 weeks of age. Results: In patients, elevated levels of the signature microRNAs (miR-122-5p, miR-192-5p, and miR-885-5p) correlated with serum activities of aspartate transaminase, alanine aminotransferase and gamma-glutamyl transferase. In Atp7b−/− mice, levels of miR-122-5p and miR-192-5p (miR-885-5p lacking a murine orthologue) increased from 12 weeks of age in serum, while exhibiting fluctuations in the liver, possibly attributable to hepatocyte regenerative capacity post-injury and the release of hepatic microRNAs into the bloodstream. Conclusions: The upregulation of the signature miR-122-5p, miR-192-5p, and miR-885-5p in patients and their correlation with liver disease progression in WD mice support their potential as biomarkers of WD. [ABSTRACT FROM AUTHOR]

Cuproptosis, a newly characterized form of regulated cell death driven by copper accumulation, has emerged as a significant mechanism underlying various non-cancerous diseases. This review delves into the complex interplay between copper metabolism and the pathogenesis of conditions such as Wilson's disease (WD), neurodegenerative disorders, and cardiovascular pathologies. We examine the molecular mechanisms by which copper dysregulation induces cuproptosis, highlighting the pivotal roles of key copper transporters and enzymes. Additionally, we evaluate the therapeutic potential of copper chelation strategies, which have shown promise in experimental models by mitigating copper-induced cellular damage and restoring physiological homeostasis. Through a comprehensive synthesis of recent advancements and current knowledge, this review underscores the necessity of further research to translate these findings into clinical applications. The ultimate goal is to harness the therapeutic potential of targeting cuproptosis, thereby improving disease management and patient outcomes in non-cancerous conditions associated with copper dysregulation. [ABSTRACT FROM AUTHOR]

Pathogenic germline mutations in the P-type copper-transporting ATPase (ATP7B) gene cause Wilson's disease (WD), a hereditary disorder characterized by disrupted copper metabolism. The Arg778Leu (R778L) mutation in exon 8 is prevalent among individuals with WD in East Asia and is associated with more severe phenotypes. In this study, we generated a WD mouse model harboring R778L mutation (R778L mice) using CRISPR/Cas9. R778L mice exhibit a range of pathological characteristics resembling those of patients with WD and the same point mutations, including aberrant copper metabolism, pathological cellular injury, inflammation, and severe hepatic fibrosis. At 3–5 months of age, these mice started to display neurological deficits in motor coordination and cognitive dysfunction, accompanied by increased expression of inflammatory cytokines in the central nervous system. Microglia in the striatum and cortex exhibit significant activation, shorter processes, and decreased branch points. However, the Cu2+ levels in the brain tissue of R778L mice did not differ significantly from those of wild-type mice. Notably, inhibition of hepatic inflammation with PJ34 or siNfkb markedly alleviated the deficiencies in cognitive performance and improved locomotor activity in R778L mice. Thus, this study establishes a novel murine model to investigate the pathophysiology of WD, highlights the liver-brain crosstalk responsible for neurological manifestations in individuals with WD caused by the R778L point mutation, and demonstrates the potential of modulating liver inflammation as a therapeutic strategy for alleviating the neurological manifestations of WD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

BackgroundAimMethodsResultsConclusionWilson disease is an autosomal recessive disorder owing to defective copper metabolism which causes abnormal accumulation of copper and damage to the liver, brain, kidneys and other organs.To describe the clinical features, laboratory investigations and outcome of Wilson disease in children.A retrospective observational study was conducted in the paediatric department of a tertiary- care hospital in South India by reviewing medical records between January 2018 and March 2023. The diagnosis of Wilson disease was confirmed by the presence of low serum ceruloplasmin and/or high urine copper excretion in combination with clinical and ophthalmological features.A total of 32 cases were analysed. The mean (SD) age at presentation was 110 (36) months with a M:F ratio of 1.6:1. Isolated hepatic involvement was seen in 19 (60%) patients while 13 (40%) patients had a neurological presentation, either as an isolated entity or in combination with hepatic manifestations. Low serum ceruloplasmin levels were detected in 31 (96%) patients. Urine copper levels were elevated in all patients. Twenty-one patients were commenced on D penicillamine while 11 patients were treated with a combination chelation therapy with zinc. Eighteen patients (56%) were on regular follow-up.The clinical presentation of Wilson disease in children is diverse, varying from the more common hepatic or neurological manifestations to the less common atypical forms of the disease. Diagnosis is based on clinical and ophthalmological features in combination with biochemical abnormalities in the form of low ceruloplasmin and high urinary copper. The majority of patients can be medically managed with chelation therapy. [ABSTRACT FROM AUTHOR]

Hepatolenticular degeneration, also known as Wilson disease (WD), is a kind of autosomal recessive hereditary disease with the disorder of copper metabolism, which is clinically manifested as liver damage, neuropsy-chiatric disorder. The molecular pathological mechanism has been not fully revealed. It is commonly known that excessive copper accumulation inside hepatotic cells is the main reason of WD. However, the emerging roles of cuproptosis and other trace elements such as zinc, iron and lead in WD have recently attracted attention and become the research hotspots. This present review summarized the pathological factors, molecular mechanisms of liver damage and neuropsychiatric disorder of WD, which will help identify novel diagnostic biomarkers, and provide new therapeutics for WD. [ABSTRACT FROM AUTHOR]

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

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. [ABSTRACT FROM AUTHOR]

Ferroptosis, an iron‐dependent form of cell death, plays a crucial role in the progression of liver injury in Wilson's disease (WD). Gandouling (GDL) has emerged as a potential therapeutic agent for preventing and treating liver injury in WD. However, the precise mechanisms by which GDL mitigates ferroptosis in WD liver injury remain unclear. In this study, we discovered that treating Toxic Milk (TX) mice with GDL effectively decreased liver copper content, corrected iron homeostasis imbalances, and lowered lipid peroxidation levels, thereby preventing ferroptosis and improving liver injury. Bioinformatics analysis and machine learning algorithms identified Hspb1 as a pivotal regulator of ferroptosis. GDL treatment significantly upregulated the expression of HSPB1 and its upstream regulatory factor HSF1, thereby activating the HSF1/HSPB1 pathway. Importantly, inhibition of this pathway by NXP800 reversed the protective effects of GDL on ferroptosis in the liver of TX mice. In conclusion, GDL shows promise in alleviating liver injury in WD by inhibiting ferroptosis through modulation of the HSF1/HSPB1 pathway, suggesting its potential as a novel therapeutic agent for treating liver ferroptosis in WD. [ABSTRACT FROM AUTHOR]

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.

Objective To investigate the clinical characteristics of the hepatolenticular degeneration in children, and to clarify the significance of gene diagnosis in children with hepatolenticular degeneration. Methods A total of 75 patients with hepatolenticular degeneration were enrolled in the Department of Pediatrics, Peking Union Medical College Hospital from 2011 to 2018. All of them carried out a generation of gene sequencing for ATPase Cu2+ transporting beta polypeptide (ATP7B) gene and multiplex ligation-dependent probe amplification (MLPA) analysis. Results Among the 75 pediatric patients, 55 patients were asymptomatic and had elevated aminotransferases as the incidental findings. All the pediatric patients had decreased ceruloplasmin. Seventy-two of pediatric patients had 24-hour urinary copper＞40 μg/d. There were 16 cases that had Kayser-Fleischer(K-F) rings. Sixteen six out of 75(21.33%)cases were diagnosed clinically and 15 cases were＞7 years old. All the remaining patients needed genetic diagnosis. Sixty-six patients had two mutations and 9 patients had only one mutation, 1 had no mutation. Forty eight different mutations were found to be localized in ATP7B gene. These mutations included 32 missense mutations, 6 splice mutations, 5 deletion mutations, 2 repeated mutations, 2 insert mutations and 1 nonsense mutations. The most frequently three mutations were c.2333G＞T,p.R778L,c.2621C＞T, p.A874V,c.2975C＞T, p.P992L,whose allele frequencies were 30.49%,14.89%,9.92%. Conclusions The research showed that in young aged patients, the nervous system symptoms are not obvious and the positive rate of laboratory tests are lower than adults so is a challenge to clinical diagnosis. So Genetic testing is of great significance for the early diagnosis and early treatment of disease in pediatric patients.

Wilson's disease (WD) is a rare, autosomal recessive disorder of copper metabolism caused by pathogenic mutations in the ATP7B gene. Cellular copper overload is associated with impaired iron metabolism. Oxidative stress, cuproptosis, and ferroptosis are involved in cell death in WD. The clinical picture of WD is variable. Hepatic/neuropsychiatric/other symptoms may manifest in childhood/adulthood and even old age. It has been shown that phenotypic variability may be determined by the type of ATP7B genetic variants as well as the influence of various genetic/epigenetic, environmental, and lifestyle modifiers. In 1976, immunological abnormalities were first described in patients with WD. These included an increase in IgG and IgM levels and a decrease in the percentage of T lymphocytes, as well as a weakening of their bactericidal effect. Over the following years, it was shown that there is a bidirectional relationship between copper and inflammation. Changes in serum cytokine concentrations and the relationship between cytokine gene variants and the clinical course of the disease have been described in WD patients, as well as in animal models of this disease. Data have also been published on the occurrence of antinuclear antibodies (ANAs), antineutrophil cytoplasmic antibodies (ANCAs), anti-muscle-specific tyrosine kinase antibodies, and anti-acetylcholine receptor antibodies, as well as various autoimmune diseases, including systemic lupus erythematosus (SLE), myasthenic syndrome, ulcerative colitis, multiple sclerosis (MS), polyarthritis, and psoriasis after treatment with d-penicillamine (DPA). The occurrence of autoantibodies was also described, the presence of which was not related to the type of treatment or the form of the disease (hepatic vs. neuropsychiatric). The mechanisms responsible for the occurrence of autoantibodies in patients with WD are not known. It has also not been clarified whether they have clinical significance. In some patients, WD was differentiated or coexisted with an autoimmune disease, including autoimmune hepatitis or multiple sclerosis. Various molecular mechanisms may be responsible for immunological abnormalities and/or the inflammatory processes in WD. Their better understanding may be important for explaining the reasons for the diversity of symptoms and the varied course and response to therapy, as well as for the development of new treatment regimens for WD. [ABSTRACT FROM AUTHOR]

Background: Wilson's disease is an inherited disease characterized by impaired copper metabolism that causes damage to many organs, including the brain. Patients having neurological involvement usually present with varied neuropsychiatric symptoms. Magnetic resonance imaging (MRI) Brain plays an indispensable role in identifying the structural involvement in these patients, aiding in early accurate diagnosis and timely management. Typically, basal ganglia, thalami and brainstem are involved, with bright claustrum sign, face of giant panda sign and miniature panda signs on MRI. Conclusions: Having knowledge about the commonly encountered and known MRI brain findings in Wilson's disease are essential in aiding accurate diagnosis and initiating early management. However, identifying the Atypical MRI brain characteristics is all the more imperative and should be considered in patients with prolonged or severe disease or in patients with rapid clinical progression and in patients showing poor response to treatment. [ABSTRACT FROM AUTHOR]