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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]

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 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 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]

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]

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]

Summary: Background and Aims: Wilson's disease may progress to cirrhosis and clinically significant portal hypertension (CSPH). We aimed to assess the prevalence and prognostic impact of CSPH‐related features on hepatic decompensation and transplant‐free survival in patients with Wilson's disease. Methods and Results: About 137 patients with Wilson's disease (Leipzig score ≥4), followed for a median observation period of 9.0 (3.9–17.7) years at the Vienna General Hospital, were included in this retrospective study. Overall, 49 (35.8%) developed features of CSPH: 14 (10.2%) varices, 40 (29.2%) splenomegaly, 20 (14.6%) ascites, 18 (13.1%) hepatic encephalopathy and 3 (2.2%) experienced acute variceal bleeding. Overall, 8 (5.8%) patients died, including three deaths caused by CSPH‐related complications. Within 10 years, compensated patients with features of CSPH developed more decompensation events (8.3% vs. 1.5% in patients without CSPH, p = 0.3) and had worse transplant‐free‐survival (91.7% vs. 98.6%), which further declined in patients with hepatic decompensation (26.7%, log‐rank: p < 0.0001). Patients with liver stiffness <15 kPa and normal platelets (≥150 G/L) were less likely to decompensate within 10 years (2.6% vs. 8.4%, p = 0.002) and had a better 10‐year transplant‐free‐survival (97.7% vs. 83.9%, p = 0.006). Conclusions: Patients with Wilson's disease developing features of CSPH are at an increased risk for hepatic decompensation and liver‐related mortality, warranting for regular screening and timely initiation of effective CSPH‐directed treatments. [ABSTRACT FROM AUTHOR]

The article discusses a case study of a 20-year-old male patient with genetically proven Salih ataxia due to a novel truncating variant in the RUBCN gene. The patient presented with seizures, intellectual disability, and tremulousness of both upper limbs, among other symptoms. The study expands the phenotypic and genotypic spectrum of SCAR15, a rare disorder characterized by early-onset ataxia, cognitive impairment, and dysarthria. The identified variant in the RUBCN gene is classified as likely pathogenic, leading to endolysosomal machinery defects and impacting autophagy and lipid metabolism. The article highlights the importance of considering RUBCN-related ataxia in patients with childhood-onset ataxia, dystonia, epilepsy, and intellectual disability, especially when cerebellar atrophy is absent. [Extracted from the article]

Introduction: Previous studies have shown that Gandouling (GDL) may alleviate the nerve damage caused by Wilson's disease (WD) by inhibiting the autophagy of nerve cell mitochondria. However, its mechanisms are still unclear. Revealing the therapeutic mechanism of GDL is beneficial for its clinical application and provides theoretical support for the development of new formulations for treating WD. Method: This time we found that the oxidative stress level in the body of the copper‐overloaded WD rates increased, neurons in the hippocampus were damaged, and autophagy occurred. GDL reversed these situations and significantly improved the learning, memory, and spatial cognitive abilities of the high‐copper‐loaded WD rates. After GDL intervention, the expression of phosphatidylinositol‐3 kinase (PI3K), phosphorylated serine–threonine protein kinase (AKT), and phosphorylated forkhead box protein O1 (FoxO1) significantly increased, whereas FoxO1 in the nucleus decreased and phosphorylated FoxO1 in the cytoplasm also significantly raised. In addition, the expression of Sirt1 significantly declined, and Ac‐FoxO1 in the nucleus also significantly increased. Results: These data indicated that GDL may promote the phosphorylation of FoxO1 and promote its nucleation by activating the PI3K/AKT/FoxO1 signaling pathway and inhibit Ac‐FoxO1 hydrolysis in the nucleus through the Sirt1/FoxO1 signaling pathway to suppress the transcriptional activity of FoxO1. Conclusion: Furthermore, it inhibited the expression of autophagy genes Atg12 and Gabarapl1. In summary, our work provides new insights into the potential mechanisms of GDL repairing WD neuronal damage through autophagy pathways. [ABSTRACT FROM AUTHOR]

The article explores the potential of olfactory dysfunction as a biomarker for neurological involvement in Wilson's disease, an inherited disorder of copper metabolism. While previous studies have shown impaired sense of smell in WD patients, the current study did not find significant differences in non-sulfur threshold. Further research with larger patient groups and standardized methodologies is needed to determine the utility of olfactory dysfunction as a biomarker for neurological involvement in WD management. [Extracted from the article]

This article discusses a case of oculogyric crisis (OGC) in a patient with Wilson's disease (WD). The patient, a 30-year-old Chinese female, presented with walking difficulties, dysarthria, and sustained upward gaze of both eyes. The article provides a detailed description of the patient's symptoms and clinical findings, including video footage of the OGC attacks. The patient was diagnosed with WD based on copper biochemical examination, brain magnetic resonance imaging (MRI), and genetic testing. The article also discusses the etiology and mechanism of OGC in WD, as well as its occurrence in other inherited metabolic and neurodegenerative diseases. [Extracted from the article]

Background: Wilson's disease (WD) is a rare genetic condition characterized by a copper overload in organs secondary to mutation in ATP7B gene. Lifelong decoppering treatments are the keystone of the treatment but must be regularly adapted to obtain a correct copper balance and could lead to copper deficiency (CD). Objectives: Study the characteristics of CD in WD patients. Methods: CD cases from our cohort of 338 WD patients have been investigated. CD was defined by the association of serum copper, exchangeable copper and urinary copper excretion assays less than two standard deviations from the mean with cytopenia and/or neurological damage of spinal cord origin. A systematic review of literature about cases of CD in WD patient was performed in PubMed database according to PRISMA guidelines. Results: Three WD patients were diagnosed with CD in our cohort. Review of the literature found 17 other patients. Most of the patients had anemia and neutropenia associated with neurological symptoms (especially progressive posterior cord syndrome). All the patients were treated with Zinc salts and the symptoms occurred more than a decade after the initiation of treatment. The adaptation of the treatment allowed a correction of the cytopenia but only a partial improvement of the neurological symptoms. Conclusions: WD patients can develop CD after many years of zinc therapy. Anemia and neutropenia are red flags that should evoke CD. [ABSTRACT FROM AUTHOR]

Key Clinical Message: WD is diagnosed with the help of a brain MRI, which frequently reveals hyperintensities in the lentiform nucleus. But occasionally, high signals can be seen in the pons, thalamus, and midbrain. Wilson disease is a rare inherited disorder due to impaired copper excretion. The brain MRI mainly shows hyperintensities in the lentiform nucleus. We report the case of an 18 years old female diagnosed with neurological Wilson disease, presenting with uncommon brain MRI hyperintensities, predominantly in the pons, thalamus, and midbrain. [ABSTRACT FROM AUTHOR]

Increasing evidence shows that abnormal copper (Cu) metabolism is highly related to many diseases, such as Alzheimer's disease, Wilson's disease, hematological malignancies and Menkes disease. Very recently, cuproptosis, a Cu‐dependent, programmed cell death was firstly described by Tsvetkov et al. in 2022. Their findings may provide a new perspective for the treatment of related diseases. However, the concrete mechanisms of these diseases, especially cuproptosis, remain completely unclear, the reason of which may be a lack of reliable tools to conduct highly selective, sensitive and high‐resolution imaging of Cu in complex life systems. So far, numerous small‐molecular fluorescent probes have been designed and utilized to explore the Cu signal pathway. Among them, fluorescence turn‐on probes greatly enhance the resolution and accuracy of imaging and may be a promising tool for research of investigation into cuproptosis. This review summarizes the probes developed in the past decade which have the potential to study cuproptosis, focusing on the design strategies, luminescence mechanism and biological‐imaging applications. Besides, we put forward some ideas concerning the design of next‐generation probes for cuproptosis, aiming to tackle the main problems in this new field. Furthermore, the prospect of cuproptosis in the treatment of corresponding diseases is also highlighted. [ABSTRACT FROM AUTHOR]

Objective: To study the aggravation of clinical symptoms after discontinuation of metal chelating agent therapy in Wilson's disease (WD) patients, analyze the causes of aggravation, and observe the prognosis. Methods: 40 WD patients (cerebral type 30 cases and hepatic type 10 cases) who stopped using metal chelating agent were selected, 40 WD patients with normal therapy, and 10 normal control cases were selected. All patients underwent neurological symptom evaluation using modified Young scale, Child‐Pugh liver function grading, metal metabolism, and disease typing. Magnetic sensitivity imaging (SWI), diffusion tensor imaging (DTI), and magnetic resonance spectroscopy imaging (MRS) were performed. According to the imaging results, WD patients were divided into metal deposition stage, fiber damage stage, and neuron necrosis stage. All patients were treated with metal chelating agent for 6 months. Results: The score of modified Young scale in drug withdrawal group was lower than that in normal treatment group before drug withdrawal (p =.032). The score of modified Young scale was higher after drug withdrawal than before (p =.011). The number of Child‐Pugh B‐grade patients after drug withdrawal was more than that before drug withdrawal and in normal treatment group. The proportion of patients in the stage of neuronal necrosis after drug withdrawal (25%) was higher than that before drug withdrawal (10%) (p =.025). After drug withdrawal, urine copper was significantly higher than that before drug withdrawal and in the normal treatment group (p =.032,.039). After the withdrawal group resumed metal chelating agent treatment, 34.2% of neurological symptoms worsened. Conclusions: WD patients showed neurological symptoms aggravation and increased liver injury after metal chelating agent withdrawal. Increased metal deposition and new nerve injury occurred in the brain. After re‐treatment, the aggravated neurological symptoms of WD patients are difficult to reverse. [ABSTRACT FROM AUTHOR]

Wilson's disease (WD, MIM#277900) is an autosomal recessive disorder resulting in copper excess caused by biallelic variants in the ATP7B gene (MIM#606882) encoding a copper transporting P‐type ATPase. ATP7B variants of unknown significance (VUS) are detected frequently, sometimes impeding a clear diagnosis. Functional analyses can help to classify these variants as benign or pathogenic. Additionally, variants already classified as (likely) pathogenic benefit from functional analyses to understand their pathomechanism, thus contribute to the development of personalized treatment approaches in the future. We described clinical features of six WD patients and functionally characterized five ATP7B missense variants (two VUS, three yet uncharacterized likely pathogenic variants), detected in these patients. We determined the protein level, copper export capacity, and cellular localization in an in vitro model and potential structural consequences using an ATP7B protein model based on AlphaFold. Our analyses give insight into the pathomechanism and allowed reclassification for the two VUS to likely pathogenic and for two of the three likely pathogenic variants to pathogenic. [ABSTRACT FROM AUTHOR]

Background. Gandoufumu decoction (GDFMD) is a traditional Chinese medicine that has been widely used to treat Wilson's disease (WD) liver damage patients. However, its specific molecular mechanism currently remains unclear. Autophagy as a key contributor to WD liver damage has been intensely researched in the recent years. Therefore, the aim of this present study is to explore the effect of GDFMD on autophagy in WD liver damage, and the final purpose is to provide scientific evidence for GDFMD treatment in WD liver damage. Methods. The molecular mechanisms and autophagy-related pathways of GDFMD in the treatment of WD liver damage were predicted using network pharmacology. Copper assay kit was used to determine copper content in serum. Enzyme-linked immunosorbent assay (ELISA) was utilized to quantify serum levels of liver enzymes and oxidative stress-related indicators. Hematoxylin-eosin (HE), Masson, and Sirius red staining were used for the characterization of liver pathological changes. Transmission electron microscopy, immunofluorescence, and Western blot analyses were used to evaluate autophagy activity. The impact of the GDFMD on typical autophagy-related pathway (PI3K/Akt/mTOR pathway) molecules was also assessed via Western blot analysis. Results. GDFMD effectively attenuated serum liver enzymes, oxidative stress, autophagy, and degree of hepatic histopathological impairment and reduced serum copper content. Through network pharmacological approaches, PI3K/Akt/mTOR pathway was identified as the typical autophagy-related pathway of GDFMD in the treatment of WD liver damage. Treatment with GDFMD activated the PI3K/Akt/mTOR pathway, an effect that was able to be counteracted by LY294002, a PI3K antagonist or Rapa (rapamycin), an autophagy inducer. Conclusions. GDFMD imparted therapeutic effects on WD through autophagy suppression by acting through the PI3K/Akt/mTOR pathway. [ABSTRACT FROM AUTHOR]

The increasing availability of molecular genetic testing has changed the landscape of both genetic research and clinical practice. Not only is the pace of discovery of novel disease‐causing genes accelerating but also the phenotypic spectra associated with previously known genes are expanding. These advancements lead to the awareness that some genetic movement disorders may cluster in certain ethnic populations and genetic pleiotropy may result in unique clinical presentations in specific ethnic groups. Thus, the characteristics, genetics and risk factors of movement disorders may differ between populations. Recognition of a particular clinical phenotype, combined with information about the ethnic origin of patients could lead to early and correct diagnosis and assist the development of future personalized medicine for patients with these disorders. Here, the Movement Disorders in Asia Task Force sought to review genetic movement disorders that are commonly seen in Asia, including Wilson's disease, spinocerebellar ataxias (SCA) types 12, 31, and 36, Gerstmann‐Sträussler‐Scheinker disease, PLA2G6‐related parkinsonism, adult‐onset neuronal intranuclear inclusion disease (NIID), and paroxysmal kinesigenic dyskinesia. We also review common disorders seen worldwide with specific mutations or presentations that occur frequently in Asians. [ABSTRACT FROM AUTHOR]

Background: Morphological changes of retina in patients with Wilson's disease (WD) can be found by optical coherence tomography (OCT), and such changes had significant differences between neurological forms (NWD) and hepatic forms (HWD) of WD. The aim of this study was to evaluate the relationship between morphological parameters of retina and brain magnetic resonance imaging (MRI) lesions, course of disease, type of disease, and sexuality in WD. Methods: A total of 46 WD patients and 40 health controls (HC) were recruited in this study. A total of 42 WD patients were divided into different groups according to clinical manifestations, course of disease, sexuality, and brain MRI lesions. We employed the Global Assessment Scale to assess neurological severity of WD patients. All WD patients and HC underwent retinal OCT to assess the thickness of inner limiting membrane (ILM) layer to retinal pigment epithelium layer and inner retina layer (ILM to inner plexiform layer, ILM–IPL). Results: Compared to HWD, NWD had thinner superior parafovea zone (108.07 ± 6.89 vs. 114.40 ± 5.54 μm, p <.01), temporal parafovea zone (97.17 ± 6.65 vs. 103.60 ± 4.53 μm, p <.01), inferior parafovea zone (108.114 ± 7.65 vs. 114.93 ± 5.84 μm, p <.01), and nasal parafovea zone (105.53 ± 8.01 vs. 112.10 ± 5.44 μm, p <.01) in inner retina layer. Course of disease influenced the retina thickness. Male patients had thinner inner retina layer compared to female patients. Conclusion: Our results demonstrated that WD had thinner inner retina layer compared to HC, and NWD had thinner inner retina layer compared to HWD. We speculated the thickness of inner retina layer may be a potential useful biomarker for NWD. [ABSTRACT FROM AUTHOR]

The article "Patients with Wilson's Disease Are Insensitive to Sulfur Odors" explores the olfactory function of individuals with Wilson's Disease (WD) and their perception of sulfur odors. The study found that WD patients have a reduced sensitivity to sulfur odors compared to healthy controls, indicating a specific insensitivity to sulfur odorants in most WD patients. This insensitivity appears to be independent of the clinical type of WD and not related to age or disease duration, potentially serving as an early diagnostic marker for the disease. [Extracted from the article]

LINKED CONTENT: This article is linked to Burghart et al papers. To view these articles, visit https://doi.org/10.1111/apt.18060 and https://doi.org/10.1111/apt.18153 [ABSTRACT FROM AUTHOR]

LINKED CONTENT: This article is linked to Burghart et al papers. To view these articles, visit https://doi.org/10.1111/apt.18060 and https://doi.org/10.1111/apt.18203 [ABSTRACT FROM AUTHOR]

A 72-year-old man with gait disturbances and behavioral changes was referred to a Movement Disorders unit. Brain MRI images showed the face of the giant panda sign, which is typically associated with Wilson's disease. However, further investigation revealed a diffuse B-cell primary central nervous system lymphoma. The article emphasizes the importance of considering alternative diagnoses in cases with atypical features or gadolinium-enhanced brain lesions. The authors obtained informed consent from the patient and confirm that there are no conflicts of interest or funding sources relevant to this work. [Extracted from the article]

Background: Friedreich ataxia (FA) is the most common form of autosomal recessive (AR) ataxia. It is a rare disease, but carriers are frequent (1/100). Pseudodominance in FA has seldomly been reported; it may pose additional challenges for diagnosis. Cases: A family with two consecutive generations affected by FA is described. The proband and two younger siblings had typical FA, characterized by infantile‐onset ataxia, hyporeflexia, Babinski sign, cardiomyopathy, and loss of ambulation in the second decade of life. Another female sibling had delayed‐onset (>25 years old), with mild cerebellar and sensitive ataxia since her mid‐30s. Their father presented very late‐onset FA (>40 years old), with sensitive axonal neuropathy. All five patients had biallelic (GAA)n expansion in FXN. The first three had larger expansions (>800 repeats), while the latter two had one shorter expanded allele (~90 repeats). Literature Review: Pseudodominant inheritance has been described in 13 neurological disorders. Seven are movement disorders, of which three were associated with high frequency of carriers (FA, Wilson's disease and PRKN‐related parkinsonism). Conclusions: Clinicians should be aware of the possibility of pseudodominance when facing an apparent autosomal dominant pedigree, particularly in disorders with high frequency of carriers and variable expression. Otherwise, genetic diagnoses may be delayed. [ABSTRACT FROM AUTHOR]

Backgrounds: Nonalcoholic fatty liver disease (NAFLD) is linked to obesity and metabolic syndrome conditions. However, a subset of NAFLD patients express a normal or low body mass index (lean NAFLD [L‐NAFLD]). Our aim is to compare the prevalence of L‐NAFLD to the obesity‐associated NAFLD in the United States by assessing prevalence, potential risk factors, liver‐related complications, and coronary artery disease outcomes. Methodology: A multicenter database (Explorys Inc.) of >70 million patients across the United States was screened. A cohort of patients with "nonalcoholic fatty liver" between 1999 and 2021 was identified. Two sub‐cohorts of NAFLD patients were identified: those with a body mass index (BMI) < 25 kg/m2 (L‐NAFLD) and those with a BMI > 30 kg/m2 (obesity‐associated NAFLD). We excluded patients with age <18 and those who have viral hepatitis, hemochromatosis, Wilson's disease, biliary cirrhosis, alcoholic liver disease, cystic fibrosis, alpha‐1‐antitrypsin deficiency, and autoimmune hepatitis. Multivariate analysis was performed to adjust for confounders. Results: 68 892 260 individuals were screened. NAFLD prevalence was four per 100 000, and L‐NAFLD prevalence was 0.6 per 100 000. Compared with those without, patients with L‐NAFLD tended to be older (OR 2.16), females (OR 1.28), and smokers (OR 4.67) and of Asian race (OR 2.12). L‐NAFLD patients were more likely to have acute coronary syndromes (OR 30.00) and metabolic syndrome (OR 2.31) despite the normal/low BMI. Esophageal varices and hepatocellular carcinoma risks were high in both cirrhosis patients. Conclusion: This is the largest study to assess L‐NAFLD prevalence in the United States. L‐NAFLD are at a significantly higher risk for acute coronary syndromes, esophageal varices, and hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Penicillamine is a chelator that has been used in Wilson's disease, cystinuria, rheumatoid arthritis and heavy metal intoxication. We report a case of a 31‐year‐old man presented with skin atrophy, purpura and milia on the hips and shoulders after taking penicillamine for 1.5 years. According to literature review, this type of penicillamine‐associated cutaneous adverse effect belongs to degenerative dermopathy, which mostly occurs on bony prominences and points of pressure in patients with Wilson's disease or cystinuria. Withdrawal or reduction of drug dose can improve the features of degenerative dermopathy. [ABSTRACT FROM AUTHOR]

The peculiar "scleroderma-like" skin alteration presented here in a patient with DPA-induced EPS has not been previously described in the literature. Wilson's disease (WD) is a rare autosomal recessive neurometabolic disorder of copper metabolism, whose treatment consists of metal ion excretion with the use of copper chelating agents, among which D-penicillamine is used most frequently. Generalized scleroderma-like induration associated with D-penicillamine elastosis perforans serpiginosa in Wilson's disease. [Extracted from the article]

The article "Reply to: Olfactory Dysfunction: A Potential Biomarker of Neurological Involvement in Wilson's Disease" discusses the correlation between olfactory dysfunction and Wilson's Disease (WD). The authors agree with previous studies that WD patients exhibit reduced olfactory function, particularly in the neurological type. Their study also found a specific insensitivity to sulfur odors in WD patients, independent of clinical type. The research supports the diagnostic value of olfactory changes in WD and highlights the potential of olfactory dysfunction as a biomarker for neurological involvement in the disease. [Extracted from the article]

Chronic diseases claim millions of lives every year, and it is of great significance to explore and develop advanced drugs to improve the cure rate of chronic diseases. Nanotheranostics are innovative strategies that enable the integration of diagnostic and therapeutic properties into a single nanosystem. Despite great success in nanotheranostics, their applications of nanotheranostics in nanomedicine are still in their infancy. This is because each disease has its corresponding characteristic pathological microenvironment, which motivates the development of endogenous biomarker‐responsive nanosystems to meet the requirements of diagnosis and treatment. Herein, recent progress is presented in biomarker‐responsive nanosystems and their biomedical applications. First, biomarker‐responsive nanosystems are classified into eight subsections according to the type of chronic diseases, including tumors, cardiovascular diseases, neurological diseases, Wilson's diseases, chronic liver diseases, chronic kidney diseases, diabetes mellitus, and rheumatoid arthritis. In the following, a variety of intriguing applications of biomarkers‐responsive nanosystems are briefly elaborated, such as biosensing, diagnosis, therapy, combined theranostics, and early evaluation of therapy effect, etc. Finally, the challenges and future directions from research to clinical translation of these responsive nanosystems are also presented. [ABSTRACT FROM AUTHOR]

Objective: To study the clinical features and power spectral entropy (PSE) of electroencephalography signals in Wilson's disease (WD) patients with dystonia. Methods: Several scale evaluations were performed to assess the clinical features of WD patients. Demographic information and electroencephalography signals were obtained in all subjects. Results: 34 WD patients with dystonia were recruited in the case group and 24 patients without dystonia were recruited in the control group. 20 healthy individuals were included in the healthy control group. The mean body mass index (BMI) in the case group was significantly lower than that in the controls (p <.05). The case group had significantly higher SAS, SDS, and Bucco‐Facial‐Apraxia Assessment scores (p <.05). Total BADS scores in the case group were lower than those in the control group (p <.01). Note that 94.11% of the case group presented with dysarthria and 70.59% of them suffered from dysphagia. Dysphagia was mainly related to the oral preparatory stage and oral stage. Mean power spectral entropy (PSE) values in the case group were significantly different (p <.05) from those in the control group and the healthy group across the different tasks. Conclusions: The patients with dystonia were usually accompanied with low BMI, anxiety, depression, apraxia, executive dysfunction, dysarthria and dysphagia. The cortical activities of the WD patients with dystonia seemed to be more chaotic during the eyes‐closed and reading tasks but lower during the swallowing stages than those in the control group. [ABSTRACT FROM AUTHOR]

This article discusses the diagnostic challenges in Wilson's disease (WD), a rare metabolic disorder characterized by copper accumulation in the liver and brain. The clinical manifestations of WD can vary widely, including hepatic, neurologic, and psychiatric symptoms. Steatosis, or fatty infiltration of the liver, is a common early pathological change in WD and can mimic other liver diseases such as alcoholic liver disease and non-alcoholic fatty liver disease. The article highlights the importance of clinical suspicion and a combination of clinical and laboratory findings for diagnosing WD, as well as the introduction of a new nomenclature for steatotic liver disease (SLD) that helps classify different causes of steatosis. The authors emphasize the need for increased awareness and early detection of WD, especially in patients with abnormal liver tests or unexplained histologic findings. [Extracted from the article]

Omphalolith is a rare and underdiagnosed entity due to the accumulation of sebum and keratin in the umbilicus. It usually occurs in the elderly with deep and narrow umbilicus. Early recognition of omphalolith is important to prevent complications, unnecessary investigations, and anxiety. We report herein two new cases of omphalolith. [ABSTRACT FROM AUTHOR]

Background: Neurological Wilson's disease (WD) presentation in the pediatric population is rare, and liver transplantation (LT) in these patients remains controversial. The aim of the present study was to assess the role of brain magnetic resonance imaging (MRI) in predicting reversion of brain lesions and neurological outcomes in pediatric WD patients after LT. Methods: Patients with confirmed WD (Leipzig score ≥4), disease onset in pediatric age (<18 years), neurological involvement, and submitted to LT were selected. Clinical records and pre‐ and post‐LT brain MRI were evaluated. Results: Six patients met the pre‐defined inclusion criteria, one of whom died shortly after LT and was excluded. The indication for LT was end‐stage liver disease in two patients and neurological worsening despite optimized treatment in three patients. After LT, the neurological picture progressively improved in all patients. Pre‐LT brain MRI showed T1‐weighted hyperintensities in four patients, which quickly resolved afterward. T2‐weighted hyperintensities were observed in four patients before LT, completely resolving in one patient, stabilizing in two, and improving in one after LT. A direct correlation could not be found between clinical and neuroradiological improvement. Progressive clinical improvement was observed even in patients with irreversible brain MRI changes. Conversely, some patients with normal MRI had only slight neurological improvement. Conclusions: The pattern of T2‐weighted hyperintensities after LT was unpredictable and did not correlate with neurological outcomes, suggesting that these changes may not entail irreversible clinical damage. Therefore, brain MRI does not seem to have prognostic value for assessing clinical response to LT. [ABSTRACT FROM AUTHOR]

Wilson's disease is a rare genetic condition that affects copper metabolism, resulting in tissue copper accumulation and resultant organ damage. We report a case of a young woman who presents with Wilson's disease complicated by hemolysis, impaired hepatic function, coagulopathy, and acute kidney injury. She was treated with plasmapheresis as a bridge to a liver transplant. Her mental state, renal function, and bilirubin level improved after starting plasmapheresis. She successfully underwent a liver transplant and remained stable post-liver transplant. We share our experience on the use of plasmapheresis in treating Wilson's disease. [ABSTRACT FROM AUTHOR]

Firstly, fulminant SSPE is a rare presentation, while its presentation as a predominant movement disorder is even more unusual.[[2]] Most cases of fulminant SSPE usually present with cognitive impairment, myoclonus and visual loss. SSPE, dystonia, myoclonus, opisthotonus Keywords: SSPE; dystonia; myoclonus; opisthotonus EN SSPE dystonia myoclonus opisthotonus 830 832 3 05/18/23 20230501 NES 230501 Fulminant SSPE (Subacute Sclerosing Panencephalitis) has been defined as the development of at least 66% neurological disability within 3 months of the first neurological symptom and death or a severe neurological disability (exceeding 90%) within 6 months of onset.[1] This case emphasizes the highly fulminant presentation of SSPE as a hyperkinetic movement disorder, due to which the classical clinical features could not be appreciated. [Extracted from the article]

(E) Patient's left-hand dystonia manifested in 2021. gl The patient was first seen in 2015 for intermittent fatigue, anorexia, and lower extremity edema for 3 years without any neurological symptoms at that time. Emerging neurological symptoms after liver transplantation: A 6-year follow-up of an adolescent patient with Wilson's disease Keywords: liver transplantation; neurological symptoms; Wilson's disease EN liver transplantation neurological symptoms Wilson's disease 788 791 4 04/07/22 20220501 NES 220501 Dear Editor, Liver transplantation (LT) is a promising treatment modality for patients with Wilson's disease (WD).1 According to AASLD, the indication of LT for WD patients is acute liver failure or decompensated cirrhosis unresponsive to chelation treatment.2 It is generally believed that LT can benefit patients with hepatic WD and also improve patients with severe neurological symptoms or mixed type WD, but the survival rate of the latter is lower than that of patients with simple hepatic WD.3,4 And the efficacy and prognosis of LT in patients with neurological WD are always open to debate,5-7 and we found that a patient with hepatic WD developed neurological symptoms less than a year after successfully receiving LT for acute liver failure at a young age, and that the patient's neurological symptoms continued to worsen over the next 6 years of regular follow-up and treatment. [Extracted from the article]

Oculomotor assessment is an essential element of the neurological clinical examination and is particularly important when evaluating patients with movements disorders. Most of the brain is involved in oculomotor control, and thus many neurological conditions present with oculomotor abnormalities. Each of the different classes of eye movements and their features can provide important information that can facilitate differential diagnosis. This educational review presents a clinical approach to eye movement abnormalities that are commonly seen in parkinsonism, ataxia, dystonia, myoclonus, tremor, and chorea. In parkinsonism, subtle signs such as prominent square wave jerks, impaired vertical optokinetic nystagmus, and/or the "round the houses" sign suggest early progressive supranuclear gaze palsy before vertical gaze is restricted. In ataxia, nystagmus is common, but other findings such as oculomotor apraxia, supranuclear gaze palsy, impaired fixation, or saccadic pursuit can contribute to diagnoses such as ataxia with oculomotor apraxia, Niemann‐Pick type C, or ataxia telangiectasia. Opsoclonus myoclonus and oculopalatal myoclonus present with characteristic phenomenology and are usually easy to identify. The oculomotor exam is usually unremarkable in isolated dystonia, but oculogyric crisis is a medical emergency and should be recognized and treated in a timely manner. Gaze impersistence in a patient with chorea suggests Huntington's disease, but in a patient with dystonia or tremor, Wilson's disease is more likely. Finally, functional eye movements can reinforce the clinical impression of a functional movement disorder. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Wilson's disease is a genetic disorder of copper metabolism that primarily manifests with hepatic and neurological features. Kayser–Fleischer rings (KF rings) are pathognomonic of Wilson's disease and helps in establishing its diagnosis. [ABSTRACT FROM AUTHOR]

Wilson's disease (WD) is a rare autosomal recessive genetic disease that affects copper metabolism. Anomalies can be seen in the dento‐maxillofacial structures of WD patients. Dens invaginatus (DI) is an uncommon tooth anomaly, and its incidence in decidious and permanent molars is even lower. This case report primarily explored the multiple DI of a patient with WD. A 9‐year‐old boy was admitted to our clinic with complaints of pain and swelling in the right lower molar area. It was learnt that the patient was diagnosed with WD after he was born. Fistula, submandibular lymphadenopathy and diffuse swelling were detected. Using cone‐beam computed tomography (CBCT), multiple DIs were observed in bilateral bimaxillary four first molars and deciduous molars. When the patient's systemic condition was considered, extraction was planned under oral antibiotic therapy and was performed. During the 6‐month follow‐up, uneventful healing was observed. [ABSTRACT FROM AUTHOR]

Case Description. A two-month-old, female, Aberdeen-Angus calf was presented for congenital cataracts and blindness in both eyes (OU). The dam had a reported history of visual defects (not specified) and had produced other affected calves (per owner history). Ophthalmic examination revealed mature bilateral cataracts, attenuation of the iridic granules, persistent pupillary membranes, and dyscoric pupils. Additionally, the calf had a poor body condition, prognathism, dome-shaped head, excessive nasal drainage, limb contracture, and fever. Histopathology of both eyes revealed lenticular degeneration (congenital cataracts), retinal dysplasia, and optic nerve hypoplasia. BVDV IHC detected antigen within only the left eye (OS), consisting of intrahistiocytic and endothelial immunoreactivity within the ciliary body, iris, and choroid. No BVDV immunoreactivity could be detected in the right eye (OD). This case highlights the unique ocular changes present in in utero BVDV infection of cattle with a different immunohistochemical staining profile than previously described. [ABSTRACT FROM AUTHOR]

Background: Wilson's disease (WD) is a rare autosomal recessive inherited disorder that is induced by defects of the ATP7B gene and characterized by damage to the liver and nervous system caused by aberrant copper metabolism. The identification of pathogenic mutations on two homologous chromosomes has become the gold standard for the diagnosis of WD. Methods: Sanger sequencing and multiplex ligation‐dependent probe amplification (MLPA) were combined to establish a genetic diagnosis for patients from 53 unrelated Chinese WD families. Results: Biallelic mutations were detected by Sanger sequencing in 50 of the probands, while single heterozygous mutations were detected in the remaining three probands. A total of 45 diverse pathogenic mutations were detected, and 6 previously unreported mutations were involved. Five asymptomatic patients were screened from 85 family members of 38 probands participating in the study. Conclusion: This study contributes to the enlargement of the mutational spectrum of the ATP7B gene among the population of China and highlights the significance of genetic testing for asymptomatic patients. [ABSTRACT FROM AUTHOR]

Purpose. To report a female with a history of Wilson's disease who underwent a successful photorefractive keratectomy (PRK) for myopic correction. Case Presentation. A twenty-year-old female with a history of Wilson's disease and D-penicillamine use was referred to our clinic for myopic refractive surgery. Her best-corrected visual acuity (BCVA) was 20/20 for both eyes with a refraction of ‐ 1.25 ‐ 0.5 ∗ 75 ° and ‐ 1.25 ‐ 0.25 ∗ 55 ° for the right and left eyes. The slit examination showed a prominent Kayser-Fleischer ring (K-F ring) in both eyes. She underwent a successful myopic PRK surgery, and her BCVA became 20/20 with no significant refraction. Conclusions. In this report, we report a successful PRK surgery for myopic correction in a case of Wilson's disease with prominent K-F rings in both eyes. [ABSTRACT FROM AUTHOR]

Background: Despite the increasing number of reports on the analysis of ATP7B variants, reports on carrier screening for Wilson's disease (WD, OMIM:277900) are rare. Methods: Peripheral blood samples were collected from 42 patients from Qingdao Women and Children's Hospital diagnosed with WD for direct sequencing of ATP7B gene. Twelve hotspot variants of ATP7B were selected for carrier screening in Qingdao area based on an analysis of information related to ATP7B variants and literature reports in China. We screened 5012 dried blood spots (DBSs) from asymptomatic newborns in Qingdao area to estimate carrier frequency. DNA was extracted from dried blood spots. Gene sequencing was performed using multiplex polymerase chain reaction (PCR) combined with second‐generation sequencing. The carrier frequency of each hotspot variant was calculated using the count data (expressed as number of carriers (%) obtained by direct counting. Results: The carrier frequency of 12 hotspot variants was 1.46% (95% CI: 1.16–1.83%). The ATP7B variant with the highest carrier frequency was c.2333G>T, accounting for 54.79% of all variants screened, followed by c.2975C>T and c.2621C>T, accounting for 17.81% and 15.07% of all variants screened, respectively. Conclusion: Carrier frequency of ATP7B gene pathogenic variants is high in the population in Qingdao area. [ABSTRACT FROM AUTHOR]

Background: Wilson disease (WD) is an autosomal recessive disorder caused by mutations in the ATP7B gene. In 1984, Scheinberg and Sternlieb estimated the prevalence of WD to be 1:30 000. However, recent epidemiological studies have reported increasing prevalence rates in different populations. The carrier frequency of ATP7B variants and the prevalence of WD in the Japanese population have not been reported using multiple databases. Methods: Multiple public databases were used. First, we included mutations in the ATP7B gene that were registered in the Human Gene Mutation Database (HGMD) Professional, where 885 ATP7B variants were identified as pathogenic. Next, we investigated the allele frequencies of these 885 variants in Japanese individuals using the Human Genetic Variation Database (HGVD) and the Japanese Multi Omics Reference Panel (jMorp). Results: Of the 885 variants of ATP7B, 7 and 12 missense and nonsense variants, zero and three splicing variants, and zero and two small deletions were found in the HGVD and in jMorp, respectively. The total allele frequencies of the ATP7B mutations were 0.011 in the HGVD and 0.014 in the jMorp. According to these data, the carrier frequencies were 0.022 (2.2%) and 0.028 (2.8%), respectively, and patient frequencies were 0.000121 (1.21/10 000 individuals) and 0.000196 (1.96/10 000 individuals), respectively. Conclusions: This is the first study to report the carrier frequency of ATP7B variants and the prevalence of WD in Japan using multiple databases. The calculated prevalence of WD was comparatively higher than that of previous reports, indicating previous underdiagnosis or the existence of less severe phenotypes. [ABSTRACT FROM AUTHOR]