Characteristics of patients with Wilson disease in the United States: An insurance claims database study

BACKGROUND Wilson disease(WD)is a progressive,potentially fatal degenerative disease affecting the liver and central nervous system.Given its low prevalence,collecting data on large cohorts of patients with WD is challenging.Comprehensive insur-ance claims databases provide powerful tools to collect retrospective data on large numbers of patients with rare diseases.AIM To describe patients with WD in the United States,their treatment and clinical outcome,using a large insurance claims database.METHODS This retrospective,longitudinal study was performed in the Clarivate Real-World Data Product database.All patients with≥2 claims associated with an Interna-tional Classification of Diseases 10(ICD-10)diagnostic code for WD(E83.01)between 2016 and 2021 were included and followed until death or study end.Patients were divided into two groups by whether or not they were documented to have received a specific treatment for WD.Clinical manifestations,hospital-isations,liver transplantation and death were documented.RESULTS Overall,5376 patients with an ICD-10 diagnostic code for WD were identified.The mean age at inclusion was 41.2 years and 52.0%were men.A specific WD treatment was documented for 885 patients(15.1%),although the number of patients taking zinc salts may be underestimated due to over the counter purchase.At inclusion,the mean age of patients with a documented treatment was 36.6±17.8 years vs 42.2±19.6 years in those without a documented treatment.During follow-up,273 patients(5.1%)died.Compared with the American general population,the standardised mortality ratio was 2.19.The proportion of patients with a documented WD-specific treatment who died during follow-up was 4.0%and the mean age at death 52.7 years.CONCLUSION Patients treated for WD in the United States had an excess early mortality compared with the American population.These findings indicate that there is a significant unmet need for effective treatment for WD in the United States.

Hepatitis B virus infection in patients with Wilson disease:A large retrospective study

BACKGROUND Wilson disease(WD)is the most common genetic metabolic liver disease.Some studies have shown that comorbidities may have important effects on WD.Data on hepatitis B virus(HBV)infection in patients with WD are limited.AIM To investigate the prevalence and clinical impact of HBV infection in patients with WD.METHODS The clinical data of patients with WD were analyzed retrospectively,and the data of patients with concurrent WD and HBV infection were compared with those of patients with isolated WD.RESULTS Among a total of 915 WD patients recruited,the total prevalence of current and previous HBV infection was 2.1%[95%confidence interval(CI):1.2%-3.0%]and 9.2%(95%CI:7.3%-11.1%),respectively.The main finding of this study was the identification of 19 patients with concurrent WD and chronic hepatitis B(CHB)infection.The diagnosis of WD was missed in all but two patients with CHB infection.The mean delay in the diagnosis of WD in patients with concurrent WD and CHB infection was 32.5 mo,which was significantly longer than that in patients with isolated WD(10.5 mo).The rates of severe liver disease and mortality in patients with concurrent WD and CHB infection were significantly higher than those in patients with isolated WD(63.1%vs 19.3%,P=0.000 and 36.8%vs 4.1%,P<0.001,respectively).Binary logistic regression analysis revealed a significantly higher risk of severe liver disease at the diagnosis of WD in patients with current HBV infection[odds ratio(OR)=7.748;95%CI:2.890-20.774;P=0.000)]or previous HBV infection(OR=5.525;95%CI:3.159-8.739;P=0.000)than in patients with isolated WD.CONCLUSION The total prevalence of current HBV infection in patients with WD was 2.1%.The diagnosis of WD in CHB patients is usually missed.HBV infection is an independent risk factor for severe liver disease in WD patients.The diagnosis of WD should be ruled out in some patients with CHB infection.

Wilson disease: Identification of two novel mutations and clinical correlation in Eastern Chinese patients

AIM: To study mutations in the P-type ATPase (ATP7B) gene responsible for Wilson disease (WD) in the Eastern Chinese population, and the possible correlation of specific mutations with clinical characteristics. METHODS: Mutations of the ATP7B gene were sought by means of direct sequencing in 50 Eastern Chinese WD patients of Han ethnic origin. RESULTS: Two novel mutations, Asp96Gly and Asp196Glu, were first identified. We also compared the characterization of mutations in ATP7B with the clinical findings, and a significant correlation with hepatic manifestations between patients carrying the Arg778Leu mutation and those without was found. CONCLUSION: Gene sequencing analysis was shown to have a high detection rate and accuracy. It may become the first priority in screening of WD patients.

Diagnostic criteria for acute liver failure due to Wilson disease

AIM： To describe the diagnostic criteria for acute liver failure due to Wilson disease （WD）, which is an uncommon cause of acute liver failure （ALF）. METHODS： We compared findings of patients presenting with ALF due to WD to those with ALF of other etiologies. RESULTS： Previously described criteria, such as low alkaline phosphatase activity, ratio of low alkaline phosphatase to total bilirubin or ratio of high aspartate arninotransferase （AST） to alanine arninotransferase （ALT）, failed to identify patients with ALF due to WD. There were significant differences in low ALT and AST activities （53 ± 43 vs 1982 ± 938, P 〈 0.0001 and 87 ± 44 vs 2756 ± 2941, P = 0.037, respectively）, low choline esterase activity （1.79 ± 1.2 vs 4.30 ± 1.2, P = 0.009）, high urine copper concentrations （93.4 ± 144.0 vs 3.5 ± 1.8, P = 0.001） and low hemoglobin （7.0 ± 2.2 vs 12.6 ± 1.8, P 〈 0.0001） in patients with ALF caused by WD as compared with other etiologies. Interestingly, 4 of 7 patients with ALF due to WD survived without liver transplantation. CONCLUSION： In ALF, these criteria can help establish a diagnosis of WD. Where applicable, slitlamp examination for presence of Kayser-Fleischer rings and liver biopsy for determination of hepatic copper concentration still remain important for the diagnosis of ALF due to WD. The need for liver transplantation should be evaluated carefully as the prognosis is not necessarily fatal.

Wilson disease:Histopathological correlations with treatment on follow-up liver biopsies

AIM:To investigate the progression of hepatic histopathology in serial liver biopsies from Wilson disease(WD)patients.METHODS:We report a group of 12 WD patients treated with zinc and/or penicillamine who underwent multiple follow-up liver biopsies.Demographic,clinical and laboratory data were gathered and all patients underwent an initial biopsy and at least one repeat biopsy.RESULTS:Time to repeat biopsy ranged from 2 to 12 years.Six patients(non-progressors)showed stable hepatic histology or improvement.In one case,we observed improvement of fibrosis from stage 2 to 0.Six patients(progressors)had worsening of fibrosis.There was no significant correlation between the histological findings and serum aminotransferases or copper me-tabolism parameters.The hepatic copper concentration reached normal levels in only two patients:one from the non-progressors and one from the progressors group.The estimated rate of progression of hepatic fibrosis in the entire group was 0 units per year in the time frame between the first and the second liver biopsy(4 years),and 0.25 between the second and the third(3 years).In the progressors group,the rate of progression of liver fibrosis was estimated at 0.11 fibrosis units per year between the first and second biopsy and,0.6 fibrosis units between the second and third biopsy.CONCLUSION:The inability of clinical tools to detect fibrosis progression in WD suggests that a liver biopsy with hepatic copper quantification every 3 years should be considered.

Diminution of toxic copper accumulation in toxic milk mice modeling Wilson disease by embryonic hepatocyte intrasplenic transplantation

AIM: To observe the therapeutic effect of intrasplenic transplantation with embryonic hepatocytes on amelioration of hereditary copper accumulation in toxic milk (TX) mouse modeling Wilson disease. METHODS: Donor hepatocytes were harvested from 14-d fetal liver of a pregnant homogeneous DL mouse. These cells were successively cultured, labeled with fluorescein dye Hoechst 33342 for 24 h, and sequentially infused into the spleen parenchyma of the recipient TX mice. No host immunosuppression measures were taken. Two and four weeks after transplantation, the recipients were killed for routine histologic investigation and immunohistochemistry study up to 4 wk after transplantation. The serum copper and ceruloplasmin concentrations of the recipient mice were determined by graphite furnace atomic absorption spectroscopy.RESULTS: In the following 2nd and 4th wk after transplantation, the donor hepatocytes could be visualized in the livers of 47.3% recipients. The serum ceruloplasmin and copper concentrations increased by 1.6-fold after 2 wk and 2.0-fold times after 4 wk respectively, which ultimately rose from about 30% of the normal level to nearly 60%(P＜0.01). The hepatic copper concentration decreased 7.2%, 4 wk after transplantation. Pathologic examination showed that there were many actively proliferative hepatocyte precursor cells with specific embryonic hepatocyte marker AFP migrated into hepatic sinusoidsof the recipients. A large number of cells carrying hepatocytes marker and albumin were observed in the recipient spleen tissues.CONCLUSION: Embryonic hepatocytes are capable of differentiating into mature hepatocytes in vivo. After transplantation, the hereditary abnormalities of copper metabolism in TX mice could be corrected partially by intrasplenic transplantation of homogeneous embryonic hepatocytes.

Copper toxicosis gene MURRl is not changed in Wilson disease patients with normal blood ceruloplasmin levels

AIM： To analyze our Wilson disease patient cohort （n = 106） for alterations in the gene coding for MURR1. METHODS： Patients with an established diagnosis of Wilson disease but normal ceruloplasmin blood levels were chosen for our study （n = 14）. Patients with two known disease-causing mutations in the ATPTB gene were not included. The three exons of the human MURR1 gene were sequenced after amplification of the genomic DNA by polymerase chain reaction. RESULTS： Our study did not reveal any mutations leading to an amino acid change in the MURR1 sequence of Wilson disease patients. A polymorphism at 472 bp of the coding sequence could be confirmed. CONCLUSION： The MURRI gene plays no role in the pathogenesis of Wilson disease patients with normal serum ceruloplasmin levels.

Pediatric Wilson disease presenting as acute liver failure:Prognostic indices

BACKGROUND Acute liver failure(ALF)can be a primary presentation of Wilson disease(WD).Mortality rates are high in WD with ALF(WDALF).Predictions of mortality in WDALF vary by model and are sometimes contradictory,perhaps because few patients are studied or WD diagnoses are questionable.AIM To determine the outcomes among well-documented WDALF patients and assess mortality model performance in this cohort.METHODS We reviewed the medical records of our pediatric WDALF patients(n=41 over 6-years-old,single-center retrospective study)and compared seven prognostic models(King’s College Hospital Criteria,model for end-stage liver disease/pediatric end-stage liver disease scoring systems,Liver Injury Unit[LIU]using prothrombin time[PT]or international normalized ratio[INR],admission LIU using PT or INR,and Devarbhavi model)with one another.RESULTS Among the 41 Han Chinese patients with ALF,WD was established by demonstrating ATP7B variants in 36.In 5 others,Kayser-Fleischer rings and Coombs-negative hemolytic anemia permitted diagnosis.Three died during hospitalization and three underwent liver transplantation(LT)within 1 mo of presentation and survived(7.3%each);35(85.4%)survived without LT when given enteral D-penicillamine and zinc-salt therapy with or without urgent plasmapheresis.Parameters significantly correlated with mortality included encephalopathy,coagulopathy,and gamma-glutamyl transpeptidase activity,bilirubin,ammonia,and serum sodium levels.Area under the receiver operating curves varied among seven prognostic models from 0.981 to 0.748 with positive predictive values from 0.214 to 0.429.CONCLUSION WDALF children can survive and recover without LT when given D-penicillamine and Zn with or without plasmapheresis,even after enlisting for LT.

Impact of COVID-19 on the clinical status of patients with Wilson disease

The coronavirus disease 2019(COVID-19)pandemic has greatly impacted health systems.Many guidelines on chronic liver diseases have been released to optimize the use of medical resources and patient management.However,most of these guidelines have been established through expert consensus because the existing data do not provide strong evidence for developing effective recommendations.As Wilson disease(WD)is a rare chronic liver disease,the impact of COVID-19 on the clinical status of patients with WD is unclear.The present study showed a marked shortage of medical resources for clinically managing patients with WD during the pandemic.Although patients with WD who consistently took anticopper therapy showed no significant differences in hepatic and extrahepatic markers before and after the pandemic,their complication incidences,especially the infection incidence,were significantly increased during the study period.Therefore,patients with WD should be encouraged to adhere to anticopper therapy and be closely monitored to prevent infections and other complications.The present study provides a clinical basis for further managing WD during the pandemic.

Wilson disease-the impact of hyperimmunity on disease activity:A case report

BACKGROUND In Wilson disease lack of biliary copper excretion causes hepatocellular injury by accumulation of free toxic copper.Its overspill to serum accounts for neuronal damage as second common manifestation.Therapy with copper chelators or zinc targets the removal of this free copper.However,in some patients liver disease persists for unknown reason despite normalized free copper.The discovery of a hyperimmunity as a contributing pathogenetic factor was discovered in this case report with implication also for other liver diseases.CASE SUMMARY A 9-year-old girl was diagnosed in August 2009 by family screening of having asymptomatic Wilson disease with elevated transaminases.Already at time of diagnosis antinuclear antibodies(ANA)were elevated without hyperimmunoglobulinemia(immunoglobulin G,IgG).After one year of therapy with Dpenicillamine transaminases normalized together with free serum copper.Under continuous therapy with copper chelators free copper remained normal until today,whereas transaminases raised to alanine aminotransferase values of 571 U/L in December 2019.For hyperimmunity a tentative steroid course on top of Dpenicillamine improved transaminases.Thus,hyperimmunity may have impact on liver inflammation after control of the metabolic disturbance.A retrospective cohort study confirmed the common association of elevated transaminases with ANA,but no IgG elevation.CONCLUSION This hyperimmune-triggered condition may represent a new entity which per se or on top of other liver diseases induces liver inflammation responsive to steroids.

CLONING AND CHARACTERIZATION OF A METAL RESPONSIVE ELEMENT-CONTAINING FRAGMENTF ROM THE WILSON DISEASE GENE LOCUS BY JUNCTION TRAPPING

All mammalian metallothionein genes studied to date have several metal responsive elements (MRE) with consensus sequences of TGCRCNC (R, purine) in their regulatory region. MRE-like sequences were also found in many other metal-related genes. To see whether there is also such a sequence at the genetic locus (13q14. 3) of Wilson disease, which is a genetic disorder of copper metabolism, junction-trapping method based on the MRE sequence was used. A fragment containing MRE and MRE-like sequences from YAC 27D8 at the WND locus was successfully cloned and mapped back to the YAC by PCR. Presence of such a sequence in the copper transporter gene at the WD locus might imply that it has a possible interesting role in the regulation of WD gene expression.

Mechanism of Gan Dou Ling in improving liver fibrosis in Wilson disease based on network pharmacology and experimental verification

Objective:To explore and verify the mechanism of Gan Dou Ling in improving liver fibrosis in Wilson disease(WD)by network pharmacology and copper loaded mice experiments.Methods:The main chemical components and corresponding gene targets of each drug in Gan Dou Ling were obtained by using TCMSP database.The database of gene mutation and disease related gene was searched through the GeneCards database,DrugBank database,PharmGKB database and the DisGeNET database.After the intersection of drug and disease target genes.The STRING website was used to analyze the protein-protein interaction degree of target genes,and import the data to Cytoscape software 38.2 to analyze protein interaction network.The GO databases and KEGG databases were obtained in R language for enrichment analysis.On this basis,Masson staining were used to observe the degree of liver fibrosis in copper loaded mouse model,and the results of network pharmacological analysis were verified by Western Blot(WB).Results:A total of 108 drug disease intersection genes were analyzed by network pharmacology.Through PPI network analysis,JUN was found to be the key genes.The enrichment analysis of KEGG pathway showed that MAPK signal pathway was the important potential target pathways.Animal experiments showed that Gan Dou Ling could reduce liver fibrosis and inhibit the phosphorylation of P38,JNK and C-JUN in copper loaded mice.Conclusion:Gan Dou Ling may achieve the effect of treating WD liver fibrosis by inhibiting P38/JNK signaling pathway.

Abnormal skeletal metabolism and its changes after decopper therapy in patients with Wilson disease

BACKGROUND: Researches indicate that patients with Wilson disease (WD) have abnormal skeletal metabolism, which is induced by various factors. OBJECTIVE: To probe into the changing characteristics of abnormal skeletal metabolism in WD patients and observe the effect of decopper therapy. DESIGN: Case-contrast and self-control study. SETTING: Department of Neurology, Affiliated Hospital of Neurological Institute, Anhui College of Traditional Chinese Medicine. PARTICIPANTS: A total of 35 patients with WD including 21 males and 14 females aged from 10 to 42 years with the mean age of (20±8) years were selected from Department of Neurology, Affiliated Hospital of Neurological Institute, Anhui College of Traditional Chinese Medicine from September 2000 to February 2001. All the patients were in compliance with the diagnostic criteria: history of family heredity; cone symptoms in vitro, physical sign or liver symptoms; positive Kayser-Fleischer ring; serum copper protein < 200 mg/L or A copper oxidase < 0.2; urine copper > 1.6 μmol/24 hours; liver copper > 250 μg/g (dry weight). The control group was selected from 25 cases of health individuals including 13 males and 12 females aged from 16 to 35 years with the mean age of (22±6) years. All patients who participated in the study were informed first and consented. METHODS: Patients in treatment group were treated with venous injection of 1.0 g sodium dimercaptosulfonate, once a day for totally 6 successive days. And then, patients rested for 2 days. This procedure mentioned above was regarded as a course, and the treatment lasted for 4-8 courses. Before and after injection of sodium dimercaptosulfonate, serum calcitonin (CT), osteocalcin (BGP), parathyroid hormone (PTH) and 1,25-(OH)2VitD3 were measured with radio-immunity method; blood, urine calcium, phosphorum and urine creatinine were measured with biochemical analyzer; urine dihydropyrimidine dehydrogenase(DPD) was detected with enzyme-immunity method; bone mineral density (BMD) was checked at the one third from distal end of ulna and radius with single photon absorptiometry (SPA). MAIN OUTCOME MEASURES: Relative indexes of bone metabolism of blood and urine and results of BMD in both two groups before and after treatment. RESULTS: Among 35 patients with WD and 25 healthy subjects, 5 patients were excluded because of uncompleted decopper therapy; therefore, 30 patients with WD and 25 healthy subjects were involved in the final analysis. ① Comparisons between the two groups: Contents of serum calcium, PTH and 1,25-(OH)2VitD3 were lower in treatment group than those in control group [(2.49±0.34) mmol/L vs. (2.69±0.19) mmol/L; (218.7±50.5) ng/L vs. (262.5±88.9) ng/L; (23.53±14.21) ng/L vs. (42.78±14.44) ng/L; P < 0.05-0.01]; however, contents of serum BGP and CT were higher in treatment group than those in control group [(10.22±6.11) μg/L vs. (5.78±4.22) μg/L; (282.8±109.6) ng/L vs. (62.5±37.9) ng/L, P < 0.01]; moreover, there was no significant difference of contents of serum phosphorum, urine calcium, phosphorum and DPD/creatinine between treatment group and control group (P > 0.05). BMD of males and females was lower in treatment group than that in control group [(0.617±0.197) g/cm2 vs. (0.718±0.274) g/cm2; (0.594±0.124) g/cm2 vs. (0.677±0.157) g/cm2, P < 0.05]. ② Comparisons in treatment group before and after treatment: Contents of CT and urine calcium were lower after treatment than those before treatment [(95.3±55.4) ng/L vs. (283.3±96.7) ng/L; (2.38±1.68) mmol/L vs. (3.31±2.30) mmol/L; P < 0.01, 0.05]; however, contents of 1,25-(OH)2VitD3 and DPD/creatinine were higher after treatment than those before treatment [(33.61±19.30) ng/L vs. (24.21±14.47) ng/L; (42.95±19.92) nmol/mmol vs. (19.51±9.96) nmol/mmol, P < 0.05]; moreover, there were no significant differences among other indexes before and after treatment (P > 0.05). Furthermore, there was no significant difference of BMD before and after treatment (P > 0.05). CONCLUSION: WD patients have changes in the related indexes of abnormal skeletal metabolism. In addition, contents of CT and urine calcium are decreased remarkably after decopper therapy; however, value of BMD is not changed obviously.

A Case Report and Literature Review of Wilson Disease

To investigate the clinical characteristics,auxiliary examination and treatment of Wilson’s disease(WD).The clinical data of a child with WD were summarized and analyzed comprehensively in conjunction with the literature reference.WD is a hereditary disease with a large age span,diverse early symptoms,high misdiagnosis rate,abnormal liver function,decreased ceruloplasmin,increased urinary copper,K-F rings,ATP7B gene mutation,ATP7B gene mutations,and abnormalities in abdominal and cranial brain imaging,which can be clearly diagnosed and require lifelong treatment.WD can be diagnosed according to the clinical manifestations and auxiliary examination to reduce misdiagnosis.The timely diagnosis and treatment will improve the prognosis the quality of life.

Wilson's disease in two siblings from Ecuador:Two case reports

BACKGROUND Wilson's disease(WD)is a rare metabolic disorder of copper accumulation in organs such as liver,brain,and cornea.Diagnoses and treatments are challenging in settings,where advanced diagnostic tests are unavailable,copper chelating agents are frequently scarce,healthcare professionals lack disease awareness,and medical follow-ups are limited.Prompt diagnoses and treatments help prevent complications,improve patients’quality of life,and ensure a normal life expectancy.The clinical presentations and outcomes of WD can vary within a single family.CASE SUMMARY We present the cases of two siblings(19 and 27 years)from a consanguineous family in rural Ecuador,diagnosed as having WD during a family screening.The male patient,diagnosed at age 19 after his brother’s death from acute liver failure,presented with compensated cirrhosis,neurological symptoms,and bilateral Kayser-Fleischer rings.He developed progressive neurological deterioration during an irregular treatment with D-penicillamine due to medication shortages.His condition improved upon switching to trientine tetrahydrochloride,and his neurological symptoms improved over an 8-year period of follow-ups.The female patient,diagnosed at age 10,exhibited only biochemical alterations.Her treatment history was similar;however,she remained asymptomatic without disease progression over the same follow-up period.We discuss the potential influence of epigenetic mechanisms and modifier genes on the various phenotypes,emphasizing the need for research in these areas to optimize therapeutic strategies.CONCLUSION Our patients’medical histories show how early diagnosis and treatment can prevent disease progression;and,how suboptimal treatments impact disease outcomes.

High frequency of the c.3207C>A (p.H1069Q) mutation in ATP7B gene of Lithuanian patients with hepatic presentation of Wilson's disease

AIM： To investigate the prevalence of the ATP7B gene mutation in patients with hepatic presentation of Wilson＇s disease （WD） in Lithuania. METHODS： Eleven unrelated Lithuanian families, including 13 WD patients were tested. Clinically WD diagnosis was established in accordance to the Leipzig scoring system. Genomic DNA was extracted from whole venous blood using a salt precipitation method. Firstly, the semi-nested polymerase chain reaction （PCR） technique was used to detect the c.3207C〉A （p.H1069Q） mutation. Patients not homozygous for the c.3207C〉A （p.H1069Q） mutation were further analyzed. The 21 exons of the WD gene were amplified in a thermal cycler （Biometra T3 Thermocycler, G0ttingen, Germany）. Direct sequencing of the amplified PCR products was performed by cycle sequencing using fluorescent dye terminators in an automatic sequencer （Applied Biosystems, Darmstadt, Germany）. RESULTS： Total of 13 WD patients （mean age 26.4 years; range 17-40; male/female 3/10） presented with hepatic disorders and 16 their first degree relatives （including 12 siblings） were studied. Some of WD patients, in addition to hepatic symptoms, have had extrahepatic disorders （hemolytic anemia 3; Fanconi syndrome 1; neurophsychiatric and behavioural disorder 2）. Liver biopsy specimens were available in all of 13 WD patients （8 had cirrhosis; 1-chronic hepatitis; 3-acute liver failure, 1-1iver steatosis）. Twelve of 13 （92.3%） WD patients had the c.3207C〉A （p.HI069Q） mutation, 6 of them in both chromosomes, 6 were presented as compound heterozygotes with additional c.3472-82delGGTTTAACCAT, c.3402delC, c.3121C〉T （p.RI041W） or unknown mutations. For one patient with liver cirrhosis and psychiatric disorder （Leipzig score 6）, no mutations were found. Out of 16 first degree WD relatives, 11 （68.7%） were heterozygous for the c.3207C〉A （p.H1069Q） mutation. Two patients with fulminant WD died from acute liver failure and ii are in full remission under peniciilamine or zinc acetate treatment. Three women with WD successfully delivered healthy babies. CONCLUSION： The c.3207C〉A （p.HI069Q） missense mutation is the most characteristic mutation for Lithuanian patients with WD. Even 92.3% of WD patients with hepatic presentation of the disease are homozygous or compound heterozygotes for the p.H1069Q mutation.

Identification of a mutation hotspot in exon 8 of Wilson disease gene by cycle sequencing

Objective To screen for mutation hotspot of Wilson disease (WD) gene in Chinese population Methods Cycle sequencing was used to detect mutation in exon 8 of WD gene in 30 patients with Wilson disease Results The same missense mutation, Arg779Leu, was identified in 14 WD patients, four of whom were homozygous and the other heterozygous for this mutation The frequency of this mutation in Chinese patients was 30% Conclusion The codon 779 (CCG→CTG) of exon 8 of WD gene was one of mutation hotspots in Chinese

Advance in the pathogenesis and treatment of Wilson disease

Wilson disease is an autosomal recessive disorder of copper metabolism.Diagnosis depends primarily on clinical features,biochemical parameters and the presence of the Kayser-Fleischer ring.Genetic analysis for mutations within ATP7B is a convincing diagnostic tool.The traditional treatment for WD includes chelation of excessive copper accumulation and reduction of copper intake.Medical therapy is effective but WD is not yet curable.Liver transplantation is especially helpful for patients who fail to respond to medical therapy or present with fulminant liver failure,although evaluation of its long-term effect are still in need.

The role of mTOR signaling pathway in regulating autophagy in liver injury of TX mice with Wilson’s disease

Wilson disease(WD),known as hepatolenticular degeneration(HLD),is a treatable autosomal recessive disorder of copper metabolism.Because copper deposits in the liver first,the liver is not only the original defective organ but also the most affected organ.The liver injury is also one of the main causes of death throughout the course of the disease.Therefore,the treatment of liver injury is the main task of WD treatment,which is of great significance to improve the prognosis of patients.Autophagy is a process that promotes cell survival through degradation,recycling,and absorption in order to maintain the normal physiological function of cells,while excessive autophagy can aggravate cell death.In view of the abnormal damage of liver cells in patients with WD,which may be related to the change of autophagy level,in this study,we established an animal model of WD through toxic milk(TX)mice,observed the change of autophagy level in the liver,and observed the change of liver damage in mice after treatment with autophagy inhibitors.It was found that the mTOR signaling pathway was activated and autophagy was inhibited in Wilson mouse liver.After treatment with rapamycin,the autophagy level of mice liver was upregulated,and the copper content of mice liver was reduced,and the damage was alleviated.TX mouse hepatocytes were isolated,after using siRNA to interfere with mTOR expression,the copper accumulation was significantly reduced,which was the same with RAPA treatment.The results showed that in TX mice,the damage caused by copper accumulation in the liver may be related to the decrease of autophagy level caused by the activation of the mTOR signaling pathway.Our findings suggested that RAPA or the use of siRNA targeting mTOR may have potential applications in the treatment of Wilson’s disease.

Wilson disease:At the crossroads between genetics and epigeneticsdA review of the evidence

Environmental factors,including diet,exercise,stress,and toxins,profoundly impact disease phenotypes.This review examines how Wilson disease(WD),an autosomal recessive genetic disorder,is influenced by genetic and environmental inputs.WD is caused by mutations in the copper-transporter gene ATP7B,leading to the accumulation of copper in the liver and brain,resulting in hepatic,neurological,and psychiatric symptoms.These symptoms range in severity and can first appear anytime between early childhood and old age.Over 300 disease-causing mutations in ATP7B have been identified,but attempts to link genotype to the phenotypic presentation have yielded little insight,prompting investigators to identify alternative mechanisms,such as epigenetics,to explain the highly varied clinical presentation.Further,WD is accompanied by structural and functional abnormalities in mitochondria,potentially altering the production of metabolites that are required for epigenetic regulation of gene expression.Notably,environmental exposure affects the regulation of gene expression and mitochondrial function.We present the“multi-hit”hypothesis of WD progression,which posits that the initial hit is an environmental factor that affects fetal gene expression and epigenetic mechanisms and subsequent“hits”are environmental exposures that occur in the offspring after birth.These environmental hits and subsequent changes in epigenetic regulation may impact copper accumulation and ultimately WD phenotype.Lifestyle changes,including diet,increased physical activity,stress reduction,and toxin avoidance,might influence the presentation and course of WD,and therefore may serve as potential adjunctive or replacement therapies.