Wilson disease is an autosomal recessive disorder affecting the ATP7B gene located on chromosome 13q.This leads to copper deposition in various organs,most importantly in the liver and brain.The genetic mutations are ...Wilson disease is an autosomal recessive disorder affecting the ATP7B gene located on chromosome 13q.This leads to copper deposition in various organs,most importantly in the liver and brain.The genetic mutations are vast,well reported in the West but poorly documented in developing countries.Hence the diagnosis is made with a constellation of clinico-laboratory parameters which have significant overlap with other liver diseases and often pose a significant dilemma for clinicians.Diagnostic scoring systems are not fool-proof.The availability and affordability of chelators in developing countries impact the drug compliance of patients.While D-penicillamine is a potent drug,its side effects lead to drug discontinuation.Trientine is cost-prohibitive in developing countries.There is no single test to assess the adequacy of chelation.Exchangeable urinary copper is an essential upcoming diagnostic and prognostic tool.In the presence of cirrhosis,hypersplenism clouds the assessment of myelosuppression of drugs.Similarly,it may be difficult to distinguish disease tubulopathy from druginduced glomerulonephritis.Neurological worsening due to chelators may appear similar to disease progression.Presentation as fulminant hepatic failure requires rapid workup.There is a limited window of opportunity to salvage these patients with the help of plasmapheresis and other liver-assisted devices.This review addresses the challenges and clinical dilemmas faced at beside in developing countries.展开更多
Wilson’s disease is a rare disorder of copper transport in hepatic cells,and may present as cholestatic liver disease;pancreatitis and cholangitis are rarely associated with Wilsons’s disease.Moreover,cases of Wilso...Wilson’s disease is a rare disorder of copper transport in hepatic cells,and may present as cholestatic liver disease;pancreatitis and cholangitis are rarely associated with Wilsons’s disease.Moreover,cases of Wilson s disease presenting as pigmented gallstone pancreatitis have not been reported in the literature.In the present report,we describe a case of a 37-year-old man who was admitted with jaundice and abdomina pain.The patient was diagnosed with acute pancreatitis,cholangitis,and obstructive jaundice caused by pigmented gallstones that were detected during retrograde cholangiopancreatography.However,because of his long-term jaundice and the presence of pigmented gallstones,the patient underwent further evaluation for Wilson’s disease,which was subsequently confirmed.This patient’s unique presentation exemplifies the overlap in the clinical and laboratory parameters of Wilson’s disease and cholestasis,and the difficulties associated with their differentiation.It suggests thatWilson’s disease should be considered in patients with pancreatitis,cholangitis,and severe protracted jaundice caused by pigmented gallstones.展开更多
BACKGROUND Wilson’s disease(WD)is a rare autosomal recessive inherited disorder of copper metabolism.Acute liver failure(ALF)and hemolytic anemia represent the most severe presentation of WD in children.No clear geno...BACKGROUND Wilson’s disease(WD)is a rare autosomal recessive inherited disorder of copper metabolism.Acute liver failure(ALF)and hemolytic anemia represent the most severe presentation of WD in children.No clear genotype-phenotype correlations exist in WD.Protein-truncating nonsense,frame-shift,or splice-site variants may be associated with more severe disease.In contrast,missense variants may be associated with late-onset,less severe disease,and more neurological manifestations.Recently,a gene variant(HSD17B13:TA,rs72613567)with a possible hepatic protective role against toxins was associated with a less severe hepatic phenotype in WD.AIM To analyze the possible genotype-phenotype correlations in children with WD presented with ALF and non-immune hemolytic anemia.METHODS The medical records of children with WD diagnosed and treated in our hospital from January 2006 to December 2020 were retrospectively analyzed.The clinical manifestations(ALF with non-immune hemolytic anemia or other less severe forms),laboratory parameters,copper metabolism,ATP7B variants,and the HSD17B13:TA(rs72613567)variant were reviewed to analyze the possible genotype-phenotype correlations.RESULTS We analyzed the data of 51 patients with WD,26 females(50.98%),with the mean age at the diagnosis of 12.36±3.74 years.ALF and Coombs-negative hemolytic anemia was present in 8 children(15.67%),all adolescent girls.The Kayser-Fleisher ring was present in 9 children(17.65%).The most frequent variants of the ATP7B gene were p.His1069Gln(c.3207A>G)in 38.24% of all alleles,p.Gly1341Asp(c.4021G>A)in 26.47%,p.Trp939Cys(c.2817G>T)in 9.80%,and p.Lys844Ter(c.2530A>T)in 4.90%.In ALF with hemolytic anemia,p.Trp939Cys(c.2817G>T)and p.Lys844Ter(c.2530A>T)variants were more frequent than in other less severe forms,in which p.His1069Gln(c.3207A>G)was more frequent.p.Gly1341Asp(c.4021G>A)has a similar frequency in all hepatic forms.For 33 of the patients,the HSD17B13 genotype was evaluated.The overall HSD17B13:TA allele frequency was 24.24%.Its frequency was higher in patients with less severe liver disease(26.92%)than those with ALF and hemolytic anemia(14.28%).CONCLUSION It remains challenging to prove a genotype-phenotype correlation in WD patients.In children with ALF and hemolytic anemia,the missense variants other than p.His1069Gln(c.3207A>G)and frame-shift variants were the most frequently present in homozygous status or compound heterozygous status with site splice variants.As genetic analysis is usually time-consuming and the results are late,the importance at the onset of the ALF is questionable.If variants proved to be associated with severe forms are found in the pre-symptomatic phase of the disease,this could be essential to predict a possible severe evolution.展开更多
Wilson’s disease(WD)is a rare inherited disorder of human copper metabolism,with an estimated prevalence of 1:30000-1:50000 and a broad spectrum of hepatic and neuropsychiatric manifestations.In healthy individuals,t...Wilson’s disease(WD)is a rare inherited disorder of human copper metabolism,with an estimated prevalence of 1:30000-1:50000 and a broad spectrum of hepatic and neuropsychiatric manifestations.In healthy individuals,the bile is the main route of elimination of copper.In WD patients,copper accumulates in the liver,it is released into the bloodstream,and is excreted in urine.Copper can also be accumulated in the brain,kidneys,heart,and osseous matter and causes damage due to direct toxicity or oxidative stress.Hepatic WD is commonly but not exclusively diagnosed in childhood or young adulthood.Adherent,non-cirrhotic WD patients seem to have a normal life expectancy.Nevertheless,chronic management of patients with Wilson’s disease is challenging,as available biochemical tests have many limitations and do not allow a clear identification of non-compliance,overtreatment,or treatment goals.To provide optimal care,clinicians should have a complete understanding of these limitations and counterbalance them with a thorough clinical assessment.The aim of this review is to provide clinicians with practical tools and suggestions which may answer doubts that can arise during chronic management of patients with hepatic WD.In particular,it summarises current knowledge on Wilson’s disease clinical and biochemical monitoring and treatment.It also analyses available evidence on pregnancy and the role of low-copper diet in WD.Future research should focus on trying to provide new copper metabolism tests which could help to guide treatment adjustments.展开更多
We have read with interest the Letter to the Editor by Drs.Zhuang and Zhong,who presented the clinical data of 68 patients with Wilson’s disease(WD)who were admitted to the hospital before and during the coronavirus ...We have read with interest the Letter to the Editor by Drs.Zhuang and Zhong,who presented the clinical data of 68 patients with Wilson’s disease(WD)who were admitted to the hospital before and during the coronavirus disease 2019(COVID-19)pandemic,and appreciated their findings on hepatic and some extrahepatic manifestations.Nevertheless,given the strong impact of the pandemic on patients with neurological and psychiatric disorders,we would have expected a worsening of the psychiatric and/or neurological impairments in these patients.In contrast,according to the authors,these manifestations remained,somewhat unexpectedly,unchanged.This finding is in contrast with most of the current literature that highlights not only an increased incidence of mental health disorders in the general population but also an exacerbation of neurological and psychiatric symptoms in patients with chronic diseases,especially in those with pre-existing neuropsychiatric disorders,such as WD.Although the study was mainly focused on the hepatic features of WD patients taking anti-copper treatment,a generic and cumulative definition of neurological and psychiatric manifestations,as in this study,does not allow for further considerations.Future studies during and after the pandemic are necessary to clarify the real impact,either direct or indirect,of the COVID-19 pandemic on the neurological and psychiatric symptoms of WD patients.展开更多
Background and Objective: Wilson’s disease is a genetic disorder of copper metabolism that affects liver and other organs including heart. In early stages of myocardial affection, the left ventricle (LV) appears appa...Background and Objective: Wilson’s disease is a genetic disorder of copper metabolism that affects liver and other organs including heart. In early stages of myocardial affection, the left ventricle (LV) appears apparently normal when evaluated by traditional two-dimensional (2D) echocardiography. The aim of this study was to detect subclinical LV dysfunction in children with Wilson’s disease using 2D speckle tracking echocardiography. Patients and Methods: Twenty children with Wilson’s disease were compared with age- and sex-matched 20 healthy children. All subjects were evaluated by traditional 2D echocardiography and speckle tracking echocardiography. Results: There were no significant differences between patients and controls regarding conventional echo parameters except for lower E mitral flow and E' annular septal peak velocity in patient group. The regional peak longitudinal strain of apical 4 chamber view was -17.8% ± 4.2% in patients and -20.1% ± 2.3 % in control subjects (P = 0.043), and for apical 2 chambers view, it was -20.1%± 3.6% in patients and -22.6% ± 3.4% in control subjects (P = 0.034) and it was -18% ± 3.5% in patients and -20.5% ± 3.2% in control subjects (P = 0.025) in apical long axis view. The global peak longitudinal strain was also lower in patients than control group (18.3% ± 3.2%, and 20.85% ± 2.4%) respectively (P = 0.014). There were no significant differences between both groups regarding circumferential and radial strains (P > 0.05). Conclusions: Despite apparently normal LV systolic function, the children with Wilson’s disease demonstrated significantly lower peak longitudinal strain as an indicator for early affection of LV systolic function.展开更多
Wilson’s disease is an autosomal-recessive disorder with an ATP7B mutation that causes a functional failure of the copper-transporting protein ATP7B(1,2).As a result,unbound copper in the blood increases,and due to c...Wilson’s disease is an autosomal-recessive disorder with an ATP7B mutation that causes a functional failure of the copper-transporting protein ATP7B(1,2).As a result,unbound copper in the blood increases,and due to copper accumulation,multiple organs show various symptoms,e.g.,Kayser-Fleischer rings,acute liver failure,liver cirrhosis,liver cancer,dysarthria,tremors,character changes,renal disorders,rheumatological symptoms,endocrinopathy,heart failure,and arrhythmias(3,4).This disease afflicts approximately 1 in 40,000 people,with approximately 1 carrier for every 100 people,and early diagnosis is difficult.展开更多
The combination of disease-specific human induced pluripotent stem cells(iPSC)and directed cell differentiation offers an ideal platform for modeling and studying many inherited human diseases.Wilson’s disease(WD)is ...The combination of disease-specific human induced pluripotent stem cells(iPSC)and directed cell differentiation offers an ideal platform for modeling and studying many inherited human diseases.Wilson’s disease(WD)is a monogenic disorder of toxic copper accumulation caused by pathologic mutations of the ATP7B gene.WD affects multiple organs with primary manifestations in the liver and central nervous system(CNS).In order to better investigate the cellular pathogenesis of WD and to develop novel therapies against various WD syndromes,we sought to establish a comprehensive platform to differentiate WD patient iPSC into both hepatic and neural lineages.Here we report the generation of patient iPSC bearing a Caucasian population hotspot mutation of ATP7B.Combining with directed cell differentiation strategies,we successfully differentiated WD iPSC into hepatocyte-like cells,neural stem cells and neurons.Gene expression analysis and cDNA sequencing confirmed the expression of the mutant ATP7B gene in all differentiated cells.Hence we established a platform for studying both hepatic and neural abnormalities of WD,which may provide a new tool for tissue-specific disease modeling and drug screening in the future.展开更多
A 64-year-old woman was referred to our hospital with jaundice of the bulbar conjunctiva and general fatigue. After admission, she developed hepatic encephalopathy and was diagnosed with fulminant hepatitis based on t...A 64-year-old woman was referred to our hospital with jaundice of the bulbar conjunctiva and general fatigue. After admission, she developed hepatic encephalopathy and was diagnosed with fulminant hepatitis based on the American Association for the Study of Liver Disease(AASLD) position paper. Afterwards, additional laboratory findings revealed that serum ceruloplasmin levels were reduced, urinary copper levels were greatly elevated and Wilson's disease(WD)-specific routine tests were positive, but the Kayser-Fleischer ring was not clear. Based on the AASLD practice guidelines for the diagnosis and treatment of WD, the patient was ultimately diagnosed with fulminant WD. Then, administration of penicillamine and zinc acetate was initiated; however, the patient unfortunately died from acute pneumonia on the 28 th day of hospitalization. At autopsy, the liver did not show a bridging pattern of fibrosis suggestive of chronic liver injury. Here, we present the case of a patient with clinically diagnosed late-onset fulminant WD without cirrhosis, who had positive disease-specific routine tests.展开更多
Background: Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism caused by ATP7B (encoding a copper-transporting P-type ATPase) variants that shows various characteristics according to race a...Background: Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism caused by ATP7B (encoding a copper-transporting P-type ATPase) variants that shows various characteristics according to race and geographical region. This study was aimed to provide a comprehensive analysis of ATP7B variants in China and to investigate a plausible role of common variants in WD manifestations. Methods: A total of 1366 patients (1302 index patients and 64 siblings) clinically diagnosed with WD (Leipzig score ≥ 4) were recruited. They underwent ATP7B gene sequencing and information of age and symptoms at onset was collected. The genotype-phenotype correlation was assessed in the index patients who were examined with two pathogenic variants and onset with hepatic (n = 276) or neurologic (n = 665) symptoms. Results: We identified 294 potentially pathogenic ATP7B variants (112 truncating, 174 missense, 8 in-frame) in the 1302 index patients, including 116 novel variants. The most frequent variant was c.2333G>T (R778L, allele fre-quency: 28.96%), followed by c.2975C>T (P992L, 13.82%), c.2621C>T (A874V, 5.99%), c.2755C>G (R919G, 2.46%), and c.3646G>A (V1216M, 1.92%). In 1167 patients, both pathogentic variants were identified, of which 532 differ-ent variant combinations were found. By binary logistic regression analysis, the factor associated with neurological presentation was high age-at-onset, but not sex, protein-truncating variant (PTV), or the common missense variants (R778L, P992L, and A874V). In the neurological group, low age-at-onset was a factor associated with dystonia, gait abnormality, and salivation;high age-at-onset was a factor associated with tremor;and the sex, low age-at-onset and A874V were independent factors associated with dysarthria. In addition, PTV, R778L, and P992L were predominant in early-onset patients, whereas A874V was predominant in late-onset patients, and patients with R778L/A874V geno-type displayed a higher age-at-onset than patients with R778L/R778L or R778L/P992L genotype. Conclusions: Our work expanded the ATP7B variant spectrum and highlighted the differences among patients with WD in age-at-onset and ATP7B variants, which may provide some valuable insights into the diagnosis, counseling, and treatment of patients with WD.展开更多
文摘Wilson disease is an autosomal recessive disorder affecting the ATP7B gene located on chromosome 13q.This leads to copper deposition in various organs,most importantly in the liver and brain.The genetic mutations are vast,well reported in the West but poorly documented in developing countries.Hence the diagnosis is made with a constellation of clinico-laboratory parameters which have significant overlap with other liver diseases and often pose a significant dilemma for clinicians.Diagnostic scoring systems are not fool-proof.The availability and affordability of chelators in developing countries impact the drug compliance of patients.While D-penicillamine is a potent drug,its side effects lead to drug discontinuation.Trientine is cost-prohibitive in developing countries.There is no single test to assess the adequacy of chelation.Exchangeable urinary copper is an essential upcoming diagnostic and prognostic tool.In the presence of cirrhosis,hypersplenism clouds the assessment of myelosuppression of drugs.Similarly,it may be difficult to distinguish disease tubulopathy from druginduced glomerulonephritis.Neurological worsening due to chelators may appear similar to disease progression.Presentation as fulminant hepatic failure requires rapid workup.There is a limited window of opportunity to salvage these patients with the help of plasmapheresis and other liver-assisted devices.This review addresses the challenges and clinical dilemmas faced at beside in developing countries.
文摘Wilson’s disease is a rare disorder of copper transport in hepatic cells,and may present as cholestatic liver disease;pancreatitis and cholangitis are rarely associated with Wilsons’s disease.Moreover,cases of Wilson s disease presenting as pigmented gallstone pancreatitis have not been reported in the literature.In the present report,we describe a case of a 37-year-old man who was admitted with jaundice and abdomina pain.The patient was diagnosed with acute pancreatitis,cholangitis,and obstructive jaundice caused by pigmented gallstones that were detected during retrograde cholangiopancreatography.However,because of his long-term jaundice and the presence of pigmented gallstones,the patient underwent further evaluation for Wilson’s disease,which was subsequently confirmed.This patient’s unique presentation exemplifies the overlap in the clinical and laboratory parameters of Wilson’s disease and cholestasis,and the difficulties associated with their differentiation.It suggests thatWilson’s disease should be considered in patients with pancreatitis,cholangitis,and severe protracted jaundice caused by pigmented gallstones.
文摘BACKGROUND Wilson’s disease(WD)is a rare autosomal recessive inherited disorder of copper metabolism.Acute liver failure(ALF)and hemolytic anemia represent the most severe presentation of WD in children.No clear genotype-phenotype correlations exist in WD.Protein-truncating nonsense,frame-shift,or splice-site variants may be associated with more severe disease.In contrast,missense variants may be associated with late-onset,less severe disease,and more neurological manifestations.Recently,a gene variant(HSD17B13:TA,rs72613567)with a possible hepatic protective role against toxins was associated with a less severe hepatic phenotype in WD.AIM To analyze the possible genotype-phenotype correlations in children with WD presented with ALF and non-immune hemolytic anemia.METHODS The medical records of children with WD diagnosed and treated in our hospital from January 2006 to December 2020 were retrospectively analyzed.The clinical manifestations(ALF with non-immune hemolytic anemia or other less severe forms),laboratory parameters,copper metabolism,ATP7B variants,and the HSD17B13:TA(rs72613567)variant were reviewed to analyze the possible genotype-phenotype correlations.RESULTS We analyzed the data of 51 patients with WD,26 females(50.98%),with the mean age at the diagnosis of 12.36±3.74 years.ALF and Coombs-negative hemolytic anemia was present in 8 children(15.67%),all adolescent girls.The Kayser-Fleisher ring was present in 9 children(17.65%).The most frequent variants of the ATP7B gene were p.His1069Gln(c.3207A>G)in 38.24% of all alleles,p.Gly1341Asp(c.4021G>A)in 26.47%,p.Trp939Cys(c.2817G>T)in 9.80%,and p.Lys844Ter(c.2530A>T)in 4.90%.In ALF with hemolytic anemia,p.Trp939Cys(c.2817G>T)and p.Lys844Ter(c.2530A>T)variants were more frequent than in other less severe forms,in which p.His1069Gln(c.3207A>G)was more frequent.p.Gly1341Asp(c.4021G>A)has a similar frequency in all hepatic forms.For 33 of the patients,the HSD17B13 genotype was evaluated.The overall HSD17B13:TA allele frequency was 24.24%.Its frequency was higher in patients with less severe liver disease(26.92%)than those with ALF and hemolytic anemia(14.28%).CONCLUSION It remains challenging to prove a genotype-phenotype correlation in WD patients.In children with ALF and hemolytic anemia,the missense variants other than p.His1069Gln(c.3207A>G)and frame-shift variants were the most frequently present in homozygous status or compound heterozygous status with site splice variants.As genetic analysis is usually time-consuming and the results are late,the importance at the onset of the ALF is questionable.If variants proved to be associated with severe forms are found in the pre-symptomatic phase of the disease,this could be essential to predict a possible severe evolution.
文摘Wilson’s disease(WD)is a rare inherited disorder of human copper metabolism,with an estimated prevalence of 1:30000-1:50000 and a broad spectrum of hepatic and neuropsychiatric manifestations.In healthy individuals,the bile is the main route of elimination of copper.In WD patients,copper accumulates in the liver,it is released into the bloodstream,and is excreted in urine.Copper can also be accumulated in the brain,kidneys,heart,and osseous matter and causes damage due to direct toxicity or oxidative stress.Hepatic WD is commonly but not exclusively diagnosed in childhood or young adulthood.Adherent,non-cirrhotic WD patients seem to have a normal life expectancy.Nevertheless,chronic management of patients with Wilson’s disease is challenging,as available biochemical tests have many limitations and do not allow a clear identification of non-compliance,overtreatment,or treatment goals.To provide optimal care,clinicians should have a complete understanding of these limitations and counterbalance them with a thorough clinical assessment.The aim of this review is to provide clinicians with practical tools and suggestions which may answer doubts that can arise during chronic management of patients with hepatic WD.In particular,it summarises current knowledge on Wilson’s disease clinical and biochemical monitoring and treatment.It also analyses available evidence on pregnancy and the role of low-copper diet in WD.Future research should focus on trying to provide new copper metabolism tests which could help to guide treatment adjustments.
文摘We have read with interest the Letter to the Editor by Drs.Zhuang and Zhong,who presented the clinical data of 68 patients with Wilson’s disease(WD)who were admitted to the hospital before and during the coronavirus disease 2019(COVID-19)pandemic,and appreciated their findings on hepatic and some extrahepatic manifestations.Nevertheless,given the strong impact of the pandemic on patients with neurological and psychiatric disorders,we would have expected a worsening of the psychiatric and/or neurological impairments in these patients.In contrast,according to the authors,these manifestations remained,somewhat unexpectedly,unchanged.This finding is in contrast with most of the current literature that highlights not only an increased incidence of mental health disorders in the general population but also an exacerbation of neurological and psychiatric symptoms in patients with chronic diseases,especially in those with pre-existing neuropsychiatric disorders,such as WD.Although the study was mainly focused on the hepatic features of WD patients taking anti-copper treatment,a generic and cumulative definition of neurological and psychiatric manifestations,as in this study,does not allow for further considerations.Future studies during and after the pandemic are necessary to clarify the real impact,either direct or indirect,of the COVID-19 pandemic on the neurological and psychiatric symptoms of WD patients.
文摘Background and Objective: Wilson’s disease is a genetic disorder of copper metabolism that affects liver and other organs including heart. In early stages of myocardial affection, the left ventricle (LV) appears apparently normal when evaluated by traditional two-dimensional (2D) echocardiography. The aim of this study was to detect subclinical LV dysfunction in children with Wilson’s disease using 2D speckle tracking echocardiography. Patients and Methods: Twenty children with Wilson’s disease were compared with age- and sex-matched 20 healthy children. All subjects were evaluated by traditional 2D echocardiography and speckle tracking echocardiography. Results: There were no significant differences between patients and controls regarding conventional echo parameters except for lower E mitral flow and E' annular septal peak velocity in patient group. The regional peak longitudinal strain of apical 4 chamber view was -17.8% ± 4.2% in patients and -20.1% ± 2.3 % in control subjects (P = 0.043), and for apical 2 chambers view, it was -20.1%± 3.6% in patients and -22.6% ± 3.4% in control subjects (P = 0.034) and it was -18% ± 3.5% in patients and -20.5% ± 3.2% in control subjects (P = 0.025) in apical long axis view. The global peak longitudinal strain was also lower in patients than control group (18.3% ± 3.2%, and 20.85% ± 2.4%) respectively (P = 0.014). There were no significant differences between both groups regarding circumferential and radial strains (P > 0.05). Conclusions: Despite apparently normal LV systolic function, the children with Wilson’s disease demonstrated significantly lower peak longitudinal strain as an indicator for early affection of LV systolic function.
文摘Wilson’s disease is an autosomal-recessive disorder with an ATP7B mutation that causes a functional failure of the copper-transporting protein ATP7B(1,2).As a result,unbound copper in the blood increases,and due to copper accumulation,multiple organs show various symptoms,e.g.,Kayser-Fleischer rings,acute liver failure,liver cirrhosis,liver cancer,dysarthria,tremors,character changes,renal disorders,rheumatological symptoms,endocrinopathy,heart failure,and arrhythmias(3,4).This disease afflicts approximately 1 in 40,000 people,with approximately 1 carrier for every 100 people,and early diagnosis is difficult.
基金supported by Sanofi-Aventis,The Helmsley Charitable Trust and The Ellison Medical Foundationsupported by"Thousand Young Talents"program of China+3 种基金National Laboratory of Biomacromolecules,Strategic Priority Research Program of the Chinese Academy of Sciencesa CIRM training grant fellowship(No.TG2-01158)a Glenn foundation grantpartially supported by an AFAR/Ellison Medical Foundation postdoctoral fellowship.
文摘The combination of disease-specific human induced pluripotent stem cells(iPSC)and directed cell differentiation offers an ideal platform for modeling and studying many inherited human diseases.Wilson’s disease(WD)is a monogenic disorder of toxic copper accumulation caused by pathologic mutations of the ATP7B gene.WD affects multiple organs with primary manifestations in the liver and central nervous system(CNS).In order to better investigate the cellular pathogenesis of WD and to develop novel therapies against various WD syndromes,we sought to establish a comprehensive platform to differentiate WD patient iPSC into both hepatic and neural lineages.Here we report the generation of patient iPSC bearing a Caucasian population hotspot mutation of ATP7B.Combining with directed cell differentiation strategies,we successfully differentiated WD iPSC into hepatocyte-like cells,neural stem cells and neurons.Gene expression analysis and cDNA sequencing confirmed the expression of the mutant ATP7B gene in all differentiated cells.Hence we established a platform for studying both hepatic and neural abnormalities of WD,which may provide a new tool for tissue-specific disease modeling and drug screening in the future.
文摘A 64-year-old woman was referred to our hospital with jaundice of the bulbar conjunctiva and general fatigue. After admission, she developed hepatic encephalopathy and was diagnosed with fulminant hepatitis based on the American Association for the Study of Liver Disease(AASLD) position paper. Afterwards, additional laboratory findings revealed that serum ceruloplasmin levels were reduced, urinary copper levels were greatly elevated and Wilson's disease(WD)-specific routine tests were positive, but the Kayser-Fleischer ring was not clear. Based on the AASLD practice guidelines for the diagnosis and treatment of WD, the patient was ultimately diagnosed with fulminant WD. Then, administration of penicillamine and zinc acetate was initiated; however, the patient unfortunately died from acute pneumonia on the 28 th day of hospitalization. At autopsy, the liver did not show a bridging pattern of fibrosis suggestive of chronic liver injury. Here, we present the case of a patient with clinically diagnosed late-onset fulminant WD without cirrhosis, who had positive disease-specific routine tests.
基金the National Natural Science Foundation of China(81903895,81973825,and 82104783)the Natural Science Foundation of Anhui Province(1908085QC90)the Anhui University Collaborative Innovation Project(GXXT-2020-025).
文摘Background: Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism caused by ATP7B (encoding a copper-transporting P-type ATPase) variants that shows various characteristics according to race and geographical region. This study was aimed to provide a comprehensive analysis of ATP7B variants in China and to investigate a plausible role of common variants in WD manifestations. Methods: A total of 1366 patients (1302 index patients and 64 siblings) clinically diagnosed with WD (Leipzig score ≥ 4) were recruited. They underwent ATP7B gene sequencing and information of age and symptoms at onset was collected. The genotype-phenotype correlation was assessed in the index patients who were examined with two pathogenic variants and onset with hepatic (n = 276) or neurologic (n = 665) symptoms. Results: We identified 294 potentially pathogenic ATP7B variants (112 truncating, 174 missense, 8 in-frame) in the 1302 index patients, including 116 novel variants. The most frequent variant was c.2333G>T (R778L, allele fre-quency: 28.96%), followed by c.2975C>T (P992L, 13.82%), c.2621C>T (A874V, 5.99%), c.2755C>G (R919G, 2.46%), and c.3646G>A (V1216M, 1.92%). In 1167 patients, both pathogentic variants were identified, of which 532 differ-ent variant combinations were found. By binary logistic regression analysis, the factor associated with neurological presentation was high age-at-onset, but not sex, protein-truncating variant (PTV), or the common missense variants (R778L, P992L, and A874V). In the neurological group, low age-at-onset was a factor associated with dystonia, gait abnormality, and salivation;high age-at-onset was a factor associated with tremor;and the sex, low age-at-onset and A874V were independent factors associated with dysarthria. In addition, PTV, R778L, and P992L were predominant in early-onset patients, whereas A874V was predominant in late-onset patients, and patients with R778L/A874V geno-type displayed a higher age-at-onset than patients with R778L/R778L or R778L/P992L genotype. Conclusions: Our work expanded the ATP7B variant spectrum and highlighted the differences among patients with WD in age-at-onset and ATP7B variants, which may provide some valuable insights into the diagnosis, counseling, and treatment of patients with WD.
