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1
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Beyzaei Z, Mehrzadeh A, Hashemi N, Geramizadeh B. The mutation spectrum and ethnic distribution of Wilson disease, a review. Mol Genet Metab Rep 2024; 38:101034. [PMID: 38149214 PMCID: PMC10750106 DOI: 10.1016/j.ymgmr.2023.101034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 11/28/2023] [Accepted: 12/01/2023] [Indexed: 12/28/2023] Open
Abstract
Wilson's disease is a complicated medical condition caused by the accumulation of copper, mostly in the liver and brain. The genetic basis of Wilson's disease is attributed to the presence of pathogenic variants in the ATP7B copper-transporting gene, which prevents the excretion of copper through the biliary tract. To date, ATP7B remains the only identified gene that has been linked to the development of this disease. Our understanding of the disease has been associated with the identification of particular disease-causing variants that present specific impairments in copper transporters. It is crucial to identify the most frequent variant in terms of ethnicity to facilitate testing of its functionality. This study represents the initial comprehensive analysis of ATP7B variants, providing insights into the extensive range of disease-causing mutations. Here, we describe the 1275 distinct ATP7B variants documented so far, with particular emphasis on their regional and ethnic prevalence. The H1069Q missense variant is the most frequently reported in Europe, Northern America, and North Africa, whereas the R778L, C271*, and M645R variants are the most prevalent in the East Asian, Middle Eastern-South Asian, and South American populations, respectively. Acquiring such knowledge would facilitate the implementation of a selective mutation screening approach, targeting the most predominant variant identified within a specific ethnic group or geographic region for better diagnosis of the disease.
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Affiliation(s)
- Zahra Beyzaei
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Arman Mehrzadeh
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Niko Hashemi
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Bita Geramizadeh
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pathology, Shiraz University of Medical Sciences, Shiraz, Iran
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2
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Lucena-Valera A, Ruz-Zafra P, Ampuero J. [Wilson's disease: overview]. Med Clin (Barc) 2023; 160:261-267. [PMID: 36697289 DOI: 10.1016/j.medcli.2022.12.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 12/27/2022] [Accepted: 12/28/2022] [Indexed: 01/25/2023]
Abstract
Wilson's disease (WD) is an uncommon hereditary disorder caused by a deficiency in the ATP7B transporter. The protein codified by this gene facilitates the incorporation of the copper into ceruloplasmin. Therefore, WD accumulates copper primary in the liver and secondary in other organs, such as the central nervous system. It represents a wide spectrum of disease, ranging from being asymptomatic in some patients to promote an acute liver failure in others. The diagnosis requires a combination of clinical signs and symptoms, as well as some diagnostic tests such as the measurement of serum ceruloplasmin, the urinary excretion of copper, the liver biopsy or the genetic testing. The treatment must be maintained lifelong and includes some drugs such as chelating agents (penicillamine and trientine) and inhibitors of the copper absorption (zinc salts). Lastly, the liver transplant should be an option for patients with end-stage liver disease.
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Affiliation(s)
- Ana Lucena-Valera
- Departamento de Enfermedades Digestivas, Hospital Universitario Virgen del Rocío, Sevilla, España
| | - Pilar Ruz-Zafra
- Departamento de Enfermedades Digestivas, Hospital Universitario Virgen del Rocío, Sevilla, España
| | - Javier Ampuero
- Departamento de Enfermedades Digestivas, Hospital Universitario Virgen del Rocío, Sevilla, España; Instituto de Biomedicina de Sevilla (IBiS), Sevilla, España; Universidad de Sevilla, Sevilla, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, España.
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3
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Lucena-Valera A, Perez-Palacios D, Muñoz-Hernandez R, Romero-Gómez M, Ampuero J. Wilson's disease: Revisiting an old friend. World J Hepatol 2021; 13:634-649. [PMID: 34239699 PMCID: PMC8239488 DOI: 10.4254/wjh.v13.i6.634] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 03/21/2021] [Accepted: 05/08/2021] [Indexed: 02/06/2023] Open
Abstract
Wilson's disease (WD) is a rare condition caused by copper accumulation primarily in the liver and secondly in other organs, such as the central nervous system. It is a hereditary autosomal recessive disease caused by a deficiency in the ATP7B transporter. This protein facilitates the incorporation of copper into ceruloplasmin. More than 800 mutations associated with WD have been described. The onset of the disease frequently includes manifestations related to the liver (as chronic liver disease or acute liver failure) and neurological symptoms, although it can sometimes be asymptomatic. Despite it being more frequent in young people, WD has been described in all life stages. Due to its fatal prognosis, WD should be suspected in all patients with unexplained biochemical liver abnormalities or neurological or psychiatric symptoms. The diagnosis is established with a combination of clinical signs and tests, including the measurement of ceruloplasmin, urinary copper excretion, copper quantification in liver biopsy, or genetic assessment. The pharmacological therapies include chelating drugs, such as D-penicillamine or trientine, and zinc salts, which are able to change the natural history of the disease, increasing the survival of these patients. In some cases of end-stage liver disease or acute liver failure, liver transplantation must be an option to increase survival. In this narrative review, we offer an overview of WD, focusing on the importance of clinical suspicion, the correct diagnosis, and treatment.
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Affiliation(s)
- Ana Lucena-Valera
- Department of Gastroenterology, Hospital Universitario Virgen del Rocio, Sevilla 41013, Spain
| | - Domingo Perez-Palacios
- Department of Gastroenterology, Hospital Universitario Virgen del Rocio, Sevilla 41013, Spain
| | - Rocio Muñoz-Hernandez
- SeLiver Group, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, España
| | - Manuel Romero-Gómez
- Department of Unit of Digestive Diseases, Hospital Universitario Virgen del Rocio, Sevilla 41014, Spain
| | - Javier Ampuero
- Department of Unit of Digestive Diseases, Hospital Universitario Virgen del Rocio, Sevilla 41014, Spain.
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4
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Malbul K, Katwal S, Khetan S, Aryal N. A case report on serendipitous diagnosis of wilson's disease in a child with brucellosis and pseudomonal infection. Clin Case Rep 2021; 9:e04178. [PMID: 34194770 PMCID: PMC8222750 DOI: 10.1002/ccr3.4178] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 03/28/2021] [Accepted: 03/31/2021] [Indexed: 12/18/2022] Open
Abstract
Wilson's disease can have varied clinical manifestations and initial presentation can be misleading as in our case. Our case depicts the necessity of suspicion of WD in variable presentation of liver disorders, especially in pediatrics population.
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Affiliation(s)
- Kiran Malbul
- Nepalese Army Institute of Health Sciences College of MedicineKathmanduNepal
| | - Srijana Katwal
- Nepalese Army Institute of Health Sciences College of MedicineKathmanduNepal
| | - Saurav Khetan
- Department of PediatricsShree Birendra HospitalKathmanduNepal
| | - Nirjala Aryal
- Department of PediatricsShree Birendra HospitalKathmanduNepal
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5
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Tinaz S, Arora J, Nalamada K, Vives-Rodriguez A, Sezgin M, Robakis D, Patel A, Constable RT, Schilsky ML. Structural and functional brain changes in hepatic and neurological Wilson disease. Brain Imaging Behav 2020; 15:2269-2282. [PMID: 33244627 DOI: 10.1007/s11682-020-00420-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/09/2020] [Indexed: 12/14/2022]
Abstract
Wilson disease (WD) can manifest with hepatic or neuropsychiatric symptoms. Our understanding of the in vivo brain changes in WD, particularly in the hepatic phenotype, is limited. Thirty subjects with WD and 30 age- and gender-matched controls participated. WD group underwent neuropsychiatric assessment. Unified WD Rating Scale neurological exam scores were used to determine neurological (WDN, score > 0) and hepatic-only (WDH, score 0) subgroups. All subjects underwent 3 Tesla anatomical and resting-state functional MRI. Diffusion tensor imaging (DTI) and susceptibility-weighted imaging (SWI) were performed only in the WD group. Volumetric, DTI, and functional connectivity analyses were performed to determine between-group differences. WDN and WDH groups were matched in demographic and psychiatric profiles. The entire WD group compared to controls showed significant thinning in the bilateral superior frontal cortex. The WDN group compared to control and WDH groups showed prominent structural brain changes including significant striatal and thalamic atrophy, more subcortical hypointense lesions on SWI, and diminished white matter integrity in the bilateral anterior corona radiata and corpus callosum. However, the WDH group also showed significant white matter volume loss compared to controls. The functional connectivity between the frontostriatal nodes was significantly reduced in the WDN group, whereas that of the hippocampus was significantly increased in the WDH group compared to controls. In summary, structural and functional brain changes were present even in neurologically non-manifesting WD patients in this cross-sectional study. Longitudinal brain MRI scans may be useful as biomarkers for prognostication and optimization of treatment strategies in WD.
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Affiliation(s)
- Sule Tinaz
- Department of Neurology, Yale University School of Medicine, 15 York St, LCI Suite 710, New Haven, CT, 06510, USA. .,Clinical Neurosciences Imaging Center, Yale University School of Medicine, New Haven, CT, USA.
| | - Jagriti Arora
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA
| | - Keerthana Nalamada
- Department of Neurology, Yale University School of Medicine, 15 York St, LCI Suite 710, New Haven, CT, 06510, USA
| | - Ana Vives-Rodriguez
- Department of Neurology, Yale University School of Medicine, 15 York St, LCI Suite 710, New Haven, CT, 06510, USA
| | - Mine Sezgin
- Department of Neurology, Yale University School of Medicine, 15 York St, LCI Suite 710, New Haven, CT, 06510, USA.,Istanbul Faculty of Medicine, Department of Neurology, Istanbul University, Istanbul, Turkey
| | - Daphne Robakis
- Department of Neurology, Yale University School of Medicine, 15 York St, LCI Suite 710, New Haven, CT, 06510, USA.,Department of Neurology, State University of New York Downstate College of Medicine, Brooklyn, NY, USA
| | - Amar Patel
- Department of Neurology, Yale University School of Medicine, 15 York St, LCI Suite 710, New Haven, CT, 06510, USA
| | - R Todd Constable
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA
| | - Michael L Schilsky
- Departments of Medicine and Surgery, Sections of Digestive Diseases and Transplant and Immunology, Yale University School of Medicine, New Haven, CT, USA
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6
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Poskanzer SA, Thies J, Collins CJ, Myers CT, Dayuha R, Duong P, Yi F, Chang IJ, Ochs HD, Torgerson TR, Hahn SH. The co-occurrence of Wilson disease and X-linked agammaglobulinemia in one family highlights the promising diagnostic potential of proteolytic analysis. Mol Genet Genomic Med 2020; 8:e1172. [PMID: 32067425 PMCID: PMC7196455 DOI: 10.1002/mgg3.1172] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 01/28/2020] [Accepted: 01/30/2020] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND We report the first case of a family with co-occurrence of Wilson disease (WD), an autosomal recessive disorder of copper metabolism, and X-linked agammaglobulinemia (XLA), a primary immunodeficiency disorder (PIDD) that features marked reduction in circulating B lymphocytes and serum immunoglobulins. METHODS AND RESULTS Through utilization of a multiplexed biomarker peptide quantification method known as the immuno-SRM assay, we were able to simultaneously and independently identify which family members are affected with WD and which are affected with XLA using dried blood spots (DBS). CONCLUSION Being able to delineate multiple diagnoses using proteolytic analysis from a single DBS provides support for implementation of this methodology for clinical diagnostic use as well as large-scale population screening, such as newborn screening (NBS). This could allow for early identification and treatment of affected individuals with WD or XLA, which have been shown to reduce morbidity and decrease mortality in these two populations.
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Affiliation(s)
- Sheri A Poskanzer
- School of Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA.,Biochemical Genetics, Seattle Children's Hospital, Seattle, WA, USA
| | - Jenny Thies
- Biochemical Genetics, Seattle Children's Hospital, Seattle, WA, USA
| | | | - Candace T Myers
- Department of Laboratories, Seattle Children's Hospital, Seattle, WA, USA
| | | | - Phi Duong
- Seattle Children's Research Institute, Seattle, WA, USA
| | - Fan Yi
- Seattle Children's Research Institute, Seattle, WA, USA
| | - Irene J Chang
- School of Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA.,Biochemical Genetics, Seattle Children's Hospital, Seattle, WA, USA.,Seattle Children's Research Institute, Seattle, WA, USA
| | - Hans D Ochs
- School of Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA.,Seattle Children's Research Institute, Seattle, WA, USA
| | - Troy R Torgerson
- School of Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA.,Seattle Children's Research Institute, Seattle, WA, USA
| | - Si Houn Hahn
- School of Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA.,Biochemical Genetics, Seattle Children's Hospital, Seattle, WA, USA.,Seattle Children's Research Institute, Seattle, WA, USA
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Poon KS, Teo ZH, Yap JH, Koay ES, Tan K. Challenges in molecular diagnosis of Wilson disease: viewpoint from the clinical laboratory. J Clin Pathol 2019; 73:231-234. [PMID: 31796634 DOI: 10.1136/jclinpath-2019-206054] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 09/01/2019] [Accepted: 09/13/2019] [Indexed: 01/11/2023]
Affiliation(s)
- Kok-Siong Poon
- Molecular Diagnosis Centre, Department of Laboratory Medicine, National University Hospital, Singapore
| | | | | | - Evelyn Sc Koay
- Department of Pathology, National University of Singapore, Singapore
| | - Karen Tan
- Molecular Diagnosis Centre, Department of Laboratory Medicine, National University Hospitals, Singapore
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8
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Clark-Feoktistova Y, Ruenes-Domech C, García-Bacallao E, Roblejo-Balbuena H, Feoktistova L, Clark-Feoktistova I, Jay-Herrera O, Collazo-Mesa T. Presence of the p.L456V polymorphism in Cuban patients clinically diagnosed with Wilson's disease. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2019. [DOI: 10.1016/j.rgmxen.2018.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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9
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Clark-Feoktistova Y, Ruenes-Domech C, García-Bacallao EF, Roblejo-Balbuena H, Feoktistova L, Clark-Feoktistova I, Jay-Herrera O, Collazo-Mesa T. Presence of the p.L456V polymorphism in Cuban patients clinically diagnosed with Wilson's disease. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2019; 84:143-148. [PMID: 29898862 DOI: 10.1016/j.rgmx.2018.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 03/02/2018] [Accepted: 03/18/2018] [Indexed: 06/08/2023]
Abstract
INTRODUCTION AND AIMS Wilson's disease is characterized by the accumulation of copper in different organs, mainly affecting the liver, brain, and cornea, and is caused by mutations in the ATP7B gene. More than 120 polymorphisms in the ATP7B gene have been reported in the medical literature. The aim of the present study was to identify the conformational changes in the exon 3 region of the ATP7B gene and detect the p.L456V polymorphism in Cuban patients clinically diagnosed with Wilson's disease. MATERIAL AND METHODS A descriptive study was conducted at the Centro Nacional de Genética Médica and the Instituto Nacional de Gastroenterología within the time frame of 2007-2012 and included 105 patients with a clinical diagnosis of Wilson's disease. DNA extraction was performed through the salting-out method and the fragment of interest was amplified using the polymerase chain reaction technique. The conformational shift changes in the exon 3 region and the presence of the p.L456V polymorphism were identified through the Single-Strand Conformation Polymorphism analysis. RESULTS The so-called b and c conformational shift changes, corresponding to the p.L456V polymorphism in the heterozygous and homozygous states, respectively, were identified. The allelic frequency of the p.L456V polymorphism in the 105 Cuban patients that had a clinical diagnosis of Wilson's disease was 41% and liver-related symptoms were the most frequent in the patients with that polymorphism. CONCLUSION The p.L456V polymorphism was identified in 64 Cuban patients clinically diagnosed with Wilson's disease, making future molecular study through indirect methods possible.
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Affiliation(s)
- Y Clark-Feoktistova
- Máster en Ciencias Biológicas, Universidad de Guantánamo (UG). Laboratorio de Biología Molecular, Guantánamo, Cuba.
| | - C Ruenes-Domech
- Especialista de primer grado en Gastroenterología, Directora del Instituto Nacional de Gastroenterología (ING), La Habana, Guantánamo, Cuba
| | - E F García-Bacallao
- Especialista de primer grado en Gastroenterología, Subdirectora de Docencia del Instituto Nacional de Gastroenterología (ING), La Habana, Guantánamo, Cuba
| | - H Roblejo-Balbuena
- Especialista de primer grado de Genética Clínica, Centro Nacional de Genética Médica, La Habana, Guantánamo, Cuba
| | - L Feoktistova
- Especialista en Lenguas Extranjeras, Universidad de Guantánamo, Guantánamo, Cuba
| | | | - O Jay-Herrera
- Especialista en Bioestadística, Universidad de Guantánamo (UG), Guantánamo, Cuba
| | - T Collazo-Mesa
- Laboratorio de Biología Molecular, Centro Nacional de Genética Médica, La Habana, Guantánamo, Cuba
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10
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Abstract
Consideration of a diagnosis of Wilson disease is still the critical factor in testing for and establishing disease diagnosis. In association with other clinical and biochemical tests, liver biopsy results and molecular genetic testing can also be used to generate a score for diagnosing Wilson disease. Medical therapy is effective for most patients; liver transplant can rescue those with acute liver failure or those with advanced liver disease who fail to respond to or discontinue medical therapy. Treatment monitoring must be done at regular intervals and includes clinical evaluation, liver tests and blood counts, and copper metabolic parameters.
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Affiliation(s)
- Michael L Schilsky
- Yale University Medical Center, 333 Cedar Street, LMP 1080, New Haven CT 06520, USA.
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11
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A special case of recurrent gross hematuria: Answers. Pediatr Nephrol 2017; 32:273-275. [PMID: 26650869 DOI: 10.1007/s00467-015-3265-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2015] [Revised: 10/19/2015] [Accepted: 10/19/2015] [Indexed: 10/22/2022]
Abstract
Wilson's disease (WD) is an autosomal recessive disorder, and has a variety of presentations. We reported a case of 9-year-old girl who presented with a history of recurrent gross hematuria, renal histological changes of IgA nephropathy, and finally had been confirmed to be Wilson's disease-associated IgA nephropathy.
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12
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Susnea I, Weiskirchen R. Trace metal imaging in diagnostic of hepatic metal disease. MASS SPECTROMETRY REVIEWS 2016; 35:666-686. [PMID: 25677057 DOI: 10.1002/mas.21454] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2014] [Revised: 11/25/2014] [Accepted: 12/02/2014] [Indexed: 06/04/2023]
Abstract
The liver is the most central organ and the largest gland of the body that influences and controls a variety of metabolic and catabolic processes. It produces inconceivable many essential proteins, is responsible for the recovery of various food components, degrades toxins, mediates the bile production, and is involved in the excretion of unwanted metabolites. Several of these anabolic or catabolic functions of the liver depend on trace elements. These are either integral part of enzymes, cofactors, or act as chemical catalysts. Therefore, a lack of trace elements can lead to organ failure or systemic illness. Conversely, excessive hepatic trace element deposition resulting from genetic disorders, intoxication, extensive dietary supply, or long-term parenteral nutrition may cause hepatic inflammation, fibrosis, cirrhosis, and even hepatocellular carcinoma. Although specific serum parameters currently allow rough assessment of metal deficit and excess, the precise quantification of hepatic metal content in liver is presently only possible by different titration or staining techniques of biopsy specimens. Recently, novel innovative metal imaging techniques were developed that are on the way to replace these traditional methods. In the present review, we summarize the function of different trace elements in liver health and disease and discuss the present knowledge on how quantitative biometal imaging techniques such as synchrotron X-ray fluorescence microscopy, secondary ion mass spectrometry, and laser ablation inductively coupled plasma mass spectrometry enrich diagnostics in the detection and quantification of hepatic metal disorders. We will further discuss sample preparation, sensitivity, spatial resolution, specificity, quantification strategies, and potential future applications of metal bioimaging in experimental research and clinical daily routine. © 2015 Wiley Periodicals, Inc. Mass Spec Rev 35:666-686, 2016.
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Affiliation(s)
- Iuliana Susnea
- Central Institute of Engineering, Electronics and Analytics (ZEA-3), Forschungszentrum Jülich, D-52425, Jülich, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, D-52074, Aachen, Germany.
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13
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Mašková J, Školoudík D, Burgetová A, Fiala O, Brůha R, Záhoráková D, Serranová T, Slovák M, Ulmanová O, Růžička E, Dušek P. Comparison of transcranial sonography-magnetic resonance fusion imaging in Wilson's and early-onset Parkinson's diseases. Parkinsonism Relat Disord 2016; 28:87-93. [DOI: 10.1016/j.parkreldis.2016.04.031] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Revised: 04/20/2016] [Accepted: 04/26/2016] [Indexed: 11/16/2022]
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14
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Karakurt C, Çelik S, Selimoğlu A, Varol I, Karabiber H, Yoloğlu S. Strain and strain rate echocardiography in children with Wilson's disease. Cardiovasc J Afr 2016; 27:307-314. [PMID: 27176875 PMCID: PMC5378936 DOI: 10.5830/cvja-2016-028] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Accepted: 03/08/2016] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE This study aimed to evaluate strain and strain rate echocardiography in children with Wilson's disease to detect early cardiac dysfunction. METHODS In this study, 21 patients with Wilson's disease and a control group of 20 age- and gender-matched healthy children were included. All the patients and the control group were evaluated with two-dimensional (2D) and colour-coded conventional transthoracic echocardiography by the same paediatric cardiologist using the same echocardiography machine (Vivid E9, GE Healthcare, Norway) in standard precordial positions, according to the American Society of Echocardiography recommendations. 2D strain and strain rate echocardiography were performed after the ECG probes of the echocardiography machine were adjusted for ECG monitoring. Longitudinal, transverse and radial strain, and strain rate were assessed from six basal and six mid-ventricular segments of the left ventricle, as recommended by the American Society of Echocardiography. RESULTS Left ventricular wall thickness, systolic and diastolic diameters, left ventricular diameters normalised to body surface area, end-systolic and end-diastolic volumes, cardiac output and cardiac index values were within normal limits and statistically similar in the patient and control groups (p > 0.05). Global strain and strain rate: the patient group had a statistically significant lower peak A longitudinal velocity of the left basal point and peak E longitudinal velocity of the left basal (VAbasR) point, and higher global peak A longitudinal/circumferential strain rate (GSRa) compared to the corresponding values of the control group (p < 0.05). Radial strain and strain rate: end-systolic rotation [ROT (ES)] was statistically significantly lower in the patient group (p < 0.05). Longitudinal strain and strain rate: end-systolic longitudinal strain [SLSC (ES)] and positive peak transverse strain (STSR peak P) were statistically significantly lower in the patient group (p < 0.05). Segmental analysis showed that rotational strain measurement of the anterior and lateral segments of the patient group were statistically significantly lower than the corresponding values of the control group (p < 0.05). Segmental analysis showed statistically significantly lower values of endsystolic longitudinal strain [STSR (ES)] of the basal lateral (p < 0.05) and end-systolic longitudinal strain [SLSC (ES)] of the basal septal segment (p < 0.05) in the patient group. End-systolic longitudinal strain [SLSC (ES)] and positive peak transverse strain (STSR peak P) were statistically significantly lower in the patient group (p < 0.05). Segmental analysis showed statistically significantly lower values of endsystolic longitudinal strain [SLSC (ES)] of the mid-anterior and basal anterior segments (p < 0.05), end-systolic longitudinal strain [STSR (ES)] measurements of the posterior and mid-posterior segments, end-systolic longitudinal displacement [DLDC (ES)] of the basal posterior, mid-posterior and mid-antero-septal segments in the patient group. CONCLUSION Cardiac arrhythmias, cardiomyopathy and sudden cardiac death are rare complications but may be seen in children with Wilson's disease due to copper accumulation in the heart tissue. Strain and strain rate echocardiography is a relatively new and useful echocardiographic technique to evaluate cardiac function and cardiac deformation abnormalities. Our study showed that despite normal systolic function, patients with Wilson's disease showed diastolic dysfunction and regional deformation abnormalities, especially rotational strain and strain rate abnormalities.
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Affiliation(s)
- Cemşit Karakurt
- Department of Pediatric Cardiology, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - Serkan Çelik
- Department of Pediatric Cardiology, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - Ayşe Selimoğlu
- Department of Pediatric Gastroenterology, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - Ilknur Varol
- Department of Pediatric Gastroenterology, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - Hamza Karabiber
- Department of Pediatric Gastroenterology, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - Saim Yoloğlu
- Department of Biostatistics, Faculty of Medicine, Inonu University, Malatya, Turkey
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15
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Targeted next-generation sequencing of the ATP7B gene for molecular diagnosis of Wilson disease. Clin Biochem 2015; 49:166-71. [PMID: 26483271 DOI: 10.1016/j.clinbiochem.2015.10.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2015] [Revised: 09/09/2015] [Accepted: 10/14/2015] [Indexed: 02/08/2023]
Abstract
OBJECTIVES In recent years, next-generation sequencing (NGS) technologies, which enable high throughput sample processing at relatively lower costs, are adopted in both research and clinical settings. A multiplex PCR-based NGS assay to identify mutations in the ATP7B gene for routine molecular diagnosis of Wilson disease was evaluated in comparison with the gold standard direct Sanger sequencing. DESIGN AND METHODS Five multiplex PCRs to amplify the partial promoter, 5' untranslated and the entire coding regions of the ATP7B gene were designed. Indexed paired-end libraries were generated from the pooled amplicons using Nextera XT DNA Sample Preparation Kit and subjected to NGS on the MiSeq platform. DNA from the peripheral blood of 12 patients with Wilson disease, 2 B-lymphocyte cell lines and 3 external quality assurance samples were sequenced by the MiSeq and Sanger sequencing. RESULTS Complete coverage was achieved across the targeted bases without any drop-out sequences. The observed read depth in a single run with 20 samples was >100X. Comparison of the NGS results against Sanger sequencing data on a panel of clinical specimens, cell lines and European Molecular Genetics Quality Networks (EMQN) quality assurance samples showed 100% concordance in identifying pathogenic mutations. CONCLUSION With the capability of generating relatively higher throughput in a short time period, the NGS assay is a viable alternative to Sanger sequencing for detecting ATP7B mutations causally linked to Wilson disease in the clinical diagnostic laboratory.
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Wu F, Wang J, Pu C, Qiao L, Jiang C. Wilson's disease: a comprehensive review of the molecular mechanisms. Int J Mol Sci 2015; 16:6419-6431. [PMID: 25803104 PMCID: PMC4394540 DOI: 10.3390/ijms16036419] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2014] [Revised: 03/03/2015] [Accepted: 03/03/2015] [Indexed: 02/06/2023] Open
Abstract
Wilson's disease (WD), also known as hepatolenticular degeneration, is an autosomal recessive inherited disorder resulting from abnormal copper metabolism. Reduced copper excretion causes an excessive deposition of the copper in many organs such as the liver, central nervous system (CNS), cornea, kidney, joints, and cardiac muscle where the physiological functions of the affected organs are impaired. The underlying molecular mechanisms for WD have been extensively studied. It is now believed that a defect in P-type adenosine triphosphatase (ATP7B), the gene encoding the copper transporting P-type ATPase, is responsible for hepatic copper accumulation. Deposited copper in the liver produces toxic effects via modulating several molecular pathways. WD can be a lethal disease if left untreated. A better understanding of the molecular mechanisms causing the aberrant copper deposition and organ damage is the key to developing effective management approaches.
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Affiliation(s)
- Fei Wu
- Department of imaging, the Affiliated Zhongshan Hospital of Dalian University, 6 Jiefang Street, Zhongshan District, Dalian 116001, Liaoning, China.
| | - Jing Wang
- Department of Internal Medicine, the Second Hospital of Dalian Medical University, 467 Zhongshan Road, Shahekou District, Dalian 116023, Liaoning, China.
| | - Chunwen Pu
- Department of Biobank, the Sixth People's Hospital of Dalian, 269 Luganghuibai Road, Ganjingzi District, Dalian 116031, Liaoning, China.
| | - Liang Qiao
- Storr Liver Centre, Westmead Millennium Institute for Medical Research, Faculty of Medicine, the University of Sydney at Westmead Hospital, Westmead, NSW 2145, Australia.
| | - Chunmeng Jiang
- Department of Internal Medicine, the Second Hospital of Dalian Medical University, 467 Zhongshan Road, Shahekou District, Dalian 116023, Liaoning, China.
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Boaru SG, Merle U, Uerlings R, Zimmermann A, Flechtenmacher C, Willheim C, Eder E, Ferenci P, Stremmel W, Weiskirchen R. Laser ablation inductively coupled plasma mass spectrometry imaging of metals in experimental and clinical Wilson's disease. J Cell Mol Med 2015; 19:806-14. [PMID: 25704483 PMCID: PMC4395195 DOI: 10.1111/jcmm.12497] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Accepted: 10/21/2014] [Indexed: 12/30/2022] Open
Abstract
Wilson's disease is an autosomal recessive disorder in which the liver does not properly release copper into bile, resulting in prominent copper accumulation in various tissues. Affected patients suffer from hepatic disorders and severe neurological defects. Experimental studies in mutant mice in which the copper-transporting ATPase gene (Atp7b) is disrupted revealed a drastic, time-dependent accumulation of hepatic copper that is accompanied by formation of regenerative nodes resembling cirrhosis. Therefore, these mice represent an excellent exploratory model for Wilson's disease. However, the precise time course in hepatic copper accumulation and its impact on other trace metals within the liver is yet poorly understood. We have recently established novel laser ablation inductively coupled plasma mass spectrometry protocols allowing quantitative metal imaging in human and murine liver tissue with high sensitivity, spatial resolution, specificity and quantification ability. By use of these techniques, we here aimed to comparatively analyse hepatic metal content in wild-type and Atp7b deficient mice during ageing. We demonstrate that the age-dependent accumulation of hepatic copper is strictly associated with a simultaneous increase in iron and zinc, while the intrahepatic concentration and distribution of other metals or metalloids is not affected. The same findings were obtained in well-defined human liver samples that were obtained from patients suffering from Wilson's disease. We conclude that in Wilson's disease the imbalances of hepatic copper during ageing are closely correlated with alterations in intrahepatic iron and zinc content.
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Affiliation(s)
- Sorina Georgiana Boaru
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapie and Clinical Chemistry, RWTH Aachen University Hospital Aachen, Aachen, Germany
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Liu Y, Zhou H, Guo H, Bai Y. Genetic and Clinical Analysis in a Cohort of Patients with Wilson's Disease in Southwestern China. Arch Med Res 2015; 46:164-9. [PMID: 25704634 DOI: 10.1016/j.arcmed.2015.02.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Accepted: 02/03/2015] [Indexed: 01/06/2023]
Abstract
BACKGROUND AND AIMS Wilson's disease (WD), characterized by a disorder of copper metabolism, is an inherited autosomal recessive disease caused by mutations in the ATP7B gene. METHODS To explore genotype-phenotype correlations in Chinese WD patients and to evaluate the frequency of the ATP7B mutations, we described 77 clinically and biochemically confirmed WD patients and detected mutations in ten WD families from southwestern China. Clinical features were presented and all the exons of the ATP7B gene were screened. RESULTS The appearance of Kayser-Fleischer (K-F) rings was closely related to onset age, particularly before 10 years old. For those patients with predominantly neurological symptoms, MRI was the most sensitive and preferred examination. Eight mutations of the ATP7B gene were detected including seven reported mutations (c.2302dup, c.2304delC, c.2333 G>T, c.2621 C>T, c.2755 C>G, c.2975 C>T and c.1366 G>C) and four novel mutations (c.3446 G>A, c.3767insCA, c.3406 G>A and c.3700delG). c.2333 G>T was detected in 6/20 alleles (30%), accounting for the largest proportion, which could be regarded as a mutation hotspot in this region. CONCLUSIONS Our study extends the mutation spectrum of ATP7B and analyzes the relationship between mutations in the ATP7B gene and clinical findings of WD.
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Affiliation(s)
- Yu Liu
- Department of Medical Genetics, Third Military Medical University, Chongqing, P.R. China; The Second Battalion, Undergraduate Student Brigade, Third Military Medical University, Chongqing, P.R. China
| | - Hao Zhou
- Department of Medical Genetics, Third Military Medical University, Chongqing, P.R. China; The Second Battalion, Undergraduate Student Brigade, Third Military Medical University, Chongqing, P.R. China
| | - Hong Guo
- Department of Medical Genetics, Third Military Medical University, Chongqing, P.R. China.
| | - Yun Bai
- Department of Medical Genetics, Third Military Medical University, Chongqing, P.R. China
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Wei Z, Huang Y, Liu A, Diao S, Yu Q, Peng Z, Hong M. Mutational characterization of ATP7B gene in 103 Wilson's disease patients from Southern China: identification of three novel mutations. Neuroreport 2014; 25:1075-80. [PMID: 25089800 DOI: 10.1097/wnr.0000000000000216] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Wilson's disease (WD) is an autosomal recessive inheritance disorder of copper metabolism due to mutations in the ATP7B gene. The distribution of ATP7B gene mutations is diverse in different population. This study aimed to examine the genotypes of the ATP7B mutant alleles in WD patients from Southern China. Genomic DNA was extracted from 103 WD patients and 60 healthy patients. Mutations were screened and detected by DNA sequencing. A total of 51 different ATP7B mutations were identified in WD patients, including six homozygous, 51 compound heterozygous, and 39 single heterozygotes. Three mutations were found to be novel, including one missense mutation (c.2549C>T) and two frameshift mutations (c.3851_3876del and c.1057delC). The most frequent mutations are Arg778Leu (18.93%), Ile1148Thr (8.74%), and Pro992Leu (4.37%). Different from the published results of early studies, Ile1148Thr was found to be the second common mutation in our cohort. The highest mutation detection rate was on exon 8 (43.69%), followed by exon 16 (24.27%), and exon 12 (17.48%). The total mutation detection rate on exon 8, 12, and 16 was 85.44%. No ATP7B gene mutation was found in healthy patients. In conclusion, we identified three novel mutations and Ile1148Thr as another hotspot mutation in WD patients from Southern China. Most of the mutations can be detected by screening exon 8, 12, and 16. Our research has further enriched the mutation spectrum of the ATP7B gene in Chinese and may help to develop genetic screening strategies of WD.
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Affiliation(s)
- Zhisheng Wei
- Department of Neurology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, People's Republic of China
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Li Z, Yu X, Shen J, Liang J. Congential scoliosis in Wilson's disease: case report and review of the literature. BMC Surg 2014; 14:71. [PMID: 25252715 PMCID: PMC4177382 DOI: 10.1186/1471-2482-14-71] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Accepted: 09/18/2014] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism, which leads to the accumulation of this metal in liver, brain, cornea and kidney. Little is reported about spinal deformity associated with this syndrome. This study is to present a case of thoracic kyphosis occurring in the setting of Wilson'disease and explore the possible association between the two diseases. CASE PRESENTATION Case report and literature review. A previously unreported thoracic kyphosis in Wislon's disease is decribed. The patient was a 7-year-old Chinese female that underwent a posterior correction, using the Moss-SI spinal system performed at Thoracic 9-Lumbar 1 (T9-L1) levels. At 16-month follow-up, the patient was clinically pain free and well balanced. Plain radiographs showed solid spine fusion with no loss of deformity correction. After evaluating 211 WD patients referred to Peking Union Medical College Hospital from February 1991 to February 2012, the prevalence of congential scoliosis among patients with WD was 5.21% (11/211), much higher than that among general population (1/1000). CONCLUSIONS To the best of our knowledge, this is the first report of WD with thoracic kyphosis. During sugery, surgeons and anesthesiologists must pay particular attention to the abnormal liver and brain function associated with WD. The prevalence of scoliosis is much higher among patients with WD, indicating a potential association between congential scoliosis and WD. However, the exact mechanism how copper-chelating agents induce scoliosis is unclear.
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Affiliation(s)
| | | | - Jianxiong Shen
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China.
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21
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Fulminant Wilson's Disease Managed with Plasmapheresis as a Bridge to Liver Transplant. Case Rep Med 2014; 2014:672985. [PMID: 25276143 PMCID: PMC4174964 DOI: 10.1155/2014/672985] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Revised: 08/29/2014] [Accepted: 08/29/2014] [Indexed: 12/26/2022] Open
Abstract
New-onset jaundice can be a manifestation of multiple pathologic processes including hemolysis, parenchymal liver disease, and cholestasis; the differential diagnosis is broad and requires a systematic approach. We report a case of a patient who presented with jaundice after starting minocycline for the treatment of acne vulgaris and rapidly developed fulminant liver failure found to be due to Wilson's disease. She also manifested severe Coomb's negative hemolytic anemia and renal failure secondary to hepatorenal syndrome. As a bridge to liver transplant, she was successfully treated with plasmapheresis to decrease serum copper in addition to hemodialysis for acidosis and hyperkalemia. She was able to receive a liver and made a full recovery. The case highlights the use of plasmapheresis as an adjunctive treatment modality in cases of fulminant liver failure due to Wilson's disease.
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Scorza M, Elce A, Zarrilli F, Liguori R, Amato F, Castaldo G. Genetic diseases that predispose to early liver cirrhosis. Int J Hepatol 2014; 2014:713754. [PMID: 25132997 PMCID: PMC4123515 DOI: 10.1155/2014/713754] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Accepted: 06/30/2014] [Indexed: 12/11/2022] Open
Abstract
Inherited liver diseases are a group of metabolic and genetic defects that typically cause early chronic liver involvement. Most are due to a defect of an enzyme/transport protein that alters a metabolic pathway and exerts a pathogenic role mainly in the liver. The prevalence is variable, but most are rare pathologies. We review the pathophysiology of such diseases and the diagnostic contribution of laboratory tests, focusing on the role of molecular genetics. In fact, thanks to recent advances in genetics, molecular analysis permits early and specific diagnosis for most disorders and helps to reduce the invasive approach of liver biopsy.
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Affiliation(s)
- Manuela Scorza
- CEINGE—Biotecnologie Avanzate Scarl, Via Gaetano Salvatore 486, 80145 Napoli, Italy
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Via Sergio Pansini 5, 80131 Napoli, Italy
| | - Ausilia Elce
- CEINGE—Biotecnologie Avanzate Scarl, Via Gaetano Salvatore 486, 80145 Napoli, Italy
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Via Sergio Pansini 5, 80131 Napoli, Italy
- Università Telematica Pegaso, Piazza Trieste e Trento 48, 80132 Napoli, Italy
| | - Federica Zarrilli
- CEINGE—Biotecnologie Avanzate Scarl, Via Gaetano Salvatore 486, 80145 Napoli, Italy
- Dipartimento di Bioscienze e Territorio, Università del Molise, Contrada Fonte Lappone, Pesche, 86090 Isernia, Italy
| | - Renato Liguori
- CEINGE—Biotecnologie Avanzate Scarl, Via Gaetano Salvatore 486, 80145 Napoli, Italy
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Via Sergio Pansini 5, 80131 Napoli, Italy
| | - Felice Amato
- CEINGE—Biotecnologie Avanzate Scarl, Via Gaetano Salvatore 486, 80145 Napoli, Italy
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Via Sergio Pansini 5, 80131 Napoli, Italy
| | - Giuseppe Castaldo
- CEINGE—Biotecnologie Avanzate Scarl, Via Gaetano Salvatore 486, 80145 Napoli, Italy
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Via Sergio Pansini 5, 80131 Napoli, Italy
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Abstract
Wilson's disease is an autosomal recessive disorder of copper transport caused by mutations in the gene encoding an ATPase, ATP7B. Early detection of Wilson's disease is critical because effective medical treatments such as chelating agents and zinc salts are available, which can prevent lifelong neurological disabilities and/or cirrhosis. It is unfortunate that most patients are brought to our attention after they have developed serious complications such as brain damage or cirrhosis, despite the availability of effective treatments. The diagnosis is usually made through copper measurement in the liver tissue, followed by confirmation with genetic testing of the ATP7B gene. Currently, there are no effective biomarkers or methods suitable for newborn screening for Wilson's disease. Ceruloplasmin has been tested for pediatric and newborn screening with limited outcome. Recently, liquid chromatography-multiple reaction monitoring-mass spectrometry (LC-MRM-MS) has emerged as a robust technology that may enable multiplex quantification of signature proteotypic peptides with low abundance. The application of this technology may help facilitate the research on Wilson's disease for protein expression, biomarker study, diagnosis, and, hopefully, screening.
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Affiliation(s)
- Si Houn Hahn
- Department of Pediatrics, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, Washington
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Huarte-Muniesa MP, Lacalle-Fabo E, Uriz-Otano J, Berisa-Prado S, Moreno-Laguna S, Burusco-Paternáin MJ. [Complexity of the diagnosis of Wilson disease in clinical practice: our experience in 15 patients]. GASTROENTEROLOGIA Y HEPATOLOGIA 2014; 37:389-96. [PMID: 24720933 DOI: 10.1016/j.gastrohep.2014.02.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2013] [Revised: 02/06/2014] [Accepted: 02/18/2014] [Indexed: 10/25/2022]
Abstract
BACKGROUND Wilson disease (WD) is an inherited disorder that causes copper (Cu) accumulation, leading to mainly liver, neurological and/or psychiatric manifestations. In the absence of some of the typical features, diagnosis of WD is difficult and is based on the combination of clinical, biochemical and genetic testing. The aim of this study was to illustrate the complexity of the approach to WD in daily clinical practice. METHODS We retrospectively analyzed the medical records of patients with WD, including the clinical presentation, histological and biochemical findings, and follow up after treatment. We also carried out genetic testing, and the Leipzig diagnostic score was applied. RESULTS We included 15 patients. Four were symptomatic, with liver (n=1), neurological (n=1), psychiatric (n=1) and mixed clinical manifestations (n=1), and 11 were presymptomatic, with elevated transaminases (n=8) and family study (n=3). We observed Kayser-Fleischer ring in 2 patients, both without neurologic symptoms. Ceruloplasmin ≤ 5 mg/dL was present in 73%, and 24-hour urinary Cu> 100 μg in 40%. Liver Cu was >250 μg/g.d.t. in 85% of the patients. The final diagnosis of WD was given by genetic testing (ATP7B gene mutations) in 5 patients with minimal disease features, including one symptomatic patient (psychiatric symptoms). We identified 5 previously reported mutations (p.M645R, p.R827W, p.H1069Q, p.P768L and p.G869R) and 3 unpublished mutations (p.L1313R, p.I1311T and p.A1179D); the most frequent mutation was p.M645R. After treatment, biochemical parameters (transaminases, urinary cooper) and symptoms improved, except in patients with neurological and psychiatric manifestations. CONCLUSIONS Our series illustrates the important role of genetic testing in the diagnosis of WD. The identification of the p.M645R mutation in most of our patients should be kept in mind in the molecular analysis of the ATP7B gene in our region.
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Affiliation(s)
| | | | - Juan Uriz-Otano
- Servicio de Aparato Digestivo, Complejo Hospitalario de Navarra, Pamplona, España
| | | | - Sira Moreno-Laguna
- Servicio de Genética, Complejo Hospitalario de Navarra, Pamplona, España
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25
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Abstract
25% of all people aged 55 years and older have a family history of dementia. For most, the family history is due to genetically complex disease, where many genetic variations of small effect interact to increase risk of dementia. The lifetime risk of dementia for these families is about 20%, compared with 10% in the general population. A small proportion of families have an autosomal dominant family history of early-onset dementia, which is often due to mendelian disease, caused by a mutation in one of the dementia genes. Each family member has a 50% chance of inheriting the mutation, which confers a lifetime dementia risk of over 95%. In this Review, we focus on the evidence for, and the approach to, genetic testing in Alzheimer's disease (APP, PSEN1, and PSEN2 genes), frontotemporal dementia (MAPT, GRN, C9ORF72, and other genes), and other familial dementias. We conclude by discussing the practical aspects of genetic counselling.
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Affiliation(s)
- Clement T Loy
- School of Public Health, University of Sydney, Sydney, NSW, Australia; Neuroscience Research Australia, Randwick, NSW, Australia; Huntington Disease Service, Westmead Hospital, Westmead, NSW, Australia
| | - Peter R Schofield
- Neuroscience Research Australia, Randwick, NSW, Australia; University of New South Wales, Kensington, NSW, Australia
| | - Anne M Turner
- Department of Medical Genetics, Sydney Children's Hospital, Randwick, NSW, Australia
| | - John B J Kwok
- Neuroscience Research Australia, Randwick, NSW, Australia; University of New South Wales, Kensington, NSW, Australia.
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Forbes N, Goodwin S, Woodward K, Morgan DG, Brady L, Coulthart MB, Tarnopolsky MA. Evidence for synergistic effects of PRNP and ATP7B mutations in severe neuropsychiatric deterioration. BMC MEDICAL GENETICS 2014; 15:22. [PMID: 24555712 PMCID: PMC3996179 DOI: 10.1186/1471-2350-15-22] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Accepted: 02/12/2014] [Indexed: 11/13/2022]
Abstract
Background Wilson’s disease (WD), a rare cause of neuropsychiatric deterioration, is associated with mutations in the ATP7B gene. Prion diseases are also rare causes of neuropsychiatric deterioration that can occur sporadically without an identifiable cause, or can be attributed to mutations in the PRNP gene. Case presentation Here we describe a biological “experiment of nature” in which a patient presented with severe neuropsychiatric decline and strong biochemical evidence of WD. Genetic analysis revealed that he was a compound heterozygote for two ATP7B sequence variants (c.2165dupT, p.Arg723Glufs*32; and c.4039G > A, p.Gly1347Ser), the first having been reported once previously, and the second being novel. In addition, the patient was heterozygous for a PRNP variant, c.160G > A, p.Gly54Ser, that has been reported in a neuropsychiatric patient only once previously in association with a similarly severe clinical course of neuropsychiatric disease and early age of onset, but no accompanying information on ATP7B genotype. Of particular interest was the observation that the patient’s older sister, who carried the same ATP7B genotype and laboratory evidence for biochemical WD but was clinically asymptomatic, lacked the PRNP variant allele. Conclusions We propose that synergism may occur between at least some allelic variants of ATP7B and PRNP, possibly exerted through effects on cellular copper metabolism.
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27
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Pfeiffer RF. Other Neurologic Disorders Associated with Gastrointestinal Disease. AMINOFF'S NEUROLOGY AND GENERAL MEDICINE 2014:237-253. [DOI: 10.1016/b978-0-12-407710-2.00013-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Abstract
Hereditary hemochromatosis and Wilson disease are autosomal recessive storage disorders of iron and copper overload, respectively. These metals are involved in multiple redox reactions, and their abnormal accumulation can cause significant injury in the liver and other organs. Over the last few decades clinicians have developed a much better understanding of these metals and their mechanism of action. Moreover, sophisticated molecular genetic testing techniques that make diagnostic testing less invasive are now available. This article updates and discusses the pathogenesis, diagnosis, and management of these metal storage disorders.
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Affiliation(s)
- Pushpjeet Kanwar
- Liver Center of Excellence, Department of Gastroenterology, Digestive Disease Institute, Virginia Mason Medical Center, 1100 9th Avenue, Mailstop C3-GAS, Seattle, WA 98101, USA
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An update on laboratory diagnosis of liver inherited diseases. BIOMED RESEARCH INTERNATIONAL 2013; 2013:697940. [PMID: 24222913 PMCID: PMC3816025 DOI: 10.1155/2013/697940] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/02/2013] [Accepted: 08/26/2013] [Indexed: 12/14/2022]
Abstract
Liver inherited diseases are a group of genetically determined clinical entities that appear with an early chronic liver involvement. They include Wilson's disease (hepatolenticular degeneration), hereditary hemochromatosis, and alpha-1-antitrypsin deficiency. In addition, cystic fibrosis, although it is not specifically a liver disease, may cause a severe liver involvement in a significant percentage of cases. For all these pathologies, the disease gene is known, and molecular analysis may contribute to the unequivocal diagnosis. This approach could avoid the patient invasive procedures and limit complications associated with a delay in diagnosis. We review liver inherited diseases on the basis of the genetic defect, focusing on the contribution of molecular analysis in the multistep diagnostic workup.
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Bruguera M, Abraldes JG. [Common problems in the diagnosis and treatment of Wilson's disease]. GASTROENTEROLOGIA Y HEPATOLOGIA 2013; 36:316-25. [PMID: 23570841 DOI: 10.1016/j.gastrohep.2012.10.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Accepted: 10/16/2012] [Indexed: 12/16/2022]
Abstract
The present article aims to provide answers to questions frequently asked by physicians attending patients with Wilson's disease (WD) or those with a suspected diagnosis of WD. The article is divided into 2 parts: a first part with answers to questions relating to the diagnosis of this entity and a second with answers to questions concerning treatment. A brief appendix is included with responses to questions not falling into either of these 2 categories.
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Affiliation(s)
- Miguel Bruguera
- Servicio de Hepatología, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Barcelona, España.
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Bennett JT, Schwarz KB, Swanson PD, Hahn SH. An exceptional family with three consecutive generations affected by Wilson disease. JIMD Rep 2013; 10:1-4. [PMID: 23430806 DOI: 10.1007/8904_2012_206] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2012] [Revised: 11/27/2012] [Accepted: 12/07/2012] [Indexed: 10/27/2022] Open
Abstract
Wilson disease (WD) is a disorder of copper transport that can cause hepatic and neuropsychiatric symptoms. Because of its broad spectrum of clinical manifestations that can present in almost any decade of life, a high degree of clinical suspicion is needed for diagnosis. We present an exceptional family with three consecutive generations affected by WD. Autosomal recessive disorders are not typically present in consecutive generations, but this can occur, particularly when carrier frequencies are as high as in WD. This point is of critical importance in counseling families affected by WD. This case also highlights the importance of genetic testing in confirming the diagnosis of WD, particularly when there is a positive family history. To our knowledge, this is the first report of WD in three consecutive generations.
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Affiliation(s)
- James T Bennett
- Department of Pediatrics, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, USA
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Characteristics of neurological Wilson's disease without Kayser–Fleischer ring. J Neurol Sci 2012; 323:183-6. [DOI: 10.1016/j.jns.2012.09.013] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2012] [Revised: 09/03/2012] [Accepted: 09/10/2012] [Indexed: 12/28/2022]
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Liu JJ, Kim Y, Yan F, Ding Q, Ip V, Jong NN, Mercer JFB, McKeage MJ. Contributions of rat Ctr1 to the uptake and toxicity of copper and platinum anticancer drugs in dorsal root ganglion neurons. Biochem Pharmacol 2012; 85:207-15. [PMID: 23123662 DOI: 10.1016/j.bcp.2012.10.023] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2012] [Revised: 10/25/2012] [Accepted: 10/26/2012] [Indexed: 11/17/2022]
Abstract
Dorsal root ganglion (DRG) neurons are affected by platinum-induced neurotoxicity and neurodegenerative processes associated with disturbed copper homeostasis and transport. This study aimed to understand the role of copper transporter 1 (Ctr1) in the uptake and toxicity of copper and platinum drugs in cultured rat DRG neurons, and the functional activities of rat Ctr1 (rCtr1) as a membrane transporter of copper and platinum drugs. Heterologous expression of rCtr1 in HEK293 cells (HEK/rCtr1 cells) increased the uptake and cytotoxicity of copper, oxaliplatin, cisplatin and carboplatin, in comparison to isogenic vector-transfected control cells. Cultured rat DRG neurons endogenously expressed rCtr1 protein on their neuronal cell body plasma membranes and cytoplasm, and displayed substantial capacity for taking up copper, but were resistant to copper toxicity. The uptake of copper by both cultured rat DRG neurons and HEK/rCtr1 cells was saturable and inhibited by cold temperature, silver and zinc, consistent with it being mediated by rCtr1. Cultured rat DRG neurons accumulated platinum during their exposure to oxaliplatin and were sensitive to oxaliplatin cytotoxicity. The accumulation of platinum by both cultured rat DRG neurons and HEK/rCtr1 cells, during oxaliplatin exposure, was saturable and temperature dependent, but was inhibited by copper only in HEK/rCtr1 cells. In conclusion, rCtr1 can transport copper and platinum drugs, and sensitizes cells to their cytotoxicities. DRG neurons display substantial capacity for accumulating copper via a transport process mediated by rCtr1, but appear able to resist copper toxicity and use alternative mechanisms to take up oxaliplatin.
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Affiliation(s)
- Johnson J Liu
- Department of Pharmacology and Clinical Pharmacology and Auckland Cancer Society Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
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