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Alonso-Castellano P, Tugores A, Mariño Z, Olveira A, Berenguer M, Huarte MP, Fernández-Ramos JR, Lázaro-Ríos M, González-Diéguez ML, Moreno-Planas JM, Hernández-Guerra M, Fernández-Álvarez P, Delgado-Blanco M, Pinazo-Bandera JM, Romero M, Ampuero J, Masnou-Ridaura H, Cachero A, Vargas V, Gómez-Camarero J, Morillas-Ariño MJ, Molina-Pérez E, Miralpeix A, García-Villarreal L. Low penetrance of frequent ATP7B mutations explains the low prevalence of Wilson disease. Lessons from real-life registries. Dig Liver Dis 2025; 57:443-449. [PMID: 39322449 DOI: 10.1016/j.dld.2024.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 08/03/2024] [Accepted: 09/03/2024] [Indexed: 09/27/2024]
Abstract
BACKGROUND & AIMS Wilson disease (WD) is a copper metabolism disorder caused by mutations in ATP7B gene, with significant clinical variability. Several studies have analyzed the prevalence and penetrance of mutations. We evaluated both characteristics for our more frequent mutations. METHODS Evaluation of 260 patients from the National Registry: clinical, analytical and genetic data. Estimation of homozygotes and total cases according to Hardy-Weinberg equilibrium and comparison with Registry records. RESULTS The estimated number of homozygotes were higher than registered: p.Met645Arg (1949/6), p.His1069Gln (20/8), p.Leu708Pro (63/24) and p.Gly869Arg (147/0). p.Met645Arg homozygotes presented less cirrhosis at diagnosis, extrahepatic disease and Kayser-Fleischer ring (KFR) and more presymptomatic cases and diagnosis after 40 years of age than p.Leu708Pro and p.His1069Gln homozygotes. p.Met645Arg homozygotes presented more late diagnosis than p.Met645Arg compound heterozygotes. Compound heterozygotes carrying p.Met645Arg or p.Gly869Arg showed less cirrhosis at diagnosis, KFR and neurological symptoms and more hepatic and presymptomatic cases, despite clearly low ceruloplasmin levels. The estimated prevalence was 1:3.785, predicting more than 10.500 patients. CONCLUSIONS The widespread mutations p.Met645Arg and p.Gly869Arg show low penetrance. WD might be underdiagnosed in Spain due to less severe phenotype of the most frequent mutations, a crucial fact to avoid misdiagnosis and to offer early therapy.
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Affiliation(s)
- Pablo Alonso-Castellano
- Universidad Las Palmas Gran Canaria. Servicio Digestivo, Complejo Hospitalario Universitario Insular Materno Infantil (CHUIMI), Las Palmas de Gran Canaria, Spain.
| | - Antonio Tugores
- Unidad Apoyo Investigación, CHUIMI, Las Palmas de Gran Canaria, Spain.
| | - Zoe Mariño
- LiverUnit, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.
| | - Antonio Olveira
- Servicio Digestivo, Hospital Universitario La Paz, Madrid, Spain.
| | - Marina Berenguer
- Hospital Universitari i Politècnic La Fe, IISLaFe, Universidad de Valencia y Ciberehd, Valencia, Spain.
| | | | | | | | | | - José M Moreno-Planas
- Servicio de Aparato Digestivo, Complejo Hospitalario Universitario de Albacete, Facultad de Medicina Universidad de Castilla La Mancha, Spain.
| | | | | | | | - José M Pinazo-Bandera
- Unidad de Hepatología, Unidad de Gestión Clínica de Aparato Digestivo, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga-Plataforma Bionand, Málaga, Spain.
| | - Marta Romero
- Hospital Universitario de Toledo, Toledo, Spain.
| | - Javier Ampuero
- Hospital Universitario Virgen del Rocío, Sevilla, Spain.
| | | | - Alba Cachero
- Hospital Universitario de Bellvitge, Hospitalet de Llobregat, Spain.
| | - Víctor Vargas
- LiverUnit, Hospital Vall d'Hebron, Universitat Autónoma Barcelona, CIBERehd, Barcelona, Spain.
| | | | | | | | - Anna Miralpeix
- LiverUnit, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.
| | - Luis García-Villarreal
- Grupo de Investigación Patología Médica, Instituto de Investigaciones Biomédicas y Sanitarias. Universidad de Las Palmas de Gran Canaria. Servicio Digestivo, Complejo Hospitalario Universitario Insular Materno Infantil (CHUIMI), Las Palmas de Gran Canaria, Spain.
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2
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Yanus GA, Suspitsin EN, Imyanitov EN. The Spectrum of Disease-Associated Alleles in Countries with a Predominantly Slavic Population. Int J Mol Sci 2024; 25:9335. [PMID: 39273284 PMCID: PMC11394759 DOI: 10.3390/ijms25179335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 08/21/2024] [Accepted: 08/25/2024] [Indexed: 09/15/2024] Open
Abstract
There are more than 260 million people of Slavic descent worldwide, who reside mainly in Eastern Europe but also represent a noticeable share of the population in the USA and Canada. Slavic populations, particularly Eastern Slavs and some Western Slavs, demonstrate a surprisingly high degree of genetic homogeneity, and, consequently, remarkable contribution of recurrent alleles associated with hereditary diseases. Along with pan-European pathogenic variants with clearly elevated occurrence in Slavic people (e.g., ATP7B c.3207C>A and PAH c.1222C>T), there are at least 52 pan-Slavic germ-line mutations (e.g., NBN c.657_661del and BRCA1 c.5266dupC) as well as several disease-predisposing alleles characteristic of the particular Slavic communities (e.g., Polish SDHD c.33C>A and Russian ARSB c.1562G>A variants). From a clinical standpoint, Slavs have some features of a huge founder population, thus providing a unique opportunity for efficient genetic studies.
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Affiliation(s)
- Grigoriy A Yanus
- Laboratory of Molecular Diagnostics, St. Petersburg State Pediatric Medical University, 194100 St. Petersburg, Russia
| | - Evgeny N Suspitsin
- Department of Medical Genetics, St. Petersburg State Pediatric Medical University, 194100 St. Petersburg, Russia
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St. Petersburg, Russia
| | - Evgeny N Imyanitov
- Department of Medical Genetics, St. Petersburg State Pediatric Medical University, 194100 St. Petersburg, Russia
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St. Petersburg, Russia
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Catalano F, O’Brien TJ, Mekhova AA, Sepe LV, Elia M, De Cegli R, Gallotta I, Santonicola P, Zampi G, Ilyechova EY, Romanov AA, Samuseva PD, Salzano J, Petruzzelli R, Polishchuk EV, Indrieri A, Kim BE, Brown AEX, Puchkova LV, Di Schiavi E, Polishchuk RS. A new Caenorhabditis elegans model to study copper toxicity in Wilson disease. Traffic 2024; 25:e12920. [PMID: 37886910 PMCID: PMC10841361 DOI: 10.1111/tra.12920] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 09/28/2023] [Accepted: 10/03/2023] [Indexed: 10/28/2023]
Abstract
Wilson disease (WD) is caused by mutations in the ATP7B gene that encodes a copper (Cu) transporting ATPase whose trafficking from the Golgi to endo-lysosomal compartments drives sequestration of excess Cu and its further excretion from hepatocytes into the bile. Loss of ATP7B function leads to toxic Cu overload in the liver and subsequently in the brain, causing fatal hepatic and neurological abnormalities. The limitations of existing WD therapies call for the development of new therapeutic approaches, which require an amenable animal model system for screening and validation of drugs and molecular targets. To achieve this objective, we generated a mutant Caenorhabditis elegans strain with a substitution of a conserved histidine (H828Q) in the ATP7B ortholog cua-1 corresponding to the most common ATP7B variant (H1069Q) that causes WD. cua-1 mutant animals exhibited very poor resistance to Cu compared to the wild-type strain. This manifested in a strong delay in larval development, a shorter lifespan, impaired motility, oxidative stress pathway activation, and mitochondrial damage. In addition, morphological analysis revealed several neuronal abnormalities in cua-1 mutant animals exposed to Cu. Further investigation suggested that mutant CUA-1 is retained and degraded in the endoplasmic reticulum, similarly to human ATP7B-H1069Q. As a consequence, the mutant protein does not allow animals to counteract Cu toxicity. Notably, pharmacological correctors of ATP7B-H1069Q reduced Cu toxicity in cua-1 mutants indicating that similar pathogenic molecular pathways might be activated by the H/Q substitution and, therefore, targeted for rescue of ATP7B/CUA-1 function. Taken together, our findings suggest that the newly generated cua-1 mutant strain represents an excellent model for Cu toxicity studies in WD.
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Affiliation(s)
- Federico Catalano
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
- Institute of Biosciences and BioResources (IBBR), National Research Council (CNR), Napoli, Italy
| | - Thomas J O’Brien
- MRC London Institute of Medical Sciences, London, United Kingdom
- Institute of Clinical Sciences, Imperial College London, London, United Kingdom
| | - Aleksandra A Mekhova
- Research center of advanced functional materials and laser communication systems, ADTS Institute, ITMO University, St. Petersburg, Russia
| | | | | | - Rossella De Cegli
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | - Ivan Gallotta
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
- Institute of Genetics and Biophysics Adriano Buzzati-Traverso (IGB-ABT), National Research Council (CNR), Napoli, Italy
| | - Pamela Santonicola
- Institute of Biosciences and BioResources (IBBR), National Research Council (CNR), Napoli, Italy
| | - Giuseppina Zampi
- Institute of Biosciences and BioResources (IBBR), National Research Council (CNR), Napoli, Italy
| | - Ekaterina Y Ilyechova
- Research center of advanced functional materials and laser communication systems, ADTS Institute, ITMO University, St. Petersburg, Russia
- Department of Molecular Genetics, Research Institute of Experimental Medicine, St. Petersburg, Russia
| | - Aleksei A Romanov
- Department of applied mathematics, Institute of applied mathematics and mechanics, Peter the Great Polytechnic University, St. Petersburg, Russia
| | - Polina D Samuseva
- Research center of advanced functional materials and laser communication systems, ADTS Institute, ITMO University, St. Petersburg, Russia
| | - Josephine Salzano
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | - Raffaella Petruzzelli
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
- Scuola Superiore Meridionale (SSM, School of Advanced Studies), Genomics and Experimental Medicine program, University of Naples Federico II, Naples, Italy
| | - Elena V. Polishchuk
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
- Institute of Biosciences and BioResources (IBBR), National Research Council (CNR), Napoli, Italy
| | - Alessia Indrieri
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
- Institute for Genetic and Biomedical Research (IRGB), National Research Council (CNR), Milan, Italy
| | - Byung-Eun Kim
- Department of Animal and Avian Sciences, University of Maryland, College Park, Maryland, USA
| | - André EX Brown
- MRC London Institute of Medical Sciences, London, United Kingdom
- Institute of Clinical Sciences, Imperial College London, London, United Kingdom
| | - Ludmila V Puchkova
- Research center of advanced functional materials and laser communication systems, ADTS Institute, ITMO University, St. Petersburg, Russia
| | - Elia Di Schiavi
- Institute of Biosciences and BioResources (IBBR), National Research Council (CNR), Napoli, Italy
- Institute of Genetics and Biophysics Adriano Buzzati-Traverso (IGB-ABT), National Research Council (CNR), Napoli, Italy
| | - Roman S. Polishchuk
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
- Institute for Genetic and Biomedical Research (IRGB), National Research Council (CNR), Milan, Italy
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Stanković I, Jovanović Č, Vitković J, Svetel M, Pekmezović T, Tomić A, Kresojević N, Marković V, Ječmenica Lukić M, Petrović I, Dragašević-Mišković N, Kostić V. Long-term outcome of patients with neurological form of Wilson's disease compliant to the de-coppering treatment. J Neurol 2023:10.1007/s00415-023-11681-7. [PMID: 37016067 DOI: 10.1007/s00415-023-11681-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 02/22/2023] [Accepted: 03/21/2023] [Indexed: 04/06/2023]
Abstract
BACKGROUND A substantial proportion of Wilson's disease (WD) patients exhibit residual neurological symptoms. Data on the prognostic value of initial clinical features and treatment choices in WD patients compliant to the therapy is relatively sparse. AIM The aim of the present study was to identify predictors of the long-term outcome of patients with WD with good treatment adherence. METHODS Forty patients with neurological form of WD were evaluated before the de-coppering treatment initiation (based on the medical records) and after mean 15.25 ± 11.24 years of the stable treatment. Severity of neurological symptoms were assessed with a tier two of Global Assessment Scale (GAS) for Wilson's Disease. RESULTS The most frequent symptoms prior to treatment initiation were dysarthria (90%), tremor (90%), clumsiness (67.5%), depression (67.5%), and gait disturbance (62.5%). Significant decrease in the frequency of dysarthria, clumsiness, tremor, gait disturbance, postural instability and an improvement in school/work performance were observed after the long-term treatment, while frequency of dysphagia, drooling, bradykinesia and rigidity, dystonic and choreatic features did not change. Overall symptom severity decreased over time. Presence of dystonia before treatment initiation was the only identified predictor of worse residual GAS score. Greater severity of residual dystonia was associated with female gender and longer disease duration. CONCLUSION Although patients with neurological form of WD compliant to de-coppering treatment had favorable disease outcome, a significant burden of residual neurological symptoms was observed after the long-term follow-up. Dystonia at disease onset was the only identified predictor of the worse long-term outcome.
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Affiliation(s)
- Iva Stanković
- Neurology Clinic, University Clinical Center of Serbia, Dr Subotića 6, 11000, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Čarna Jovanović
- Neurology Clinic, University Clinical Center of Serbia, Dr Subotića 6, 11000, Belgrade, Serbia
| | - Jelena Vitković
- Neurology Clinic, University Clinical Center of Serbia, Dr Subotića 6, 11000, Belgrade, Serbia
| | - Marina Svetel
- Neurology Clinic, University Clinical Center of Serbia, Dr Subotića 6, 11000, Belgrade, Serbia.
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
| | - Tatjana Pekmezović
- Institute of Epidemiology, School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Aleksandra Tomić
- Neurology Clinic, University Clinical Center of Serbia, Dr Subotića 6, 11000, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Nikola Kresojević
- Neurology Clinic, University Clinical Center of Serbia, Dr Subotića 6, 11000, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Vladana Marković
- Neurology Clinic, University Clinical Center of Serbia, Dr Subotića 6, 11000, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Milica Ječmenica Lukić
- Neurology Clinic, University Clinical Center of Serbia, Dr Subotića 6, 11000, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Igor Petrović
- Neurology Clinic, University Clinical Center of Serbia, Dr Subotića 6, 11000, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Nataša Dragašević-Mišković
- Neurology Clinic, University Clinical Center of Serbia, Dr Subotića 6, 11000, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Vladimir Kostić
- Neurology Clinic, University Clinical Center of Serbia, Dr Subotića 6, 11000, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
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Gromadzka G, Bendykowska M, Przybyłkowski A. Wilson’s Disease—Genetic Puzzles with Diagnostic Implications. Diagnostics (Basel) 2023; 13:diagnostics13071287. [PMID: 37046505 PMCID: PMC10093728 DOI: 10.3390/diagnostics13071287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/12/2023] [Accepted: 03/18/2023] [Indexed: 03/30/2023] Open
Abstract
(1) Introduction: Wilson’s disease (WND) is an autosomal recessive disorder of copper metabolism. The WND gene is ATP7B, located on chromosome 13. WND is characterized by high clinical variability, which causes diagnostic difficulties. (2) Methods: The PubMed, Science Direct, and Wiley Online Library medical databases were reviewed using the following phrases: “Wilson’s disease”, “ATP7B genotype”, “genotype-phenotype”, “epigenetics”, “genetic modifiers”, and their combinations. Publications presenting the results of experimental and clinical studies, as well as review papers, were selected, which concerned: (i) the diversity of genetic strategies and tests used in WND diagnosis; (ii) the difficulties of genetic diagnosis, including uncertainty as to the pathogenicity of variants; (iii) genetic counseling; (iv) phenotypic effects of ATP7B variants in patients with WND and in heterozygous carriers (HzcWND); (v) genetic and epigenetics factors modifying the clinical picture of the disease. (3) Results and conclusions: The genetic diagnosis of WND is carried out using a variety of strategies and tests. Due to the large number of known variants in the ATP7B gene (>900), the usefulness of genetic tests in routine diagnostics is still relatively small and even analyses performed using the most advanced technologies, including next-generation sequencing, require additional tests, including biochemical evidence of abnormal copper metabolism, to confirm the diagnosis of WND. Pseudodominant inheritance, the presence of three various pathogenic variants in the same patient, genotypes indicating the possibility of segmental uniparental disomy, have been reported. Genotype–phenotype relationships in WND are complex. The ATP7B genotype, to some extent, determines the clinical picture of the disease, but other genetic and epigenetic modifiers are also relevant.
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Antczak‐Kowalska M, Członkowska A, Eyileten C, Palejko A, Cudna A, Wolska M, Piechal A, Litwin T. Autoantibodies in Wilson disease: Impact on clinical course. JIMD Rep 2022; 63:508-517. [PMID: 36101827 PMCID: PMC9458613 DOI: 10.1002/jmd2.12317] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 07/02/2022] [Accepted: 07/11/2022] [Indexed: 11/21/2022] Open
Abstract
Symptoms of Wilson disease (WD) vary and additional factors such as autoimmunity may play an important role in WD pathogenesis. The presence of antinuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies, neuronal surface antibodies, and onconeural antibodies in WD was investigated using standardized indirect immunofluorescence assays and Western Blot analysis. The presence of all studied autoantibodies was higher in WD patients in comparison to healthy subjects, but there was no statistically significant difference in autoantibodies frequency according to disease manifestation. D-penicillamine treatment was associated with a higher presence of ANA than zinc sulfate but without an increase in autoimmune diseases rate.
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Affiliation(s)
| | - Anna Członkowska
- 2nd Department of NeurologyInstitute of Psychiatry and NeurologyWarsawPoland
| | - Ceren Eyileten
- Center for Preclinical Research and Technology CEPT, Department of Experimental and Clinical PharmacologyMedical University of WarsawWarsawPoland
| | - Anna Palejko
- 2nd Department of NeurologyInstitute of Psychiatry and NeurologyWarsawPoland
| | - Agnieszka Cudna
- 2nd Department of NeurologyInstitute of Psychiatry and NeurologyWarsawPoland
- Center for Preclinical Research and Technology CEPT, Department of Experimental and Clinical PharmacologyMedical University of WarsawWarsawPoland
| | - Marta Wolska
- Center for Preclinical Research and Technology CEPT, Department of Experimental and Clinical PharmacologyMedical University of WarsawWarsawPoland
- Doctoral School, Medical University of WarsawWarsawPoland
| | - Agnieszka Piechal
- 2nd Department of NeurologyInstitute of Psychiatry and NeurologyWarsawPoland
- Center for Preclinical Research and Technology CEPT, Department of Experimental and Clinical PharmacologyMedical University of WarsawWarsawPoland
| | - Tomasz Litwin
- 2nd Department of NeurologyInstitute of Psychiatry and NeurologyWarsawPoland
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Despotov K, Klivényi P, Nagy I, Pálvölgyi A, Vécsei L, Rajda C. Rare co-occurrence of multiple sclerosis and Wilson's disease - case report. BMC Neurol 2022; 22:178. [PMID: 35578211 PMCID: PMC9109366 DOI: 10.1186/s12883-022-02691-5] [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: 11/15/2021] [Accepted: 04/28/2022] [Indexed: 11/25/2022] Open
Abstract
Background Wilson’s disease is a hereditary disorder of copper metabolism resulting mainly in hepatic, neurological, and psychiatric symptoms. Multiple sclerosis (MS) is an immune-mediated demyelinating disease affecting the central nervous system (CNS). The co-occurrence of these two, although not unheard of in literature, is still considered to be very rare and can give rise to diagnostic difficulties. Also, comorbidity in MS highly influences quality of life and disease progression, which makes the timely diagnosis and treatment of these conditions essential. Case presentation The aim of this study is to present a patient exhibiting symptoms of both MS and Wilson’s disease, as well as to conduct a detailed review of previously reported cases. The patient’s neurological symptoms (sensory disorder) as well as MRI and CSF findings were characteristic for MS. The diagnosis of MS preceded that of Wilson’s disease and was relatively mild in course. Currently, the patient receives cladribine as an immunomodulatory treatment after escalation from glatiramer acetate therapy. Apart from one episode of acute hepatic decompensation, during which transfusion, albumin supplementation and diuretic treatment was necessary, Wilson’s disease manifested as chronic impairment of liver function. The diagnosis of Wilson’s disease was established by the analysis of serum coeruloplasmin levels, histological examination and genetic findings. Continuous oral penicillamine therapy led to the slow normalization of hepatic function and significant amelioration of the patient’s symptoms. Correlating with cases previously reported, the course of MS was relatively mild, and like in three out of four other known cases, the symptoms of Wilson’s disease were mostly restricted to hepatic dysfunction. Conclusion The case presented in our report is similar to those reported before. The co-occurrence of the two diseases seems to be more a coincidence than a sharing of common factors in their pathogenesis; however, they are considered to influence one another. Regarding rare co-occurrences such as this one, every new case is of high importance, as it enables a better evaluation and understanding of the clinical presentations that are more characteristic of these cases, thus aiding the estimation of disease course as well as possible therapeutic choices.
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Affiliation(s)
- Katalin Despotov
- Department of Neurology, University of Szeged, Faculty of Medicine, Szeged, Hungary
| | - Péter Klivényi
- Department of Neurology, University of Szeged, Faculty of Medicine, Szeged, Hungary
| | - István Nagy
- Faculty of Medicine, Department of Internal Medicine I, University of Szeged, Szeged, Hungary
| | - Attila Pálvölgyi
- Faculty of Medicine, Department of Internal Medicine I, University of Szeged, Szeged, Hungary
| | - László Vécsei
- Department of Neurology, University of Szeged, Faculty of Medicine, Szeged, Hungary.,MTA-SZTE Neuroscience Research Group, Szeged, Hungary.,Faculty of Medicine, Interdisciplinary Excellence Center, University of Szeged, Szeged, Hungary
| | - Cecília Rajda
- Department of Neurology, University of Szeged, Faculty of Medicine, Szeged, Hungary.
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Abramov DD, Kadochnikova VV, Yakimova EG, Belousova MV, Maerle AV, Sergeev IV, Kozlov IB, Donnikov AE, Kofiadi IA, Trofimov DY. Frequency of Mutations Associated with the Development of Hereditary Hemochromatosis Type I, Wilson–Konovalov Disease, and Familial Mediterranean Fever and Peculiarities of Their Distribution in the Russian Population. RUSS J GENET+ 2021. [DOI: 10.1134/s1022795421010026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Gromadzka G, Wierzbicka D, Litwin T, Przybyłkowski A. Difference in iron metabolism may partly explain sex-related variability in the manifestation of Wilson's disease. J Trace Elem Med Biol 2020; 62:126637. [PMID: 32937238 DOI: 10.1016/j.jtemb.2020.126637] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 08/05/2020] [Accepted: 08/26/2020] [Indexed: 01/07/2023]
Abstract
BACKGROUND/AIM Wilson's disease (WD) is a hereditary disorder characterized by abnormal metabolism of copper. For unknown reasons, the clinical picture of this disease appears to be sex-dependent. Because the metabolism of copper and iron is interrelated, we aimed to evaluate whether the variability in the clinical picture of WD could be explained by the sex difference in iron metabolism. METHODS A total of 138 WD patients were examined in this study: 39 newly diagnosed, treatment naive patients and 99 individuals already treated with decoppering drugs. The serum concentration of ceruloplasmin (Cp) and copper were measured using an enzymatic colorimetric assay and by atomic absorption spectroscopy, respectively. The parameters of iron metabolism were determined by using standard laboratory methods and enzyme immunoassays. RESULTS In the treatment naive group men had a higher median serum concentration of ferritin (290.5 vs. 81.0 ng/mL, p < 10-4), and hepcidin (Hepc) (55.4 vs. 22.8 ng/mL, p < 10-3) compared to women, and tended to have higher concentration of iron, hemoglobin (HGB) and number of red blood cells (RBC). In the treated group men had higher median ferritin (122.0 vs. 46.0 ng/mL, p < 10-4), Hepc (23.5 vs. 10.8 ng/mL, p < 10-4), iron (102.5 vs. 68.0 μg/dL, p < 10-4), HGB (15.0 vs. 13.2 g/dL, p < 10-4), and RBC (5.0 vs. 4.5 M/L, p < 10-4) than women. CONCLUSION Iron metabolism differs between men and women with WD, which may partly explain the sex difference noted in the disease manifestation.
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Affiliation(s)
- Grażyna Gromadzka
- Cardinal Stefan Wyszyński University, Faculty of Medical Science, Collegium Medicum, Warsaw, Poland
| | - Diana Wierzbicka
- Institute of Psychiatry and Neurology, Second Department of Neurology, Warsaw, Poland
| | - Tomasz Litwin
- Institute of Psychiatry and Neurology, Second Department of Neurology, Warsaw, Poland
| | - Adam Przybyłkowski
- Medical University in Warsaw, Department of Gastroenterology and Internal Medicine, Warsaw, Poland.
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10
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Gromadzka G, Wierzbicka DW, Przybyłkowski A, Litwin T. Effect of homeostatic iron regulator protein gene mutation on Wilson's disease clinical manifestation: original data and literature review. Int J Neurosci 2020; 132:894-900. [PMID: 33175593 DOI: 10.1080/00207454.2020.1849190] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
OBJECTIVE Wilson's disease (WD) is a hereditary disorder of copper metabolism. The metabolic pathways of copper and iron are interrelated. Our goal was to determine the frequency of the two most common mutations in the coding region of the human iron homeostatic protein gene (HFE) in Europe: C282Y (rs1800562) and H63D (rs1799945) in WD patients, as well as to analyze their relation with WD phenotypic traits. MATERIAL AND METHODS HFE mutations were studied by PCR RFLP method in 445 WD patients and 102 controls. All patients met the diagnostic criteria of WD 8th International Conference on Wilson Disease and Menkes Disease. RESULTS HFE C282Y heterozygotes, both women and men, showed WD symptoms earlier than patients with wild-type HFE genotype. HFE 63HD heterozygous men presented symptoms later than HFE 63HH homozygotes, but HFE 63HD women manifested symptoms later than those with HFE 63HH genotype. CONCLUSIONS HFE genotype seems to be one of the factors modifying Wilson's disease phenotype.
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Affiliation(s)
- Grażyna Gromadzka
- Faculty of Medicine (Collegium Medicum), Cardinal Stefan Wyszyński University in Warsaw, Warsaw, Poland
| | | | - Adam Przybyłkowski
- Department of Gastroenterology and Internal Medicine, Medical University in Warsaw, Warsaw, Poland
| | - Tomasz Litwin
- Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
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Yu XE, Gao S, Yang RM, Han YZ. MR Imaging of the Brain in Neurologic Wilson Disease. AJNR Am J Neuroradiol 2020; 40:178-183. [PMID: 30635331 DOI: 10.3174/ajnr.a5936] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 10/30/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND PURPOSE Neurologic Wilson disease is an inherited disease characterized by a copper metabolic disorder that causes damage to many organs, especially the brain. Few studies report the relationships between these neurologic symptoms and MR imaging of the brain. Therefore, we investigated the correlation of brain abnormalities in patients with neurologic Wilson disease with their clinical symptoms, age of onset, and lag time to diagnosis. MATERIALS AND METHODS A cohort of 364 patients was recruited in China between January 2003 and December 2017. Age of onset, lag time until diagnosis, and neurologic symptoms were recorded, and cranial MR imaging was performed. Patients were divided into groups within each of these factors for correlation analysis with the MR imaging brain scans. RESULTS Abnormal signals in the MR imaging brain scans were seen in all 364 cases. Affected regions included the putamen, pons, midbrain, and thalamus, while the medulla and occipital lobe were unaffected. The putamen was the most frequently damaged brain region in this study. With the age of onset younger than 10 years, cranial MR imaging scans showed only impairment in the putamen. Patients with a longer lag time before diagnosis were more likely to have impairment in the pons, midbrain, and cortex. Among neurologic symptoms of Wilson disease, torsion spasm is associated with the midbrain and cortex, and choreoathetosis is related to the caudate nucleus. CONCLUSIONS Abnormalities in the putamen, pons, midbrain, and thalamus are part of the neuroimaging spectrum of Wilson disease. There is a significant correlation between the site of brain injury and diagnosis lag time.
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Affiliation(s)
- X-E Yu
- From the Department of Pharmacology (Y.X.-E., S.G.), Basic Medical College, Anhui Medical University, Hefei, China.,Hospital of the Institute of Neurology (X.-E.Y., R.-M.Y., Y.-Z.H.), Anhui University of Chinese Medicine, Hefei, China
| | - S Gao
- From the Department of Pharmacology (Y.X.-E., S.G.), Basic Medical College, Anhui Medical University, Hefei, China
| | - R-M Yang
- Hospital of the Institute of Neurology (X.-E.Y., R.-M.Y., Y.-Z.H.), Anhui University of Chinese Medicine, Hefei, China
| | - Y-Z Han
- Hospital of the Institute of Neurology (X.-E.Y., R.-M.Y., Y.-Z.H.), Anhui University of Chinese Medicine, Hefei, China
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Cleymaet S, Nagayoshi K, Gettings E, Faden J. A review and update on the diagnosis and treatment of neuropsychiatric Wilson disease. Expert Rev Neurother 2019; 19:1117-1126. [DOI: 10.1080/14737175.2019.1645009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Sean Cleymaet
- Department of Neurology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Katsuko Nagayoshi
- Department of Psychiatry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Edward Gettings
- Department of Neurology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Justin Faden
- Department of Psychiatry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
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Kluska A, Kulecka M, Litwin T, Dziezyc K, Balabas A, Piatkowska M, Paziewska A, Dabrowska M, Mikula M, Kaminska D, Wiernicka A, Socha P, Czlonkowska A, Ostrowski J. Whole-exome sequencing identifies novel pathogenic variants across the ATP7B gene and some modifiers of Wilson's disease phenotype. Liver Int 2019; 39:177-186. [PMID: 30230192 DOI: 10.1111/liv.13967] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 09/05/2018] [Accepted: 09/09/2018] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Wilson's disease (WD) is an autosomal recessive disorder associated with disease-causing alterations across the ATP7B gene, with highly variable symptoms and age of onset. We aimed to assess whether the clinical variability of WD relates to modifier genes. METHODS A total of 248 WD patients were included, of whom 148 were diagnosed after age of 17. Human exome libraries were constructed using AmpliSeq technology and sequenced using the IonProton platform. RESULTS ATP7B p.His1069Gln mutation was present in 215 patients, with 112 homozygotes and 103 heterozygotes. Three other mutations: p.Gln1351Ter, p.Trp779Ter and c.3402delC were identified in >10 patients. Among patients, 117 had a homozygous mutation, 101 were compound heterozygotes, 27 had one heterozygous mutation, and 3 other patients had no identifiable pathogenic variant of ATP7B. Sixteen mutations were novel, found as part of a compound mutation or as a sole, homozygous mutation. For disease phenotype prediction, age at diagnosis was a deciding factor, while frameshift allelic variants of ATP7B and being male increased the odds of developing a neurological phenotype. Rare allelic variants in ESD and INO80 increased and decreased chances for the neurological phenotype, respectively, while rare variants in APOE and MBD6 decreased the chances of WD early manifestation. Compound mutations contributed to earlier age of onset. CONCLUSIONS In a Polish population, genetic screening for WD may help genotype for four variants (p.His1069Gln, p.Gln1351Ter, p.Trp779Ter and c.3402delC), with direct sequencing of all ATP7B amplicons as a second diagnostic step. We also identified some allelic variants that may modify a WD phenotype.
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Affiliation(s)
- Anna Kluska
- Department of Genetics, Cancer Center-Institute, Warsaw, Poland
| | - Maria Kulecka
- Department of Gastroenterology and Hepatology, Centre of Postgraduate Medical Education, Warsaw, Poland
| | - Tomasz Litwin
- Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Karolina Dziezyc
- Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Aneta Balabas
- Department of Genetics, Cancer Center-Institute, Warsaw, Poland
| | | | - Agnieszka Paziewska
- Department of Gastroenterology and Hepatology, Centre of Postgraduate Medical Education, Warsaw, Poland
| | | | - Michal Mikula
- Department of Genetics, Cancer Center-Institute, Warsaw, Poland
| | - Diana Kaminska
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Anna Wiernicka
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Piotr Socha
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Anna Czlonkowska
- Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Jerzy Ostrowski
- Department of Genetics, Cancer Center-Institute, Warsaw, Poland.,Department of Gastroenterology and Hepatology, Centre of Postgraduate Medical Education, Warsaw, Poland
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Abstract
Wilson disease (WD) is an autosomal recessively-inherited disorder of copper metabolism and characterised by a pathological accumulation of copper. The ATP7B gene encodes for a transmembrane copper transporter essential for biliary copper excretion. Depending on time of diagnosis, severity of disease can vary widely. Almost all patients show evidence of progressive liver disease. Neurological impairments or psychiatric symptoms are common in WD patients not diagnosed during adolescence. WD is a treatable disorder, and early treatment can prevent the development of symptoms in patients diagnosed while still asymptomatic. This is why the early diagnosis of WD is crucial. The diagnosis is based on clinical symptoms, abnormal measures of copper metabolism and DNA analysis. Available treatment includes chelators and zinc salts which increase copper excretion and reduce copper uptake. In severe cases, liver transplantation is indicated and accomplishes a phenotypic correction of the hepatic gene defect. Recently, clinical development of the new copper modulating agent tetrathiomolybdate has started and direct genetic therapies are being tested in animal models. The following review focuses especially on biochemical markers and how they can be utilised in diagnosis and drug monitoring.
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Nagral A, Sarma MS, Matthai J, Kukkle PL, Devarbhavi H, Sinha S, Alam S, Bavdekar A, Dhiman RK, Eapen CE, Goyal V, Mohan N, Kandadai RM, Sathiyasekaran M, Poddar U, Sibal A, Sankaranarayanan S, Srivastava A, Thapa BR, Wadia PM, Yachha SK, Dhawan A. Wilson's Disease: Clinical Practice Guidelines of the Indian National Association for Study of the Liver, the Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition, and the Movement Disorders Society of India. J Clin Exp Hepatol 2019; 9:74-98. [PMID: 30765941 PMCID: PMC6363961 DOI: 10.1016/j.jceh.2018.08.009] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Accepted: 08/25/2018] [Indexed: 12/12/2022] Open
Abstract
Clinical practice guidelines for Wilson's disease (WD) have been published by the American Association for the Study of Liver Diseases and European Association for the Study of the Liver in 2008 and 2012, respectively. Their focus was on the hepatic aspects of the disease. Recently, a position paper on pediatric WD was published by the European Society of Pediatric Gastroenterology Hepatology and Nutrition. A need was felt to harmonize guidelines for the hepatic, pediatric, and neurological aspects of the disease and contextualize them to the resource-constrained settings. Therefore, experts from national societies from India representing 3 disciplines, hepatology (Indian National Association for Study of the Liver), pediatric hepatology (Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition), and neurology (Movement Disorders Society of India) got together to evolve fresh guidelines. A literature search on retrospective and prospective studies of WD using MEDLINE (PubMed) was performed. Members voted on each recommendation, using the nominal voting technique. The Grades of Recommendation, Assessment, Development and Evaluation system was used to determine the quality of evidence. Questions related to diagnostic tests, scoring system, and its modification to a version suitable for resource-constrained settings were posed. While ceruloplasmin and 24-h urine copper continue to be important, there is little role of serum copper and penicillamine challenge test in the diagnostic algorithm. A new scoring system - Modified Leipzig score has been suggested with extra points being added for family history and serum ceruloplasmin lower than 5 mg/dl. Liver dry copper estimation and penicillamine challenge test have been removed from the scoring system. Differences in pharmacological approach to neurological and hepatic disease and global monitoring scales have been included. Rising bilirubin and worsening encephalopathy are suggested as indicators predicting need for liver transplant but need to be validated. The clinical practice guidelines provide recommendations for a comprehensive management of WD which will be of value to all specialties.
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Key Words
- AASLD, American Association for the Study of Liver Diseases
- ACLF, Acute on Chronic Liver Failure
- ALF, Acute Liver Failure
- ALT, Alanine Transaminase
- AST, Aspartate Transaminase
- Cu, Copper
- DP, D-Penicillamine
- EASL, European Association for the Study of the Liver
- GAS for WD, Global Assessment Scale for Wilson's Disease
- HCC, Hepatocellular Carcinoma
- INR, International Normalized Ratio
- KF, Kayser-Fleischer
- LT, Liver Transplantation
- MARS, Molecular Absorption Recirculating System
- MELD, Model for End-Stage Liver Disease
- MRI, Magnetic Resonance Imaging
- NGS, Next-Generation Sequencing
- NWI, New Wilson's Index
- PELD, Pediatric end stage liver disease
- TPE, Total Plasma Exchange
- TTM, Tetrathiomolybdate
- WD, Wilson's Disease
- Wilson's disease scoring
- genetic disorder
- modified Leipzig scoring
- rare disease
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Affiliation(s)
- Aabha Nagral
- Department of Gastroenterology, Jaslok Hospital and Research Centre, Mumbai, India
- Department of Gastroenterology, Apollo Hospitals, Navi Mumbai, India
| | - Moinak S. Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - John Matthai
- Department of Paediatric Gastroenterology, Masonic Medical Centre for Children, Coimbatore, India
| | | | - Harshad Devarbhavi
- Department of Gastroenterology and Hepatology, St. John's Medical College Hospital, Bangalore, India
| | - Sanjib Sinha
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Seema Alam
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | | | - Radha K. Dhiman
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | | | - Vinay Goyal
- Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
| | - Neelam Mohan
- Department of Pediatric Gastroenterology, Hepatology & Liver Transplantation, Medanta – The Medicity Hospital, Gurgaon, India
| | - Rukmini M. Kandadai
- Department of Neurology, Nizam's Institute of Medical Sciences, Hyderabad, India
| | - Malathi Sathiyasekaran
- Department of Pediatric Gastroenterology, Kanchi Kamakoti Childs Trust Hospital Chennai, India
| | - Ujjal Poddar
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Anupam Sibal
- Department of Pediatric Gastroenterology and Hepatology, Indraprastha Apollo Hospitals, New Delhi, India
| | | | - Anshu Srivastava
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Baburam R. Thapa
- Department of Gastroenterology & Pediatric Gastroenterology, MM Medical Institute of Medical Sciences and Research, Mullana, Ambala, India
| | - Pettarusp M. Wadia
- Department of Neurology, Jaslok Hospital and Research Centre, Mumbai, India
| | - Surendra K. Yachha
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Anil Dhawan
- Department of Pediatrics and Pediatric Liver GI and Nutrition Center and Mowat Labs, King's College Hospital, London, UK
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Mordaunt CE, Shibata NM, Kieffer DA, Członkowska A, Litwin T, Weiss KH, Gotthardt DN, Olson K, Wei D, Cooper S, Wan YJY, Ali MR, LaSalle JM, Medici V. Epigenetic changes of the thioredoxin system in the tx-j mouse model and in patients with Wilson disease. Hum Mol Genet 2018; 27:3854-3869. [PMID: 30010856 PMCID: PMC6216211 DOI: 10.1093/hmg/ddy262] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2018] [Revised: 06/02/2018] [Accepted: 07/09/2018] [Indexed: 12/19/2022] Open
Abstract
Wilson disease (WD) is caused by mutations in the copper transporter ATP7B, leading to copper accumulation in the liver and brain. Excess copper inhibits S-adenosyl-L-homocysteine hydrolase, leading to variable WD phenotypes from widespread alterations in DNA methylation and gene expression. Previously, we demonstrated that maternal choline supplementation in the Jackson toxic milk (tx-j) mouse model of WD corrected higher thioredoxin 1 (TNX1) transcript levels in fetal liver. Here, we investigated the effect of maternal choline supplementation on genome-wide DNA methylation patterns in tx-j fetal liver by whole-genome bisulfite sequencing (WGBS). Tx-j Atp7b genotype-dependent differences in DNA methylation were corrected by choline for genes including, but not exclusive to, oxidative stress pathways. To examine phenotypic effects of postnatal choline supplementation, tx-j mice were randomized to one of six treatment groups: with or without maternal and/or continued choline supplementation, and with or without copper chelation with penicillamine (PCA) treatment. Hepatic transcript levels of TXN1 and peroxiredoxin 1 (Prdx1) were significantly higher in mice receiving maternal and continued choline with or without PCA treatment compared to untreated mice. A WGBS comparison of human WD liver and tx-j mouse liver demonstrated a significant overlap of differentially methylated genes associated with ATP7B deficiency. Further, eight genes in the thioredoxin (TXN) pathway were differentially methylated in human WD liver samples. In summary, Atp7b deficiency and choline supplementation have a genome-wide impact, including on TXN system-related genes, in tx-j mice. These findings could explain the variability of WD phenotype and suggest new complementary treatment options for WD.
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Affiliation(s)
- Charles E Mordaunt
- Department of Medical Microbiology and Immunology, Genome Center, and MIND Institute, University of California, Davis, California, USA
| | - Noreene M Shibata
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California, Davis, California, USA
| | - Dorothy A Kieffer
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California, Davis, California, USA
| | - Anna Członkowska
- Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Tomasz Litwin
- Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Karl Heinz Weiss
- Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
| | - Daniel N Gotthardt
- Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
| | - Kristin Olson
- Department of Pathology, University of California, Davis, California, USA
| | - Dongguang Wei
- Department of Pathology, University of California, Davis, California, USA
| | - Stewart Cooper
- California Pacific Medical Center, San Francisco, California, USA
| | - Yu-Jui Yvonne Wan
- Department of Pathology, University of California, Davis, California, USA
| | - Mohamed R Ali
- Department of Surgery, University of California, Davis, California, USA
| | - Janine M LaSalle
- Department of Medical Microbiology and Immunology, Genome Center, and MIND Institute, University of California, Davis, California, USA
| | - Valentina Medici
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California, Davis, California, USA
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Członkowska A, Litwin T, Dusek P, Ferenci P, Lutsenko S, Medici V, Rybakowski JK, Weiss KH, Schilsky ML. Wilson disease. Nat Rev Dis Primers 2018; 4:21. [PMID: 30190489 PMCID: PMC6416051 DOI: 10.1038/s41572-018-0018-3] [Citation(s) in RCA: 528] [Impact Index Per Article: 75.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Wilson disease (WD) is a potentially treatable, inherited disorder of copper metabolism that is characterized by the pathological accumulation of copper. WD is caused by mutations in ATP7B, which encodes a transmembrane copper-transporting ATPase, leading to impaired copper homeostasis and copper overload in the liver, brain and other organs. The clinical course of WD can vary in the type and severity of symptoms, but progressive liver disease is a common feature. Patients can also present with neurological disorders and psychiatric symptoms. WD is diagnosed using diagnostic algorithms that incorporate clinical symptoms and signs, measures of copper metabolism and DNA analysis of ATP7B. Available treatments include chelation therapy and zinc salts, which reverse copper overload by different mechanisms. Additionally, liver transplantation is indicated in selected cases. New agents, such as tetrathiomolybdate salts, are currently being investigated in clinical trials, and genetic therapies are being tested in animal models. With early diagnosis and treatment, the prognosis is good; however, an important issue is diagnosing patients before the onset of serious symptoms. Advances in screening for WD may therefore bring earlier diagnosis and improvements for patients with WD.
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Affiliation(s)
- Anna Członkowska
- 2nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland.
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland.
| | - Tomasz Litwin
- 2nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Petr Dusek
- Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Peter Ferenci
- Internal Medicine 3, Department of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Svetlana Lutsenko
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Valentina Medici
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of California, Davis, Sacramento, CA, USA
| | - Janusz K Rybakowski
- Department of Adult Psychiatry, Poznań University of Medical Sciences, Poznań, Poland
| | - Karl Heinz Weiss
- Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Heidelberg, Germany
| | - Michael L Schilsky
- Section of Digestive Diseases and Transplantation and Immunology, Department of Medicine and Surgery, Yale University School of Medicine, New Haven, CT, USA
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Członkowska A, Litwin T, Dzieżyc K, Karliński M, Bring J, Bjartmar C. Characteristics of a newly diagnosed Polish cohort of patients with neurological manifestations of Wilson disease evaluated with the Unified Wilson's Disease Rating Scale. BMC Neurol 2018; 18:34. [PMID: 29621974 PMCID: PMC5887239 DOI: 10.1186/s12883-018-1039-y] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 03/20/2018] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Wilson disease is a rare genetic disorder in which impaired copper excretion results in toxic copper levels and tissue damage. Manifestations are primarily hepatic and/or neuropsychiatric, with a variety of neurological phenotypes. The aim of this study was to characterize neurological signs of Wilson disease in newly diagnosed patients and to determine whether they correlated with disability, liver function, and copper metabolism. METHODS Fifty-three treatment-naïve patients recently diagnosed with Wilson disease who exhibited neurological symptoms were included. Neurological manifestations were characterized by examination in terms of symptom type and degree of neurological impairment (Unified Wilson's Disease Rating Scale [UWDRS] Part III) and correlated with degree of disability (UWDRS Part II), abnormalities in copper parameters and hepatic status. RESULTS Most patients (62.3%) exhibited tremor and ataxia, whereas 15.1% were dystonic, and 11.3% had parkinsonism. Discrete or unclassified signs only were observed in 11.3% of patients. A good correlation between disability (UWDRS Part II) and neurological impairment (UWDRS Part III) was observed (Pearson r = 0.84). However, there was a lack of correlation when either disability or neurological impairment were analyzed with copper parameters or liver impairment. CONCLUSIONS The predominant neurological manifestations in this cohort of newly diagnosed Wilson disease patients were ataxia and tremor. Neurological impairment measured was highly correlated with the level of disability. However, hepatic manifestations of Wilson disease and copper levels did not appear to be correlated with neurological status and disability. These results highlight the challenges faced when assessing Wilson disease with its highly variable symptomatology.
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Affiliation(s)
- Anna Członkowska
- 2nd Department of Neurology, Institute of Psychiatry and Neurology, 02 957, Warsaw, Poland. .,Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland.
| | - Tomasz Litwin
- 2nd Department of Neurology, Institute of Psychiatry and Neurology, 02 957, Warsaw, Poland
| | - Karolina Dzieżyc
- 2nd Department of Neurology, Institute of Psychiatry and Neurology, 02 957, Warsaw, Poland
| | - Michal Karliński
- 2nd Department of Neurology, Institute of Psychiatry and Neurology, 02 957, Warsaw, Poland
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Sęk JP, Kasprzak A, Bystrzejewski M, Poplawska M, Kaszuwara W, Stojek Z, Nowicka AM. Nanoconjugates of ferrocene and carbon-encapsulated iron nanoparticles as sensing platforms for voltammetric determination of ceruloplasmin in blood. Biosens Bioelectron 2018; 102:490-496. [DOI: 10.1016/j.bios.2017.11.060] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 11/09/2017] [Accepted: 11/22/2017] [Indexed: 11/28/2022]
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Lo C, Bandmann O. Epidemiology and introduction to the clinical presentation of Wilson disease. HANDBOOK OF CLINICAL NEUROLOGY 2018; 142:7-17. [PMID: 28433111 DOI: 10.1016/b978-0-444-63625-6.00002-1] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Our understanding of the epidemiology of Wilson disease has steadily grown since Sternlieb and Scheinberg's first prevalence estimate of 5 per million individuals in 1968. Increasingly sophisticated genetic techniques have led to revised genetic prevalence estimates of 142 per million. Various population isolates exist where the prevalence of Wilson disease is higher still, the highest being 885 per million from within the mountainous region of Rucar in Romania. In Sardinia, where the prevalence of Wilson disease has been calculated at 370 per million births, six mutations account for around 85% of Wilson disease chromosomes identified. Significant variation in the patterns of presentation may however exist, even between individuals carrying the same mutations. At either extremes of presentation are an 8-month-old infant with abnormal liver function tests and individuals diagnosed in their eighth decade of life. Three main patterns of presentation have been recognized - hepatic, neurologic, and psychiatric - prompting their presentation to a diverse range of specialists. Deviations in the family history from the anticipated autosomal-recessive mode of inheritance, with apparent "pseudodominance" and mechanisms of inheritance that include uniparental isodisomy (the inheritance of both chromosomal copies from a single parent), may all further cloud the diagnosis. It can therefore take the efforts of an astute clinician with a high clinical index of suspicion to clinch the diagnosis of this eminently treatable condition.
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Affiliation(s)
- Christine Lo
- Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK
| | - Oliver Bandmann
- Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
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21
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Novel mutations of ATP7B gene in Wilson's disease patients of South Indian cohort. Meta Gene 2017. [DOI: 10.1016/j.mgene.2017.08.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Abstract
OBJECTIVES The aim of the study was to analyze the clinical presentations, diagnosis, and treatment of patients ages ≤5 years with early onset Wilson disease (WD). METHODS Data from 143 pediatric patients with WD treated at our center between January 1996 and November 2015 were retrospectively analyzed. RESULTS A review of the 143 pediatric patients with WD identified 21 (10 girls, 11 boys) with first symptoms or abnormal liver function test results at age ≤5 years. The diagnosis of WD was confirmed in 8 patients younger than 5 years. At baseline the mean serum alanine aminotransferase level was 222 U/L and the mean serum aspartate aminotransferase level was 130 U/L. The mean serum ceruloplasmin concentration in 16 tested patients was <20 mg/dL. Of the 15 patients who underwent urinary copper excretion testing, 8 had levels between 40 and 100 μg/day, with only 4 having levels >100 μg/day. Liver copper quantification was >250 μg/g dry weight in 16 patients. The most common mutation was p.H1069Q, with compound heterozygosity in 5 patients and homozygosity in 9. Sixteen patients were treated with zinc salts and 5 with D-penicillamine. Both treatments were effective, with no serious side effects observed after 3 to 24 months. CONCLUSIONS WD can present as early as 2 years of age. Because biochemical tests may be less sensitive in very young children, diagnoses may require a combination of tests. If molecular tests are inconclusive, liver copper content should be measured.
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Kieffer DA, Medici V. Wilson disease: At the crossroads between genetics and epigenetics-A review of the evidence. LIVER RESEARCH 2017; 1:121-130. [PMID: 29270329 PMCID: PMC5734098 DOI: 10.1016/j.livres.2017.08.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Environmental factors, including diet, exercise, stress, and toxins, profoundly impact disease phenotypes. This review examines how Wilson disease (WD), an autosomal recessive genetic disorder, is influenced by genetic and environmental inputs. WD is caused by mutations in the copper-transporter gene ATP7B, leading to the accumulation of copper in the liver and brain, resulting in hepatic, neurological, and psychiatric symptoms. These symptoms range in severity and can first appear anytime between early childhood and old age. Over 300 disease-causing mutations in ATP7B have been identified, but attempts to link genotype to the phenotypic presentation have yielded little insight, prompting investigators to identify alternative mechanisms, such as epigenetics, to explain the highly varied clinical presentation. Further, WD is accompanied by structural and functional abnormalities in mitochondria, potentially altering the production of metabolites that are required for epigenetic regulation of gene expression. Notably, environmental exposure affects the regulation of gene expression and mitochondrial function. We present the "multi-hit" hypothesis of WD progression, which posits that the initial hit is an environmental factor that affects fetal gene expression and epigenetic mechanisms and subsequent "hits" are environmental exposures that occur in the offspring after birth. These environmental hits and subsequent changes in epigenetic regulation may impact copper accumulation and ultimately WD phenotype. Lifestyle changes, including diet, increased physical activity, stress reduction, and toxin avoidance, might influence the presentation and course of WD, and therefore may serve as potential adjunctive or replacement therapies.
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Volpert HM, Pfeiffenberger J, Gröner JB, Stremmel W, Gotthardt DN, Schäfer M, Weiss KH, Weiler M. Comparative assessment of clinical rating scales in Wilson's disease. BMC Neurol 2017; 17:140. [PMID: 28732478 PMCID: PMC5521125 DOI: 10.1186/s12883-017-0921-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Accepted: 07/12/2017] [Indexed: 01/01/2023] Open
Abstract
Background Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism resulting in multifaceted neurological, hepatic, and psychiatric symptoms. The objective of the study was to comparatively assess two clinical rating scales for WD, the Unified Wilson’s Disease Rating Scale (UWDRS) and the Global Assessment Scale for Wilson’s disease (GAS for WD), and to test the feasibility of the patient reported part of the UWDRS neurological subscale (termed the “minimal UWDRS”). Methods In this prospective, monocentric, cross-sectional study, 65 patients (median age 35 [range: 15–62] years; 33 female, 32 male) with treated WD were scored according to the two rating scales. Results The UWDRS neurological subscore correlated with the GAS for WD Tier 2 score (r = 0.80; p < 0.001). Correlations of the UWDRS hepatic subscore and the GAS for WD Tier 1 score with both the Model for End Stage Liver Disease (MELD) score (r = 0.44/r = 0.28; p < 0.001/p = 0.027) and the Child-Pugh score (r = 0.32/r = 0.12; p = 0.015/p = 0.376) were weak. The “minimal UWDRS” score significantly correlated with the UWDRS total score (r = 0.86), the UWDRS neurological subscore (r = 0.89), and the GAS for WD Tier 2 score (r = 0.86). Conclusions The UWDRS neurological and psychiatric subscales and the GAS for WD Tier 2 score are valuable tools for the clinical assessment of WD patients. The “minimal UWDRS” is a practical prescreening tool outside scientific trials. Electronic supplementary material The online version of this article (doi:10.1186/s12883-017-0921-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Hanna M Volpert
- Department of Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, Heidelberg, Germany
| | - Jan Pfeiffenberger
- Department of Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, Heidelberg, Germany
| | - Jan B Gröner
- Department of Internal Medicine I, Heidelberg University Hospital, Im Neuenheimer Feld 410, Heidelberg, Germany
| | - Wolfgang Stremmel
- Department of Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, Heidelberg, Germany
| | - Daniel N Gotthardt
- Department of Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, Heidelberg, Germany
| | - Mark Schäfer
- Department of Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, Heidelberg, Germany
| | - Karl Heinz Weiss
- Department of Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, Heidelberg, Germany.
| | - Markus Weiler
- Department of Neurology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
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25
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Mercer SW, Wang J, Burke R. In Vivo Modeling of the Pathogenic Effect of Copper Transporter Mutations That Cause Menkes and Wilson Diseases, Motor Neuropathy, and Susceptibility to Alzheimer's Disease. J Biol Chem 2017; 292:4113-4122. [PMID: 28119449 DOI: 10.1074/jbc.m116.756163] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 01/16/2017] [Indexed: 12/13/2022] Open
Abstract
Copper is an essential biometal, and several inherited diseases are directly associated with a disruption to normal copper homeostasis. The best characterized are the copper deficiency and toxicity disorders Menkes and Wilson diseases caused by mutations in the p-type Cu-ATPase genes ATP7A and ATP7B, respectively. Missense mutations in the C-terminal portion of ATP7A have also been shown to cause distal motor neuropathy, whereas polymorphisms in ATP7B are associated with increased risk of Alzheimer's disease. We have generated a single, in vivo model for studying multiple pathogenic mutations in ATP7 proteins using Drosophila melanogaster, which has a single orthologue of ATP7A and ATP7B. Four pathogenic ATP7A mutations and two ATP7B mutations were introduced into a genomic ATP7 rescue construct containing an in-frame C-terminal GFP tag. Analysis of the wild type ATP7-GFP transgene confirmed that ATP7 is expressed at the basolateral membrane of larval midgut copper cells and that the transgene can rescue a normally early lethal ATP7 deletion allele to adulthood. Analysis of the gATP7-GFP transgenes containing pathogenic mutations showed that the function of ATP7 was affected, to varying degrees, by all six of the mutations investigated in this study. Of particular interest, the ATP7BK832R Alzheimer's disease susceptibility allele was found, for the first time, to be a loss of function allele. This in vivo system allows us to assess the severity of individual ATP7A/B mutations in an invariant genetic background and has the potential to be used to screen for therapeutic compounds able to restore function to faulty copper transport proteins.
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Affiliation(s)
- Stephen W Mercer
- From the School of Biological Sciences, Monash University, Clayton, Victoria 3800, Australia
| | - Jianbin Wang
- From the School of Biological Sciences, Monash University, Clayton, Victoria 3800, Australia
| | - Richard Burke
- From the School of Biological Sciences, Monash University, Clayton, Victoria 3800, Australia
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26
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Ljubić H, Kalauz M, Telarović S, Ferenci P, Ostojić R, Noli MC, Lepori MB, Hrstić I, Vuković J, Premužić M, Radić D, Ravić KG, Sertić J, Merkler A, Barišić AA, Loudianos G, Vucelić B. ATP7B Gene Mutations in Croatian Patients with Wilson Disease. Genet Test Mol Biomarkers 2016; 20:112-117. [PMID: 26799313 DOI: 10.1089/gtmb.2015.0213] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
AIMS Wilson disease (WD) is an autosomal recessive disorder of copper metabolism, characterized by its accumulation in tissues which results in hepatic, neurological, and/or psychiatric symptoms. The aim of this study was to investigate the genetics of WD in Croatian patients. METHODS Correlation of the clinical presentation subtype and the age at onset of the diagnosis of WD with the ATP7B genotype was investigated in a group of Croatian WD patients. DNA from peripheral blood samples was tested for the p.His1069Gln by direct mutational analysis and other polymorphisms were identified by sequence analysis of coding and flanking intronic regions of ATP7B gene. RESULTS In the group of 75 WD patients of Croatian origin, 18 different mutations in ATP7B gene were detected, three of which were novel. The p.His1069Gln mutation was most frequent, being detected in 44 Croatian WD patients (58.7%). Most ATP7B mutations (90.4%) were located in exons 5, 8, 13, 14, and 15. CONCLUSIONS Clinical diagnosis of WD was confirmed in 59 patients by detecting mutations on both ATP7B alleles. The age at onset of WD and the type of WD clinical presentation showed no significant correlation with the ATP7B genotype.
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Affiliation(s)
- Hana Ljubić
- 1 Department of Laboratory Diagnostics, University Hospital Centre Zagreb , Zagreb, Croatia
| | - Mirjana Kalauz
- 2 Department of Internal Medicine, University Hospital Centre Zagreb , Zagreb, Croatia
| | - Srđana Telarović
- 3 Department of Neurology, University Hospital Centre Zagreb , Zagreb, Croatia
| | - Peter Ferenci
- 4 Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna , Vienna, Austria
| | - Rajko Ostojić
- 2 Department of Internal Medicine, University Hospital Centre Zagreb , Zagreb, Croatia
| | - Maria Cristina Noli
- 5 Department of Public Health and Clinical and Molecular Medicine, University of Cagliari , Cagliari, Italy
| | - Maria Barbara Lepori
- 5 Department of Public Health and Clinical and Molecular Medicine, University of Cagliari , Cagliari, Italy
| | - Irena Hrstić
- 6 Department of Internal Medicine, General Hospital Pula , Pula, Croatia
| | - Jurica Vuković
- 7 Department of Pediatrics, University Hospital Centre Zagreb , Zagreb, Croatia
| | - Marina Premužić
- 2 Department of Internal Medicine, University Hospital Centre Zagreb , Zagreb, Croatia
| | - Davor Radić
- 2 Department of Internal Medicine, University Hospital Centre Zagreb , Zagreb, Croatia
| | - Katja Grubelić Ravić
- 2 Department of Internal Medicine, University Hospital Centre Zagreb , Zagreb, Croatia
| | - Jadranka Sertić
- 1 Department of Laboratory Diagnostics, University Hospital Centre Zagreb , Zagreb, Croatia
| | - Ana Merkler
- 1 Department of Laboratory Diagnostics, University Hospital Centre Zagreb , Zagreb, Croatia
| | - Ana Acman Barišić
- 1 Department of Laboratory Diagnostics, University Hospital Centre Zagreb , Zagreb, Croatia
| | | | - Boris Vucelić
- 2 Department of Internal Medicine, University Hospital Centre Zagreb , Zagreb, Croatia
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Dusek P, Litwin T, Czlonkowska A. Wilson disease and other neurodegenerations with metal accumulations. Neurol Clin 2015; 33:175-204. [PMID: 25432729 DOI: 10.1016/j.ncl.2014.09.006] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Trace elements, such as iron, copper, manganese, and calcium, which are essential constituents necessary for cellular homeostasis, become toxic when present in excess quantities. In this article, we describe disorders arising from endogenous dysregulation of metal homeostasis leading to their tissue accumulation. Although subgroups of these diseases lead to regional brain metal accumulation, mostly in globus pallidus, which is susceptible to accumulate divalent metal ions, other subgroups cause systemic metal accumulation affecting the whole brain, liver, and other parenchymal organs. The latter group comprises Wilson disease, manganese transporter deficiency, and aceruloplasminemia and responds favorably to chelation treatment.
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Affiliation(s)
- Petr Dusek
- Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine and General University Hospital in Prague, Charles University in Prague, Kateřinská 30, Prague 128 21, Czech Republic; Institute of Neuroradiology, University Medicine Goettingen, Robert-Koch-Street 40, Göttingen 37075, Germany.
| | - Tomasz Litwin
- 2nd Department of Neurology, Institute Psychiatry and Neurology, Sobieskiego 9, Warsaw 02-957, Poland
| | - Anna Czlonkowska
- 2nd Department of Neurology, Institute Psychiatry and Neurology, Sobieskiego 9, Warsaw 02-957, Poland; Department of Experimental and Clinical Pharmacology, Medical University, Banacha 1b, Warsaw 02-097, Poland
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28
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Gromadzka G, Kruszyńska M, Wierzbicka D, Litwin T, Dzieżyc K, Wierzchowska-Ciok A, Chabik G, Członkowska A. Gene variants encoding proteins involved in antioxidant defense system and the clinical expression of Wilson disease. Liver Int 2015; 35:215-22. [PMID: 24517502 DOI: 10.1111/liv.12493] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Accepted: 02/04/2014] [Indexed: 12/25/2022]
Abstract
BACKGROUND & AIMS Wilson disease (WD) is an autosomal recessive disorder of copper metabolism resulting from pathogenic mutations of the ATP7B gene. The basis of phenotypic variability of the disease is not understood. The main mechanism of copper toxicity is probably related to generation of intracellular oxidative stress. To evaluate whether interindividual variability within genes encoding proteins involved in antioxidant defense system may modulate phenotypic expressions of WD. METHODS Variability within genes encoding the cytosolic enzymes: glutathione peroxidase (GPX1 rs1050450) and manganese superoxide dismutase (SOD2 rs4880), and peroxisomal enzyme: catalase (CAT rs1001179) were analysed in 435 patients. Individual genotypes were tested for their relationship with phenotypic features of WD. RESULTS GPX1 genotypes were not related to phenotypic manifestations of WD. Among males homozygocity for the SOD2 rs4880 T allele was related to earlier onset of WD. Patients homozygous for the CAT rs1001179 T allele characterized with later onset of WD [median (interquartile range) age: 29.0 (14.0) years vs. 22.0 (12.0) years, respectively, P < 0.004], later manifestation of hepatic symptoms [34.5 (14.0) years vs. 22.0 (12.0) years, P < 0.0009], and later presentation of neurological symptoms [37.0 (16.0) years vs. 28.0 (13.0) years, P < 0.03] than those having one or two C alleles. CONCLUSION Variability within the CAT gene may be an important modifier of the clinical course of WD. SOD2 genotype may influence WD phenotype among males. These observations indirectly confirm a role of oxidative stress in the pathogenesis of WD, as well as indirectly suggest that peroxisomes impairment may be involved in WD pathophysiology.
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Affiliation(s)
- Grażyna Gromadzka
- Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
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29
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Dzieżyc K, Litwin T, Chabik G, Gramza K, Członkowska A. Families with Wilson's disease in subsequent generations: Clinical and genetic analysis. Mov Disord 2014; 29:1828-32. [DOI: 10.1002/mds.26057] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Revised: 09/18/2014] [Accepted: 09/28/2014] [Indexed: 11/08/2022] Open
Affiliation(s)
- Karolina Dzieżyc
- 2nd Department of Neurology; Institute of Psychiatry and Neurology; Warsaw Poland
| | - Tomasz Litwin
- 2nd Department of Neurology; Institute of Psychiatry and Neurology; Warsaw Poland
| | - Grzegorz Chabik
- 2nd Department of Neurology; Institute of Psychiatry and Neurology; Warsaw Poland
| | - Karolina Gramza
- 2nd Department of Neurology; Institute of Psychiatry and Neurology; Warsaw Poland
| | - Anna Członkowska
- 2nd Department of Neurology; Institute of Psychiatry and Neurology; Warsaw Poland
- Department of Clinical and Experimental Pharmacology; Medical University of Warsaw; Poland
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30
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Spincemaille P, Pham DH, Chandhok G, Verbeek J, Zibert A, Libbrecht L, Schmidt H, Esguerra CV, de Witte PA, Cammue BP, Cassiman D, Thevissen K. The plant decapeptide OSIP108 prevents copper-induced toxicity in various models for Wilson disease. Toxicol Appl Pharmacol 2014; 280:345-51. [DOI: 10.1016/j.taap.2014.08.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Revised: 07/30/2014] [Accepted: 08/05/2014] [Indexed: 02/07/2023]
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Cocoş R, Şendroiu A, Schipor S, Bohîlţea LC, Şendroiu I, Raicu F. Genotype-phenotype correlations in a mountain population community with high prevalence of Wilson's disease: genetic and clinical homogeneity. PLoS One 2014; 9:e98520. [PMID: 24897373 PMCID: PMC4045667 DOI: 10.1371/journal.pone.0098520] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2014] [Accepted: 04/29/2014] [Indexed: 12/12/2022] Open
Abstract
Wilson’s disease is an autosomal recessive disorder caused by more than 500 mutations in ATP7B gene presenting considerably clinical manifestations heterogeneity even in patients with a particular mutation. Previous findings suggested a potential role of additional genetic modifiers and environment factors on phenotypic expression among the affected patients. We conducted clinical and genetic investigations to perform genotype-phenotype correlation in two large families living in a socio-culturally isolated community with the highest prevalence of Wilson’s disease ever reported of 1∶1130. Sequencing of ATP7B gene in seven affected individuals and 43 family members identified a common compound heterozygous genotype, H1069Q/M769H-fs, in five symptomatic and two asymptomatic patients and detected the presence of two out of seven identified single nucleotide polymorphisms in all affected patients. Symptomatic patients had similar clinical phenotype and age at onset (18±1 years) showing dysarthria and dysphagia as common clinical features at the time of diagnosis. Moreover, all symptomatic patients presented Kayser-Fleischer rings and lack of dystonia accompanied by unfavourable clinical outcomes. Our findings add value for understanding of genotype-phenotype correlations in Wilson’s disease based on a multifamily study in an isolated population with high extent of genetic and environmental homogeneity as opposed to majority of reports. We observed an equal influence of presumed other genetic modifiers and environmental factors on clinical presentation and age at onset of Wilson’s disease in patients with a particular genotype. These data provide valuable inferences that could be applied for predicting clinical management in asymptomatic patients in such communities.
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Affiliation(s)
- Relu Cocoş
- Chair of Medical Genetics, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Genome Life Research Centre, Bucharest, Romania
| | | | - Sorina Schipor
- National Institute of Endocrinology “C. I. Parhon”, Bucharest, Romania
| | - Laurenţiu Camil Bohîlţea
- Chair of Medical Genetics, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Sf. Pantelimon Clinical Emergency Hospital, Bucharest, Romania
| | | | - Florina Raicu
- Chair of Medical Genetics, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Francisc I. Rainer Anthropological Research Institute, Romanian Academy, Bucharest, Romania
- * E-mail:
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Przybyłkowski A, Gromadzka G, Członkowska A. Polymorphisms of metal transporter genes DMT1 and ATP7A in Wilson's disease. J Trace Elem Med Biol 2014; 28:8-12. [PMID: 24120082 DOI: 10.1016/j.jtemb.2013.08.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Revised: 07/22/2013] [Accepted: 08/14/2013] [Indexed: 11/25/2022]
Abstract
Wilson's disease (WND) is an inherited disorder of copper metabolism. Divalent metal transporter1 (DMT1) and ATP7A play important roles in metal transport in humans. The frequency of two single nucleotide polymorphisms of the DMT1 gene: DMT1 IVS4 C>A, DMT1 11245 T>C and two of the ATP7A gene: rs1062472 T>C, ATP7A rs 2227291 G>C have been evaluated in a population of 108 Wilson's disease patients and 108 sex- and age-matched healthy volunteers. The DMT1 IVS4 C(+) allele occurred more frequently in WND than in the healthy controls. The allele frequencies of other studied polymorphisms in WND group were in line with frequencies obtained for healthy volunteers. Neither of the polymorphisms had an impact on the age at onset or clinical phenotype of WND.
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Affiliation(s)
- Adam Przybyłkowski
- Department of Clinical and Experimental Pharmacology, Medical University of Warsaw, Warsaw, Poland; Department of Gastroenterology, Endoterapia, Warsaw, Poland.
| | - Grażyna Gromadzka
- Department of Clinical and Experimental Pharmacology, Medical University of Warsaw, Warsaw, Poland; 2nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Anna Członkowska
- 2nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
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Chabik G, Litwin T, Członkowska A. Concordance rates of Wilson's disease phenotype among siblings. J Inherit Metab Dis 2014; 37:131-5. [PMID: 23774950 PMCID: PMC3889629 DOI: 10.1007/s10545-013-9625-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2013] [Revised: 05/17/2013] [Accepted: 05/27/2013] [Indexed: 11/26/2022]
Abstract
Wilson's disease (WD) is an autosomal recessive disorder characterized by the functional disruption of adenosine triphosphatase 7B (ATP7B), which results in positive copper balance. Although the primary manifestations of the disease are hepatic or neurological in scope, the factors that cause a very diverse picture of WD are not well researched. We compared the first clinical presentation, ages of onset and diagnosis, copper metabolism parameters, and ceruloplasmin levels between index cases (ICs) and their siblings. We examined 73 ICs and 95 siblings from 73 families, including a total of 168 patients with biochemical and genetically confirmed WD diagnoses. We observed an 86% concordance rate of primary clinical symptoms among ICs with hepatic symptoms and their siblings. There was 66% concordance among ICs with neurological symptoms and their siblings. No differences regarding age at onset of symptoms or copper metabolism parameters at diagnosis were identified between hepatic ICs and their siblings. The age at symptom onset did not differ between neurological ICs and their siblings, although ICs presented lower ceruloplasmin and serum copper levels. These results demonstrate a high intra-familial concordance of the clinical and biochemical presentation of WD, suggesting that similar factors shared within the same families strongly influence the disease presentation.
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Affiliation(s)
- Grzegorz Chabik
- 2nd Department of Neurology, Institute of Psychiatry and Neurology, 9 Sobieskiego Str., 02-957 Warsaw, Poland
| | - Tomasz Litwin
- 2nd Department of Neurology, Institute of Psychiatry and Neurology, 9 Sobieskiego Str., 02-957 Warsaw, Poland
| | - Anna Członkowska
- 2nd Department of Neurology, Institute of Psychiatry and Neurology, 9 Sobieskiego Str., 02-957 Warsaw, Poland
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Dzieżyc K, Karliński M, Litwin T, Członkowska A. Compliant treatment with anti-copper agents prevents clinically overt Wilson's disease in pre-symptomatic patients. Eur J Neurol 2013; 21:332-7. [PMID: 24313946 DOI: 10.1111/ene.12320] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2013] [Accepted: 10/21/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND PURPOSE Wilson's disease (WD) is an inherited copper metabolism disorder that leads to dysfunction of affected tissues, mostly in the liver and brain. Anti-copper treatment should prevent clinically overt WD in pre-symptomatic patients but this has not been supported by strong evidence. Our aim was to evaluate the long-term effectiveness of treatment in clinically pre-symptomatic patients, with particular emphasis on patient compliance with treatment. METHODS Data were analyzed for 87 consecutive patients with no clinical symptoms of WD who were identified between 1957 and 2009 by family screening. All of them since diagnosis were treated with either zinc sulphate (Zn) (66.7%) or D-penicillamine (DPA) (33.3%). RESULTS During a median follow-up of 12 years (range 3-52), 55 (63%) patients remained without clinical symptoms, 13 (15%) developed neuropsychiatric symptoms and 21 (24%) developed hepatic dysfunction, including five deaths from hepatic failure. Non-compliance for at least three consecutive months was observed in 39 patients, and in 29 cases this extended for more than 12 months. Multivariate analysis showed that the odds of developing symptomatic WD were independently increased by non-compliance (odds ratio 24.0, 95% confidence interval 6.0-99.0). According to Kaplan-Meier analysis patients who were compliant to treatment had a significantly higher likelihood of remaining symptom-free, and their overall survival was similar to the survival rate observed in the general population. CONCLUSION The use of anti-copper agents in clinically pre-symptomatic patients diagnosed with WD allows clinically overt disease to be effectively prevented. However, compliance with therapy is extremely important.
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Affiliation(s)
- K Dzieżyc
- Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
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Does brain degeneration in Wilson disease involve not only copper but also iron accumulation? Neurol Neurochir Pol 2013; 47:542-6. [PMID: 24374999 DOI: 10.5114/ninp.2013.39071] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND AND PURPOSE Wilson disease (WD) is an autosomal recessive inherited disorder of hepatic copper metabolism. Clinical manifestations of WD include neurologic, hepatic and psychiatric symptoms. Most WD patients with the neuropsychiatric form, and some with the hepatic and presymptomatic forms have both hypointense and hyperintense lesions in basal ganglia on T2-weighted magnetic resonance imaging (MRI), which can be iron and copper accumulation. It has been established that T2* and susceptibility-weighted imaging (SWI) are highly sensitive in demonstrating brain iron accumulation, showing decreased signal intensity. Hypointense globus pallidus (GP) signal has been described on T2-, T2*-weighted images and on SWI as typical MRI lesion for patients with neurodegeneration with brain iron accumulation (NBIA). We investigated whether WD patients have MRI changes suggesting iron accumulation using T2*-weighted and VEN_BOLD SWI imaging protocols. MATERIAL AND METHODS Standard MRI with additional sequences (T2*-weighted and VEN_BOLD SWI) was performed in consecutively admitted, clinically stable, and treated patients. RESULTS Twenty-eight patients entered the study. Hypointensity in the GP was observed on T2*-weighted images in 10 pa-tients. Using the VEN_BOLD SWI technique, we found hypointense signal in GP in 20 patients. CONCLUSIONS MRI data suggest not only copper but also iron accumulation in GP in WD patients.
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Mirowska-Guzel D, Litwin T, Gromadzka G, Czlonkowski A, Czlonkowska A. Influence of BDNF polymorphisms on Wilson's disease susceptibility and clinical course. Metab Brain Dis 2013; 28:447-53. [PMID: 23519890 PMCID: PMC3734604 DOI: 10.1007/s11011-013-9399-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2012] [Accepted: 03/10/2013] [Indexed: 12/24/2022]
Abstract
Susceptibility to Wilson's disease (WD) and its clinical manifestations are thought to be affected by genetic factors, including polymorphisms. The role of brain-derived neurotrophic factor (BDNF) in the pathogenesis of neurodegenerative diseases is now widely discussed. The aim of the present study was to evaluate the frequency of the BDNF Val66Met (G-196A) and C-270T polymorphisms in WD patients and in healthy controls, and to determine the role of these polymorphisms in the clinical characteristics of WD. We found that the BDNF Val/Val (-196 G/G) and -270 C/T genotypes occurred more frequently in WD patients than in healthy controls (66 % versus 45.5 %, p = 0.0001, and 14 % versus 6 %, p = 0.018, respectively). Similarly, symptomatic patients carried the BDNF Val/Val genotype more often than presymptomatic patients (75 % versus 53 %, p = 0.0097). No association was detected between any of the determined polymorphisms and the dominant form of the disease or the age of onset for WD.
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Affiliation(s)
- Dagmara Mirowska-Guzel
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, 00-927 Warsaw, Poland
- 2nd Department of Neurology, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland
| | - Tomasz Litwin
- 2nd Department of Neurology, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland
| | - Grazyna Gromadzka
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, 00-927 Warsaw, Poland
- 2nd Department of Neurology, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland
| | - Andrzej Czlonkowski
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, 00-927 Warsaw, Poland
| | - Anna Czlonkowska
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, 00-927 Warsaw, Poland
- 2nd Department of Neurology, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland
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Litwin T, Gromadzka G, Członkowska A, Gołębiowski M, Poniatowska R. The effect of gender on brain MRI pathology in Wilson's disease. Metab Brain Dis 2013; 28:69-75. [PMID: 23315358 PMCID: PMC3562549 DOI: 10.1007/s11011-013-9378-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2012] [Accepted: 01/08/2013] [Indexed: 12/02/2022]
Abstract
Gender influence on the clinical manifestations of Wilson's Disease (WD) has been suggested; however, brain MRI pathology based on sexual dimorphism in WD has not yet been examined. The aim of this study was to analyse the effect of gender on brain MRI pathology according to the predominant form of WD. We retrospectively analysed the brain MR images of 204 newly diagnosed and untreated WD patients. The predominant form of the disease was neuropsychiatric (n = 105), hepatic (n = 67) or presymptomatic (n = 32). Overall, neuroimaging pathologies were found in 64.2 % WD patients. The clinical form analysis revealed significant gender-related differences. In the neuropsychiatric form, men presented with cerebellar atrophy and cortical brain atrophy more often than women (25/58 vs. 11/47; p < 0.05) and (23/58 vs. 12/47; p = 0.09), respectively. In contrast, women tended to present with globus pallidus lesions more often than men (25/47 vs. 20/58; p = 0.054). There were no gender differences observed in the hepatic form, but cortical brain atrophy presented more often in men than women (3/12 vs. 0/20; p < 0.05) in the presymptomatic form. According to our findings, there is a gender-dependent brain vulnerability to copper toxicity. We speculate that these differences are potentially related to an oestrogen protective effect and are due to differences in gender-related clinical forms.
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Affiliation(s)
- T Litwin
- Second Department of Neurology, Institute Psychiatry and Neurology, Sobieskiego 9, Warsaw, Poland.
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Kumar SS, Kurian G, Eapen CE, Roberts EA. Genetics of Wilson's disease: a clinical perspective. Indian J Gastroenterol 2012; 31:285-93. [PMID: 22941676 DOI: 10.1007/s12664-012-0237-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2012] [Accepted: 07/23/2012] [Indexed: 02/04/2023]
Abstract
Hepatic Wilson's disease is often a difficult diagnosis to confirm. This review examines the current role of genetic tests for Wilson's disease and is aimed at clinicians caring for patients with this disease. We discuss how genetic testing is carried out for Wilson's disease, indications for these tests, and genetic counseling for the family. In contrast to the advances in diagnosis of Wilson's disease by testing for ATP7B mutations, genotype-phenotype correlations are not yet sufficiently established. The non-Wilsonian copper overload syndromes causing cirrhosis in children are another important area for study. The review also identifies further areas for research into the genetics of Wilson's disease in India.
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Affiliation(s)
- S Suresh Kumar
- Department of Hepatology, Christian Medical College, Vellore 632 004, Tamil Nadu, India
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Di Stefano V, Lionetti E, Rotolo N, La Rosa M, Leonardi S. Hypercalciuria and nephrocalcinosis as early feature of Wilson disease onset: description of a pediatric case and literature review. HEPATITIS MONTHLY 2012; 12:e6233. [PMID: 23087754 PMCID: PMC3475018 DOI: 10.5812/hepatmon.6233] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/12/2012] [Revised: 05/25/2012] [Accepted: 06/16/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND Wilson's disease (WD) is a rare autosomal-recessive disorder characterized by a mutation in the ATP7B gene, located on chromosome 13, which encodes a protein involved in the metabolism of copper. CASE PRESENTATION We described the case of an Indian male with a history of polydipsia and polyuria, related to hypercalciuria and consequent nephrocalcinosis. The symptoms began at the age of five years old, but he was not diagnosed with WD until he reached an adolescent age. We started therapy with D-Penicillamine, B-vitamin complex and recommended a low copper diet. Renal involvement in Wilson's disease, characterizing by hypercalciuria, was firstly reported by Litin in 1959. CONCLUSION Our case was different and peculiar from the previously described cases because the patient presented a very long history (10 years) of permanent hypercalciuria without any acute episode of nephrolithiasis.
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Affiliation(s)
| | - Elena Lionetti
- Department of Pediatrics, University of Catania, Catania, Italy
| | - Novella Rotolo
- Department of Pediatrics, University of Catania, Catania, Italy
| | - Mario La Rosa
- Department of Pediatrics, University of Catania, Catania, Italy
| | - Salvatore Leonardi
- Department of Pediatrics, University of Catania, Catania, Italy
- Corresponding author: Salvatore Leonardi, Department of Paediatrics, University of Catania, Via Santa Sofia 78/ 95124, Catania, Italy.Tel.: +39-953782764, Fax: +39-953782395, E-mail:
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Hypercalciuria and Nephrocalcinosis as Early Feature of Wilson Disease Onset: Description of a Pediatric Case and Literature Review. HEPATITIS MONTHLY 2012. [DOI: 10.5812/hapatmon.6233] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
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Litwin T, Gromadzka G, Samochowiec J, Grzywacz A, Członkowski A, Członkowska A. Association of dopamine receptor gene polymorphisms with the clinical course of Wilson disease. JIMD Rep 2012; 8:73-80. [PMID: 23430523 DOI: 10.1007/8904_2012_163] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2012] [Revised: 05/15/2012] [Accepted: 06/11/2012] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Dopamine receptor D2 (DRD2) polymorphisms are proposed to be important factors in the presentation of neuropsychiatric symptoms in many disorders, including decreased striatum levels of dopamine D2 receptors in Wilson disease. The present study investigated the association between DRD2 gene polymorphisms and clinical manifestation of Wilson disease. METHODS Analyzing data from 97 symptomatic Wilson disease patients, we investigated the DRD2 gene polymorphisms rs1800497, rs1799732, and rs12364283. We assessed the polymorphisms impact on the phenotypic presentation of the disease. RESULTS Generally, the DRD2 gene polymorphisms had no impact on the hepatic or neuropsychiatric clinical presentation of Wilson disease. However, rs1799732 deletion allele carriers with neuropsychiatric symptoms had earlier onset of WD symptoms by almost 6 years compared with individuals without this allele (22.5 vs. 28.3 years; P < 0.05). This unfavorable effect of the rs1799732 polymorphism was even more pronounced among adenosine triphosphatase 7B gene (ATP7B) p.H1069Q homozygous patients, in whom carriership of the deletion allele was related to earlier initial neuropsychiatric manifestation by 14 years (18.4 vs. 32.2 years; P < 0.01). CONCLUSIONS Genetic variation of DRD2, specifically the rs1799732 polymorphism, may produce an earlier clinical presentation of Wilson disease neuropsychiatric symptoms and signs that occur in the course of dopaminergic system impairment due to copper accumulation in the brain. We speculate that this effect may be due to the impact of DRD2 polymorphism on dopamine D2 receptor density, but further studies are needed to understand the mechanisms of such phenotypic effects.
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Affiliation(s)
- T Litwin
- Second Department of Neurology, Institute Psychiatry and Neurology, Sobieskiego 9, 02 957, Warsaw, Poland,
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Usta J, Daya HA, Halawi H, Al-Shareef I, El-Rifai O, Malli AH, Sharara AI, Habib RH, Barada K. Homozygosity for Non-H1069Q Missense Mutations in ATP7B Gene and Early Severe Liver Disease: Report of Two Families and a Meta-analysis. JIMD Rep 2011; 4:129-137. [PMID: 23430908 PMCID: PMC3509905 DOI: 10.1007/8904_2011_91] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2011] [Revised: 08/24/2011] [Accepted: 09/07/2011] [Indexed: 02/06/2023] Open
Abstract
Most patients with Wilson's disease (WD) are compound heterozygote, which complicates establishing genotype-phenotype correlations. We identified five patients who presented with early and/or severe hepatic disease who are homozygous for W939C missense mutation on exon 12 of ATP7B. We therefore conducted a meta-analysis to determine the phenotype of patients homozygous for missense or nonsense mutations in all ATP7B exons.The meta-analysis showed that 69% and 31% of patients are homozygous for H1069Q and non-H1069Q mutations, respectively. Compared to patients with H1069Q, those with non-H1069Q mutations were significantly more likely to have a hepatic phenotype, severe liver disease, a mixed phenotype, and less likely to have a neurologic phenotype. Compared to patients with nonsense mutations, those with non-H1069Q ones were equally likely to present with a hepatic phenotype and to have severe liver disease. Mean age at symptom onset in the non-H1069Q versus the H1069Q group was 15.5 versus 20.5years (p<0.001).Our data suggest that mutation W939C and other non-H1069Q missense mutations are associated with early disease onset, a hepatic phenotype, and a high risk of hepatic failure in homozygous patients. Early identification of such patients by genetic screening is important for timely initiation of treatment and prevention of complications.
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Affiliation(s)
- Julnar Usta
- />Department of Biochemistry, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Hussein Abu Daya
- />Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Houssam Halawi
- />Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Ibraheem Al-Shareef
- />Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Omar El-Rifai
- />Department of Biochemistry, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Ahmad H. Malli
- />Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Ala I. Sharara
- />Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Robert H. Habib
- />Biostatistics and Outcomes Research Unit—Clinical Research Institute, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Kassem Barada
- />Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
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Prevalence of ATP7B Gene Mutations in Iranian Patients With Wilson Disease. HEPATITIS MONTHLY 2011. [DOI: 10.5812/kowsar.1735143x.3750] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
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Gromadzka G, Rudnicka M, Chabik G, Przybyłkowski A, Członkowska A. Genetic variability in the methylenetetrahydrofolate reductase gene (MTHFR) affects clinical expression of Wilson's disease. J Hepatol 2011; 55:913-9. [PMID: 21334398 DOI: 10.1016/j.jhep.2011.01.030] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2010] [Revised: 12/21/2010] [Accepted: 01/04/2011] [Indexed: 12/04/2022]
Abstract
BACKGROUND & AIMS Wilson's disease (WND) is an autosomal recessive disorder of copper (Cu) transport, resulting from pathogenic mutations in the ATP7B gene. The reason for the high variability in phenotypic expressions of WND is unknown. Hepatotoxic and neurotoxic effects of homocysteine (Hcy), as well as interrelationships between Hcy and Cu toxicity, were documented. METHODS We genotyped the two 5,10-methylenetetrahydrofolate reductase (one of the key folate/Hcy pathway enzymes) gene (MTHFR) polymorphisms: C677T and A1298C in 245 WND patients. Next, we tested the modulation of WND phenotypes by genotypes of MTHFR. RESULTS MTHFR C677T genotype distribution deviated from that expected from a population in Hardy-Weinberg equilibrium (C677T, χ(2) = 12.14, p = 0.0005). Patients with the MTHFR 1298C allele were younger at symptoms' onset than those without this allele (median (IQR) age, 24.9 (14.0) years vs. 28.5 (12.0) years, p = 0.006). Carriers of MTHFR "high activity" diplotype (double wild-type homozygotes 677CC/1298AA) manifested WND at older age, than non-carriers (median (IQR) age, 33.5 (9.0) years vs. 25.0 (13.0) years, p = 0.0009). Patients with the MTHFR 677T allele less frequently exhibited the neurological WND phenotype (31 (29.5%) vs. 36 (48.0%)), and more frequently presented with hepatic WND (44 (41.9%) vs. 22 (29.3%)), compared with subjects MTHFR 677T(-). CONCLUSIONS We postulate that MTHFR polymorphism contributes to the phenotypic variability of WND.
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Affiliation(s)
- Grażyna Gromadzka
- Institute of Psychiatry and Neurology, Second Department of Neurology, Warsaw, Poland.
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Clinical presentation and mutations in Danish patients with Wilson disease. Eur J Hum Genet 2011; 19:935-41. [PMID: 21610751 DOI: 10.1038/ejhg.2011.80] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
This study describes the clinical presentation and diagnosis in all Danish patients (49, 41 unrelated) with Wilson disease (WND). On the basis of the number of diagnosed patients from 1990-2008, the prevalence was estimated to be 1:49 500. Among routinely used diagnostic tests, none were consistently indicative of WND, with the exception of the 24-h urine-Cu test, which is always outside the normal range. Mutations were identified in 100% of the screened ATP7B alleles (70 unrelated), including five novel mutations: p.1021K; p.G1158V; p.L1304F; IVS20-2A>G; Ex5_6del. In all, 70% of mutations were found in exons 8, 14, 17, 18, and 20. The most frequent mutation, p.H1069Q, comprised 18%. We propose a new and simple model that correlates genotype and age of onset. By assuming that the milder of two mutations is 'functionally dominant' and determines the age of onset, we classified 25/27 mutations as either severe (age of onset <20 years) or moderate (age of onset >20 years), and correctly predicted the age of onset in 37/39 patients. This method should be tested in other Wilson populations.
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Weiss KH, Runz H, Noe B, Gotthardt DN, Merle U, Ferenci P, Stremmel W, Füllekrug J. Genetic analysis of BIRC4/XIAP as a putative modifier gene of Wilson disease. J Inherit Metab Dis 2010; 33 Suppl 3:S233-S240. [PMID: 20517649 DOI: 10.1007/s10545-010-9123-5] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2009] [Revised: 04/28/2010] [Accepted: 04/29/2010] [Indexed: 12/23/2022]
Abstract
Wilson disease (WD) is an autosomal-recessive copper overload disorder caused by mutations in the copper-transporting adenosine triphosphatase (ATPase) ATP7B. It presents with a highly variable clinical phenotype ranging from asymptomatic to fulminant hepatic failure or progressive neurological involvement. No clear genotype-phenotype correlation has been established. Thus, variants in modifier genes could have an impact on WD manifestation and severity. Recently, the antiapoptotic protein baculoviral IAP repeat-containing protein 4 BIRC4/XIAP has been suggested as a regulator of copper-induced cell death. With the aim of investigating a putative role of BIRC4/XIAP as modifier gene in individuals with copper overload, we analyzed a WD patient cohort (n = 98) for sequence variants at the BIRC4/XIAP locus. When compared with clinical data, the previously described coding single nucleotide polymorphisms (SNPs) at the BRIC4/XIAP locus (rs28382721, rs28382722, rs28382723, rs5956583, rs28382740, rs12838858, rs28382741) did not correlate with age of onset or clinical presentation in our collective. However, three previously unreported variants in the BIRC4/XIAP gene were identified (c.1-26 T > G; c.1408A > T; p.T470S; c.1019A > G; p.N340S). The two patients with variants leading to amino acid exchanges in the BIRC4/XIAP protein showed a remarkably early disease onset at the age of 5 years. Furthermore, one of these patients was only heterozygous for disease-causing mutations in the ATP7B gene. In summary, these data emphasize the need to further elucidate a role of BIRC4/XIAP variants as putative pathogenetic factors in copper overload disorders.
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Affiliation(s)
- Karl Heinz Weiss
- Department of Gastroenterology, University Hospital Heidelberg, INF 410, 69120 Heidelberg, Germany.
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Gromadzka G, Chabik G, Mendel T, Wierzchowska A, Rudnicka M, Czlonkowska A. Middle-aged heterozygous carriers of Wilson’s disease do not present with significant phenotypic deviations related to copper metabolism. J Genet 2010; 89:463-7. [DOI: 10.1007/s12041-010-0065-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
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Kriegeskotte C, Cantz T, Haberland J, Zibert A, Haier J, Köhler G, Schöler HR, Schmidt HHJ, Arlinghaus HF. Laser secondary neutral mass spectrometry for copper detection in micro-scale biopsies. JOURNAL OF MASS SPECTROMETRY : JMS 2009; 44:1417-1422. [PMID: 19753579 DOI: 10.1002/jms.1634] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Disease progression and clinical diagnostics of a number of hereditable metabolic diseases are determined by organ involvement in disturbed deposition of certain molecules. Current clinical imaging is unable to visualize this maldistribution with sufficient specificity and sensitivity, such as in Wilson's disease. The quest for understanding cellular Cu distribution in these patients requires element- and molecule-specific images with nanometer-scale spatial resolution. We have used a new cryo-mass spectrometric instrument with an integrated cryosectioning chamber for preparation and analysis of frozen hydrated samples of Wilson's disease tissue. With laser post-ionization secondary neutral mass spectrometry (laser-SNMS), we were able to image Cu and other intrinsic elements and molecules in less than 1 mg of frozen hydrated liver tissue from a murine model of Wilson's disease. A 40-50 times higher Cu concentration was measured in the disease tissue as compared to the control mouse. Furthermore, major histomorphological changes were observed using this advanced nano-science tool. The results showed that the combination of in-vacuum cryosectioning and cryo-laser-SNMS technologies is particularly well suited for identifying specific cell structures and imaging trace element concentrations with subcellular resolution and upper-parts-per-billion sensitivity in biological samples. This technology can provide a novel diagnostic tool for clinical applications in various diseases involving trace elements.
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Affiliation(s)
- C Kriegeskotte
- Physikalisches Institut, Westfälische Wilhelms-Universität Münster, Wilhelm-Klemm-Str. 10, D-48149 Münster, Germany
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Członkowska A, Gromadzka G, Chabik G. Monozygotic female twins discordant for phenotype of Wilson's disease. Mov Disord 2009; 24:1066-9. [PMID: 19306278 DOI: 10.1002/mds.22474] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Wilson's disease (WD) is an autosomal recessive disorder characterized by the functional disruption of the copper-transporting protein adenosine triphosphatase 7B (ATP-ase 7B). The disease is caused by mutations in ATP7B gene. It seems that the type of mutation in ATP7B only to some degree determines phenotypic manifestation of WD. We examined two pairs of monozygotic twins discordant for WD phenotype. The first set of twins were ATP7B compound heterozygotes c.3207C>A (p.H1069Q)/c.1211_1212insA (p.N404Kfs). The index case developed severe liver failure followed by depressive symptoms, dysarthria, and tremor at the age of 36. Her sister remained presymptomatic at diagnosis at the age of 39. The second twins were ATP7B c.3207C.A (p.H1069Q) homozygotes. The index case presented with dysarthria and tremor at the age of 26. Her sister remained clinically presymptomatic at diagnosis at the age of 28. We concluded that the phenotypic characteristics of WD are possibly attributable to epigenetic/environmental factors.
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Affiliation(s)
- Anna Członkowska
- Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland.
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Mak CM, Lam CW. Diagnosis of Wilson's disease: a comprehensive review. Crit Rev Clin Lab Sci 2008; 45:263-90. [PMID: 18568852 DOI: 10.1080/10408360801991055] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Wilson's disease is an autosomal recessive disorder of copper metabolism. The culprit gene is ATP7B. The worldwide prevalence is about 1 in 30,000, which may vary by population. Higher prevalence rates were reported using more sensitive screening techniques and pilot population screening. Typical presentations include neuropsychiatric and hepatic dysfunction, whereas atypical presentations are protean. Diagnosis relies on a high clinical suspicion, typical neurological symptoms, presence of Kayser-Fleischer rings, and reduced serum ceruloplasmin concentration. The conventional value of < 0.20 g/l is not a universal diagnostic value. Age of the subjects and analytical variations should be considered when interpreting these levels. Patients with inconclusive findings require further investigations such as 24 h urinary free-copper excretion, penicillamine challenge test, liver copper measurement, and detection of gene mutations. Direct molecular diagnosis remains the most decisive tool. Other tests such as non-ceruloplasmin-bound copper are unreliable. Potential pitfalls and limitations of these diagnostic markers are critically reviewed in this paper. The mainstays of therapy are trientine, penicillamine, and/or zinc. Liver transplantation is lifesaving for those with advanced disease. Ceruloplasmin oxidase activity and serum free-copper concentration should be monitored in patients on long-term de-coppering therapy to prevent iatrogenic copper deficiency.
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Affiliation(s)
- Chloe M Mak
- Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
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