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Carrera E, Alvarado J, Astudillo M, Pillajo G. Wilson's disease in two siblings from Ecuador: Two case reports. World J Clin Cases 2025; 13:99558. [PMID: 39866651 PMCID: PMC11577529 DOI: 10.12998/wjcc.v13.i3.99558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 10/09/2024] [Accepted: 10/29/2024] [Indexed: 11/12/2024] Open
Abstract
BACKGROUND Wilson's disease (WD) is a rare metabolic disorder of copper accumulation in organs such as liver, brain, and cornea. Diagnoses and treatments are challenging in settings, where advanced diagnostic tests are unavailable, copper chelating agents are frequently scarce, healthcare professionals lack disease awareness, and medical follow-ups are limited. Prompt diagnoses and treatments help prevent complications, improve patients' quality of life, and ensure a normal life expectancy. The clinical presentations and outcomes of WD can vary within a single family. CASE SUMMARY We present the cases of two siblings (19 and 27 years) from a consanguineous family in rural Ecuador, diagnosed as having WD during a family screening. The male patient, diagnosed at age 19 after his brother's death from acute liver failure, presented with compensated cirrhosis, neurological symptoms, and bilateral Kayser-Fleischer rings. He developed progressive neurological deterioration during an irregular treatment with D-penicillamine due to medication shortages. His condition improved upon switching to trientine tetrahydrochloride, and his neurological symptoms improved over an 8-year period of follow-ups. The female patient, diagnosed at age 10, exhibited only biochemical alterations. Her treatment history was similar; however, she remained asymptomatic without disease progression over the same follow-up period. We discuss the potential influence of epigenetic mechanisms and modifier genes on the various phenotypes, emphasizing the need for research in these areas to optimize therapeutic strategies. CONCLUSION Our patients' medical histories show how early diagnosis and treatment can prevent disease progression; and, how suboptimal treatments impact disease outcomes.
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Affiliation(s)
- Enrique Carrera
- Department of Gastroenterology and Hepatology, Hospital de Especialidades Eugenio Espejo, Quito 170136, Pichincha, Ecuador
| | - Jonathan Alvarado
- Faculty of Medicine, Pontificia Universidad Catolica del Ecuador, Quito 170143, Pichincha, Ecuador
| | - Martina Astudillo
- Faculty of Medicine, Pontificia Universidad Catolica del Ecuador, Quito 170143, Pichincha, Ecuador
| | - Galo Pillajo
- Department of Radiology, Hospital de Especialidades Eugenio Espejo, Quito 170136, Pichincha, Ecuador
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Yang W, Yang Y, Wang H, Wang J, Zhang S. Clinical and genetic characterization of patients with late onset Wilson's disease. NPJ Genom Med 2024; 9:71. [PMID: 39719440 DOI: 10.1038/s41525-024-00459-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 12/17/2024] [Indexed: 12/26/2024] Open
Abstract
Wilson's disease (WD) typically manifests in children and young adults, with little knowledge of its late-onset forms. In this study, we performed a retrospective cohort study of 105 WD patients (99 index cases, 6 siblings) with an onset age ≥35 years. We compared 99 index late-onset patients with 1237 early-onset patients and analyzed the ATP7B variant penetrance referring to the Genome Aggregation Database (gnomAD). Sixty-two ATP7B variants were identified in the late-onset patients, among which A874V, V1106I, R919G, and T935M were correlated with late presentation of WD. Regarding gnomAD, V1106I and T935M exhibited significantly low penetrance, and there is a lack of patients carrying a genotype of V1106I/V1106I, R919G/R919G, T935M/T935M, V1106I/T935M, V1106I/R919G, or T935M/R919G. Our data revealed that patients carrying a combination of two late-onset variants may be overlooked due to atypical or lack of WD symptoms, which may provide valuable insights into the genetic basis and diagnosis of WD.
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Affiliation(s)
- Wenming Yang
- Department of Neurology, the First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Yue Yang
- Department of Neurology, the First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Han Wang
- Department of Neurology, the First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Jiuxiang Wang
- Experimental Center of Clinical Research, the First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Shijie Zhang
- Experimental Center of Clinical Research, the First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.
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Garbuz M, Ovchinnikova E, Ovchinnikova A, Vinokurova V, Aristarkhova Y, Kuziakova O, Mashurova M, Kumeiko V. Spectrum of Pathogenic Variants of the ATP7B Gene and Genotype-Phenotype Correlation in Eastern Eurasian Patient Cohorts with Wilson's Disease. Biomedicines 2024; 12:2833. [PMID: 39767741 PMCID: PMC11673475 DOI: 10.3390/biomedicines12122833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Revised: 12/06/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
Background/Objectives: Wilson's disease (WD) (OMIM 277900) or hepatolenticular degeneration is an autosomal recessive disorder caused by impaired copper excretion with subsequent accumulation in the liver, brain, and other tissues of the body. The defects in copper metabolism are based on various pathogenic variants of the ATP7B gene encoding copper-transporting P-type ATPase. The aim of this work is to search for pathogenic variants of the ATP7B gene among Eastern Eurasian patient cohorts and to pick correlations between pathogenic variants, gender, age of onset of the disease, and the course of the disease. Methods: The material for the study was the biomaterial of 100 people. The search for mutations was carried out by Sanger sequencing. Multiple alignment of nucleotide sequences and their analysis was performed using the MEGA-X software. To study the genotype-phenotypic correlation, an analysis of the medical records of each patient was carried out. Results: Most common pathogenic variant (48%) in the sample is p.His1069Gln (c.3207C>A), located in exon 14 of the ATP7B gene. Pathogenic variants of p.Glu1064Lys (c.3190G>A)-20%-and p.Met769HisfsTer26 (c.2304insC)-8%-of exons 14 and 8 were also common. For patients with pathogenic alleles p.His1069Gln (c.3207C>A) and p.Glu1064Lys (c.3190G>A), typical deviations are mental and neurological manifestations of WD. In patients with the pathogenic allele p.Met769HisfsTer26 (c.2304insC), deviations are more characteristic of the liver and a combination of various symptoms that are atypical for WD. Conclusions: In this study, we were able to obtain differences in symptoms in patients with different pathogenic alleles of the ATP7B gene.
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Affiliation(s)
- Mikhail Garbuz
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Elena Ovchinnikova
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Anna Ovchinnikova
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Valeriya Vinokurova
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Yulya Aristarkhova
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Olga Kuziakova
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Mariya Mashurova
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Vadim Kumeiko
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
- A.V. Zhirmunsky National Scientific Center of Marine Biology Far Eastern Branch of Russian Academy of Sciences, Vladivostok 690041, Russia
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Choi W, Cha S, Kim K. Navigating the CRISPR/Cas Landscape for Enhanced Diagnosis and Treatment of Wilson's Disease. Cells 2024; 13:1214. [PMID: 39056796 PMCID: PMC11274827 DOI: 10.3390/cells13141214] [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: 05/27/2024] [Revised: 07/15/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) system continues to evolve, thereby enabling more precise detection and repair of mutagenesis. The development of CRISPR/Cas-based diagnosis holds promise for high-throughput, cost-effective, and portable nucleic acid screening and genetic disease diagnosis. In addition, advancements in transportation strategies such as adeno-associated virus (AAV), lentiviral vectors, nanoparticles, and virus-like vectors (VLPs) offer synergistic insights for gene therapeutics in vivo. Wilson's disease (WD), a copper metabolism disorder, is primarily caused by mutations in the ATPase copper transporting beta (ATP7B) gene. The condition is associated with the accumulation of copper in the body, leading to irreversible damage to various organs, including the liver, nervous system, kidneys, and eyes. However, the heterogeneous nature and individualized presentation of physical and neurological symptoms in WD patients pose significant challenges to accurate diagnosis. Furthermore, patients must consume copper-chelating medication throughout their lifetime. Herein, we provide a detailed description of WD and review the application of novel CRISPR-based strategies for its diagnosis and treatment, along with the challenges that need to be overcome.
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Affiliation(s)
- Woong Choi
- Department of Physiology, Korea University College of Medicine, Seoul 02841, Republic of Korea;
| | - Seongkwang Cha
- Department of Physiology, Korea University College of Medicine, Seoul 02841, Republic of Korea;
- Neuroscience Research Institute, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Kyoungmi Kim
- Department of Physiology, Korea University College of Medicine, Seoul 02841, Republic of Korea;
- Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Republic of Korea
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Ovchinnikova EV, Garbuz MM, Ovchinnikova AA, Kumeiko VV. Epidemiology of Wilson's Disease and Pathogenic Variants of the ATP7B Gene Leading to Diversified Protein Disfunctions. Int J Mol Sci 2024; 25:2402. [PMID: 38397079 PMCID: PMC10889319 DOI: 10.3390/ijms25042402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 02/14/2024] [Accepted: 02/16/2024] [Indexed: 02/25/2024] Open
Abstract
Wilson's disease (WD) is an autosomal recessive disorder characterized by toxic accumulation of copper in the liver, brain, and other organs. The disease is caused by pathogenic variants in the ATP7B gene, which encodes a P-type copper transport ATPase. Diagnosing WD is associated with numerous difficulties due to the wide range of clinical manifestations and its unknown dependence on the physiological characteristics of the patient. This leads to a delay in the start of therapy and the subsequent deterioration of the patient's condition. However, in recent years, molecular genetic testing of patients using next generation sequencing (NGS) has been gaining popularity. This immediately affected the detection speed of WD. If, previously, the frequency of this disease was estimated at 1:35,000-45,000 people, now, when conducting large molecular genetic studies, the frequency is calculated as 1:7026 people. This certainly points to the problem of identifying WD patients. This review provides an update on the performance of epidemiological studies of WD and describes normal physiological functions of the protein and diversified disfunctions depending on pathogenic variants of the ATP7B gene. Future prospects in the development of WD genetic diagnostics are also discussed.
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Affiliation(s)
- Elena Vasilievna Ovchinnikova
- Institute of Life Sciences and Biomedicine, School of Natural Sciences, Far Eastern Federal University, Vladivostok 690922, Russia (M.M.G.)
| | - Mikhail Maksimovich Garbuz
- Institute of Life Sciences and Biomedicine, School of Natural Sciences, Far Eastern Federal University, Vladivostok 690922, Russia (M.M.G.)
| | - Anna Aleksandrovna Ovchinnikova
- Institute of Life Sciences and Biomedicine, School of Natural Sciences, Far Eastern Federal University, Vladivostok 690922, Russia (M.M.G.)
| | - Vadim Vladimirovich Kumeiko
- Institute of Life Sciences and Biomedicine, School of Natural Sciences, Far Eastern Federal University, Vladivostok 690922, Russia (M.M.G.)
- A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch of Russian Academy of Sciences, Federal University, Vladivostok 690041, Russia
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Gorukmez O, Özgür T, Gorukmez O, Topak A. ATP7B Gene Variant Profile İdentified by NGS in Wilson's Disease. Fetal Pediatr Pathol 2023; 42:891-900. [PMID: 37737146 DOI: 10.1080/15513815.2023.2260005] [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: 05/15/2023] [Accepted: 09/12/2023] [Indexed: 09/23/2023]
Abstract
Background: Wilson's disease (WD) is a copper metabolism disorder caused by ATP7B gene mutations and shows an autosomal recessive pattern of inheritance. We aimed to contribute to the mutation profile of ATP7B and show demographic and phenotypic differences in this study. Materials and methods: The clinical and demographic characteristics of patients who underwent ATP7B gene sequence analysis using next-generation sequencing were evaluated to improve genotype-phenotype correlation in WD. Results: An uncertain significance (D563N) and seven likely pathogenic (Y532D, Y715Y, T977K, K1028*, E1086K, A1227Pfs*103, and E1242K) variants were identified as associated with WD. Uniparental disomy was detected in one case. Conclusion: Our work expanded the ATP7B variant spectrum and pointed to clinical heterogeneity in ATP7B variants among patients with WD. All symptomatic patients had hepatic involvement and were clinically and/or genetically diagnosed with WD in the pediatric period. T977K, A1003V, H1069Q, E1086K, and N1270S variants were associated with hepatic failure.
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Affiliation(s)
- Orhan Gorukmez
- Department of Medical Genetics, Bursa Yüksek İhtisas Training and Research Hospital, Bursa, Turkey
| | - Taner Özgür
- Department Pediatric Gastroenterology and Hepatology, Uludağ University School of Medicine, Bursa, Turkey
| | - Ozlem Gorukmez
- Department of Medical Genetics, Bursa Yüksek İhtisas Training and Research Hospital, Bursa, Turkey
| | - Ali Topak
- Department of Medical Genetics, Bursa Yüksek İhtisas Training and Research Hospital, Bursa, Turkey
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Jagota P, Lim S, Pal PK, Lee J, Kukkle PL, Fujioka S, Shang H, Phokaewvarangkul O, Bhidayasiri R, Mohamed Ibrahim N, Ugawa Y, Aldaajani Z, Jeon B, Diesta C, Shambetova C, Lin C. Genetic Movement Disorders Commonly Seen in Asians. Mov Disord Clin Pract 2023; 10:878-895. [PMID: 37332644 PMCID: PMC10272919 DOI: 10.1002/mdc3.13737] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 02/27/2023] [Accepted: 03/21/2023] [Indexed: 11/21/2023] Open
Abstract
The increasing availability of molecular genetic testing has changed the landscape of both genetic research and clinical practice. Not only is the pace of discovery of novel disease-causing genes accelerating but also the phenotypic spectra associated with previously known genes are expanding. These advancements lead to the awareness that some genetic movement disorders may cluster in certain ethnic populations and genetic pleiotropy may result in unique clinical presentations in specific ethnic groups. Thus, the characteristics, genetics and risk factors of movement disorders may differ between populations. Recognition of a particular clinical phenotype, combined with information about the ethnic origin of patients could lead to early and correct diagnosis and assist the development of future personalized medicine for patients with these disorders. Here, the Movement Disorders in Asia Task Force sought to review genetic movement disorders that are commonly seen in Asia, including Wilson's disease, spinocerebellar ataxias (SCA) types 12, 31, and 36, Gerstmann-Sträussler-Scheinker disease, PLA2G6-related parkinsonism, adult-onset neuronal intranuclear inclusion disease (NIID), and paroxysmal kinesigenic dyskinesia. We also review common disorders seen worldwide with specific mutations or presentations that occur frequently in Asians.
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Affiliation(s)
- Priya Jagota
- Chulalongkorn Centre of Excellence for Parkinson's Disease and Related Disorders, Department of Medicine, Faculty of MedicineChulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross SocietyBangkokThailand
| | - Shen‐Yang Lim
- Division of Neurology, Department of Medicine, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
- The Mah Pooi Soo & Tan Chin Nam Centre for Parkinson's & Related Disorders, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
| | - Pramod Kumar Pal
- Department of NeurologyNational Institute of Mental Health & Neurosciences (NIMHANS)BengaluruIndia
| | - Jee‐Young Lee
- Department of NeurologySeoul Metropolitan Government‐Seoul National University Boramae Medical Center & Seoul National University College of MedicineSeoulRepublic of Korea
| | - Prashanth Lingappa Kukkle
- Center for Parkinson's Disease and Movement DisordersManipal HospitalBangaloreIndia
- Parkinson's Disease and Movement Disorders ClinicBangaloreIndia
| | - Shinsuke Fujioka
- Department of Neurology, Fukuoka University, Faculty of MedicineFukuokaJapan
| | - Huifang Shang
- Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare Diseases CenterWest China Hospital, Sichuan UniversityChengduChina
| | - Onanong Phokaewvarangkul
- Chulalongkorn Centre of Excellence for Parkinson's Disease and Related Disorders, Department of Medicine, Faculty of MedicineChulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross SocietyBangkokThailand
| | - Roongroj Bhidayasiri
- Chulalongkorn Centre of Excellence for Parkinson's Disease and Related Disorders, Department of Medicine, Faculty of MedicineChulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross SocietyBangkokThailand
- The Academy of Science, The Royal Society of ThailandBangkokThailand
| | - Norlinah Mohamed Ibrahim
- Neurology Unit, Department of Medicine, Faculty of MedicineUniversiti Kebangsaan MalaysiaKuala LumpurMalaysia
| | - Yoshikazu Ugawa
- Deprtment of Human Neurophysiology, Faculty of MedicineFukushima Medical UniversityFukushimaJapan
| | - Zakiyah Aldaajani
- Neurology Unit, King Fahad Military Medical ComplexDhahranSaudi Arabia
| | - Beomseok Jeon
- Department of NeurologySeoul National University College of MedicineSeoulRepublic of Korea
- Movement Disorder CenterSeoul National University HospitalSeoulRepublic of Korea
| | - Cid Diesta
- Section of Neurology, Department of NeuroscienceMakati Medical Center, NCRMakatiPhilippines
| | | | - Chin‐Hsien Lin
- Department of NeurologyNational Taiwan University HospitalTaipeiTaiwan
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Xue Z, Chen H, Yu L, Jiang P. A Systematic Review and Meta-Analysis of the R778L Mutation in ATP7B With Wilson Disease in China. Pediatr Neurol 2023; 145:135-147. [PMID: 37354629 DOI: 10.1016/j.pediatrneurol.2023.04.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 04/10/2023] [Accepted: 04/30/2023] [Indexed: 06/26/2023]
Abstract
BACKGROUND Wilson disease (WD) is a hereditary disorder of copper metabolism, caused by mutations in the ATP7B gene. There are more than 1000 pathogenic variants identified in ATP7B. R778L is the most common ATP7B mutation in China. METHODS To estimate whether R778L is associated with the onset age of WD and other clinical variables. Genotyping results of ATP7B gene were collected in our 22 patients with WD. We then conducted a systematic review and meta-analysis in databases, using the keywords Wilson disease and R778L mutation. RESULTS After the screening, a total of 23 studies were included, including 3007 patients with WD. Patients with R778L mutation presented at an earlier age (standardized mean difference [SMD] = -0.18 [95% confidence interval, -0.28 to 0.08], P = 0.0004) and had lower ceruloplasmin concentration (SMD = -0.21 [95% confidence interval, -0.40 to -0.02], P = 0.03) than the patients without the R778L mutation. However, sex (odds ratio [OR] = 1.07 [95% confidence interval, 0.89 to 1.29], P = 0.32) and first presentation were not associated with R778L mutation in WD (hepatic: OR = 1.37 [95% confidence interval, 0.87 to 2.16, P = 0.17; neurological: OR = 0.79 [95% confidence interval, 0.48 to 1.30, P = 0.35; mix: OR = 1.04 [95% confidence interval, 0.42 to 2.53, P = 0.87; asymptomatic/others: OR = 1.98 [95% confidence interval, 0.49 to 7.96, P = 0.34). CONCLUSIONS Our results indicated that the R778L mutation is associated with an earlier presentation and lower ceruloplasmin concentration in China.
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Affiliation(s)
- Ziru Xue
- Department of Neurology at The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| | - Hongyu Chen
- The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Regional Medical Center for Children, Hangzhou, Zhejiang, China
| | - Lan Yu
- The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Regional Medical Center for Children, Hangzhou, Zhejiang, China.
| | - Peifang Jiang
- Department of Neurology at The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China; The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Regional Medical Center for Children, Hangzhou, Zhejiang, China.
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Sipilä JO, Kytövuori L, Kaasinen V. Clinical spectrum and genotype-phenotype associations in Finnish patients with Wilson's disease. J Neurol Sci 2023; 448:120620. [PMID: 36966606 DOI: 10.1016/j.jns.2023.120620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 03/11/2023] [Accepted: 03/20/2023] [Indexed: 04/01/2023]
Abstract
Genotype-phenotype correlation data covering all ages of Wilson's disease onset in Caucasian patients are limited. We therefore analyzed genotype-phenotype correlations in a retrospective cohort of Finnish patients. Six homozygous (HoZ) and 11 compound heterozygous (CoHZ) patients were included. There were no differences in the presence/absence of hepatic, neurological, psychiatric or any symptoms at diagnosis (p > 0.30 for all) between HoZ and CoHZ patients, but HoZ patients had an earlier age of diagnosis (median 6.7 versus 34.5; p = 0.003). Severe liver affliction was almost exclusively associated with the p.H1069Q variant. Patients with p.H1069Q had a later mean age of diagnosis (30.2 ± 11.6 vs. 8.7 ± 4.9 years; p < 0.001) compared to those without. There were no differences in the presence/absence of hepatic, neurological, psychiatric or any symptoms at diagnosis between p.H1069Q-positive and p.H1069Q-negative patients (p > 0.54 for all). These results suggest that population-specific factors may partly explain the high clinical variability of Wilson's disease.
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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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Vörös K, Márkus B, Atzél K, Szalay F, Gráf L, Németh D, Masszi T, Torzsa P, Kalabay L. Serum fetuin-A is decreased in cirrhotic patients with Wilson's disease. PLoS One 2023; 18:e0282801. [PMID: 36881584 PMCID: PMC9990947 DOI: 10.1371/journal.pone.0282801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 02/23/2023] [Indexed: 03/08/2023] Open
Abstract
INTRODUCTION Wilson's disease may lead to cirrhosis, but timely medical treatment could slow down its progression. Clinical markers helping early diagnosis are essential. Decreased fetuin-A concentration has been reported in cirrhosis of different etiologies. The aim of this study was to investigate whether decreased serum fetuin-A concentration could identify patients with Wilson's disease who developed cirrhosis. MATERIALS AND METHODS In this cross-sectional study we determined the serum fetuin-A concentration of 50 patients with Wilson's disease. We analyzed the data of patients with liver involvement, comparing cirrhotic and non-cirrhotic patients. RESULTS Among patients with liver involvement those with cirrhosis had significantly lower fetuin-A and albumin level, white blood cell and platelet count. Fetuin-A negatively correlated with disease duration, bilirubin level, positively with total protein and albumin concentration, but not with copper and ceruloplasmin concentrations or markers of systemic inflammation. In multivariate analysis with fetuin-A and the Nazer score or its parameters only fetuin-A was a significant determinant of having cirrhosis. In receiver operator curve analysis among patients with liver involvement the fetuin-A level of 523 μg/ml was associated with cirrhosis with 82% sensitivity and 87% specificity. The presence of the H1069Q mutation was not associated with alteration in fetuin-A concentration. CONCLUSIONS The serum concentration of fetuin-A is a sensitive marker of liver cirrhosis in Wilson's disease, independently of the H1069Q mutation, ceruloplasmin concentration or systemic inflammation.
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Affiliation(s)
- Krisztián Vörös
- Department of Family Medicine, Semmelweis University, Budapest, Hungary
- * E-mail:
| | - Bernadett Márkus
- Department of Family Medicine, Semmelweis University, Budapest, Hungary
| | - Klára Atzél
- Department of Family Medicine, Semmelweis University, Budapest, Hungary
| | - Ferenc Szalay
- Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary
| | - László Gráf
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest, Hungary
| | - Dániel Németh
- Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary
| | - Tamás Masszi
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest, Hungary
| | - Péter Torzsa
- Department of Family Medicine, Semmelweis University, Budapest, Hungary
| | - László Kalabay
- Department of Family Medicine, Semmelweis University, Budapest, Hungary
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest, Hungary
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Garbuz MM, Ovchinnikova AA, Kumeiko VV. Design, Optimization and Validation of the ARMS PCR Protocol for the Rapid Diagnosis of Wilson's Disease Using a Panel of 14 Common Mutations for the European Population. Genes (Basel) 2022; 13:1940. [PMID: 36360177 PMCID: PMC9690040 DOI: 10.3390/genes13111940] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/17/2022] [Accepted: 10/20/2022] [Indexed: 08/15/2023] Open
Abstract
BACKGROUND Wilson's disease (WD) is an autosomal recessive inherited disorder of copper metabolism resulting from various mutations in the ATP7B gene. Despite good knowledge and successful treatment options, WD is a severe disease that leads to disability, destructively affecting the quality of life of patients. Currently, none of the available laboratory tests can be considered universal and specific for the diagnosis of WD. Therefore, the introduction of genetic diagnostic methods that allow for the identification of the root cause at any stage over the course of the disease gave hope for an earlier solution of diagnostic issues in patients with WD. METHODS A method for the genetic diagnosis of WD based on ARMS PCR, DreamTaq Green PCR Master Mix and modified primers has been developed. This method is able to detect 14 mutant alleles: p.His1069Gln, p.Glu1064Lys, p.Met769HisfsTer26, p.Gly710Ser, p.Ser744Pro, p.Ala1135GlnfsTer13, p.Arg778Leu, p.Arg1041Trp, p.Arg616Gln, p.Arg778Gly, p.Trp779*, p.Val834Asp, p.Gly943Ser and p.3222_3243+21del43. RESULTS The primers for all mutations were highly specific with an absence of wild-type amplification. All the results were validated by direct DNA Sanger sequencing. CONCLUSIONS This fast and economical method provides coverage for the identified common mutations, thereby making ARMS PCR analysis using DreamTaq Green PCR Master Mix and modified primers feasible and attractive for large-scale routine use.
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Affiliation(s)
| | | | - Vadim Vladimirovich Kumeiko
- Institute of Life Sciences and Biomedicine, Far Eastern Federal University, Vladivostok 690922, Russia
- A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch of Russian Academy of Sciences, Federal University, Vladivostok 690041, Russia
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13
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Mutational analysis of exon 8 and exon 14 of ATP7B gene in Bangladeshi children with Wilson disease. Indian J Gastroenterol 2022; 41:456-464. [PMID: 36308701 DOI: 10.1007/s12664-022-01276-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 06/25/2022] [Indexed: 02/04/2023]
Abstract
UNLABELLED BACKGROUND : Wilson disease (WD) is an autosomal recessive disorder caused by mutation in the Adenosine Triphosphate 7B (ATP7B) gene. The spectrum of ATP7B mutation varies in different populations. The objective of this study was to identify the mutation in exon 8 and exon 14 of ATP7B gene in Bangladeshi children clinically diagnosed as WD. We also aimed to explore the phenotypic presentation. METHODS It was a cross sectional observational study. The study was conducted at the Department of Paediatric Gastroenterology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from January 2017 to June 2018. A total of 37 patients diagnosed with WD were enrolled for the study. Venous blood (about 3 mL) was drawn aseptically from each patient into tube containing ethyline diamine tetraacetic acid (EDTA) and preserved at -30°C for long-term preservation. The peripheral blood leukocytes of the patients and genomic DNAs were extracted. Exons 14 and 8 of ATP7B and their associated splice-site junctions were amplified by the polymerase chain reaction (PCR). The size and quantity of PCR products were verified by electrophoresis in 1.5% (w/v) agarose gel. 74 (37 × 2) PCR products were sent for Sanger Sequencing. The sequences were analyzed by Chromas version 2.6.6 software and the nucleotide blast was done by National Center for Biotechnology Information (NCBI) nucleoblast. Finally, the sequences were analyzed using AB Applied Bio systems and were matched with the reference sequences using MEGA software. RESULTS In this study, a single novel homozygous mutation pLeu.1071Val in the exon 14 was found in every (100%) studied child clinically diagnosed with WD. Heterozygous mutation p.Gly1061Glu in exon14 was also found in 6 patients (11%) with WD, which is one of the common mutations in this disease. In exon 8, p.Arg778Leu mutation was detected in one patient (2.7%), which is common in the Chinese and the South Asian populations and was heterozygous. Two novel heterozygous missense mutations p.K785R (2.7%) and p.S744F (2.7%) were also found in two other children in the exon 8. CONCLUSION We found three novel mutations in Bangladeshi children with WD, one of which may be tagged as founder mutation for Bangladeshi population. This finding indicates the necessity to study the mutation profiles of the whole ATP7B gene in our population for risk prediction. A further large-scale study will help in the development of a Mutational Data Base of Bangladeshi population with WD.
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ATP7B Genotype and Chronic Liver Disease Treatment Outcomes in Wilson Disease: Worse Survival With Loss-of-Function Variants. Clin Gastroenterol Hepatol 2022; 21:1323-1329.e4. [PMID: 36096368 DOI: 10.1016/j.cgh.2022.08.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 08/22/2022] [Accepted: 08/27/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Although a good genotype-phenotype correlation has not been established in Wilson disease (WD), patients with loss-of-function (LOF) ATP7B variants demonstrate different clinical and biochemical characteristics. We aim to describe long-term treatment outcomes in the chronic liver disease (CLD) phenotype and evaluate an association with LOF variants. METHODS This was a single-center retrospective review of WD patients with at least 1 variant in ATP7B. Demographic, biochemical, genetic, and clinical parameters were obtained. The composite clinical endpoint of liver transplantation or death was used for probands with CLD phenotype on chelators. RESULTS Of 117 patients with hepatic WD: 71 had CLD, 27 had fulminant hepatic failure requiring urgent liver transplantation, and 19 were diagnosed through family screening. Median age at diagnosis was 13.1 (interquartile range, 9.7-17.6) years. In total, 91 variants in ATP7B were identified in the study population. At least 1 LOF variant was present in 60 (51.3%) patients. During median follow-up of 10.7 (interquartile range, 6.7-18.9) years, 10 (14.1%) of the probands with CLD reached the composite endpoint. There was a worse transplant-free survival for patients prescribed chelation therapy in patients with at least 1 LOF variant (P = .03). CONCLUSIONS Patients with WD and CLD phenotype on chelators, who have at least 1 LOF variant in ATP7B, have a worse prognosis during long-term follow up. This subgroup of patients requires close monitoring for signs of progressive liver disease. Sequencing of ATP7B may be used in the diagnosis of WD, and in addition, it may provide useful prognostic information for patients with hepatic WD.
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15
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Multicentre, retrospective study to assess long-term outcomes of chelator based treatment with trientine in Wilson disease patients withdrawn from therapy with d -penicillamine. Eur J Gastroenterol Hepatol 2022; 34:940-947. [PMID: 35482910 DOI: 10.1097/meg.0000000000002387] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Trientine dihydrochloride (TETA-2HCl) has been used for the treatment of Wilson disease for over 30 years. The current study was designed to systematically evaluate existing data to further define the long-term outcome of the efficacy and tolerability of TETA-2HCl in Wilson disease patients. METHODS Medical records of 77 Wilson disease patients were reviewed to collect data on hepatic and neurologic symptoms, copper (Cu) homeostasis and adverse events. Data were collected for 48 months after initiation of TETA-2HCl after withdrawal of D-penicillamine treatment. RESULTS Mean duration of TETA-2HCl treatment was 8 years (range 5 months-32.5 years). Over the course of TETA-2HCl treatment, 35% of patients had no hepatic symptoms whereas in 49.4% of patients, hepatic symptoms improved. They remained unchanged in 10.4% of patients and worsened in 5.2% of patients. No patients progressed to acute hepatic failure or necessity of a liver transplant. During TETA-2HCl treatment, 46.7% of patients had no neurologic symptoms; in 14.3% of patients, neurologic symptoms improved whereas in 36.4% of patients, they remained stable and worsened in 2.6% of patients. During the evaluation period, 12 patients discontinued TETA-2HCl treatment due to: anemia ( N = 1), inadequate hepatic response ( N = 2), switch to zinc treatment ( N = 8) and patient's decision to withdraw from treatment ( N = 1). Treatment-emergent adverse events were reported by 24.7% of the patients of which gastrointestinal disorders (9.1%) and nervous system disorders (5.2%) were most reported. CONCLUSIONS TETA-2HCl is well-tolerated and effective in Wilson disease patients following the withdrawal of treatment with D-penicillamine. ClinicalTrials.govIdentifier : NCT02426905.
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Clinical and genetic characterization of a large cohort of patients with Wilson’s disease in China. Transl Neurodegener 2022; 11:13. [PMID: 35220961 PMCID: PMC8883683 DOI: 10.1186/s40035-022-00287-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 02/03/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism caused by ATP7B (encoding a copper-transporting P-type ATPase) variants that shows various characteristics according to race and geographical region. This study was aimed to provide a comprehensive analysis of ATP7B variants in China and to investigate a plausible role of common variants in WD manifestations.
Methods
A total of 1366 patients (1302 index patients and 64 siblings) clinically diagnosed with WD (Leipzig score ≥ 4) were recruited. They underwent ATP7B gene sequencing and information of age and symptoms at onset was collected. The genotype–phenotype correlation was assessed in the index patients who were examined with two pathogenic variants and onset with hepatic (n = 276) or neurologic (n = 665) symptoms.
Results
We identified 294 potentially pathogenic ATP7B variants (112 truncating, 174 missense, 8 in-frame) in the 1302 index patients, including 116 novel variants. The most frequent variant was c.2333G>T (R778L, allele frequency: 28.96%), followed by c.2975C>T (P992L, 13.82%), c.2621C>T (A874V, 5.99%), c.2755C>G (R919G, 2.46%), and c.3646G>A (V1216M, 1.92%). In 1167 patients, both pathogentic variants were identified, of which 532 different variant combinations were found. By binary logistic regression analysis, the factor associated with neurological presentation was high age-at-onset, but not sex, protein-truncating variant (PTV), or the common missense variants (R778L, P992L, and A874V). In the neurological group, low age-at-onset was a factor associated with dystonia, gait abnormality, and salivation; high age-at-onset was a factor associated with tremor; and the sex, low age-at-onset and A874V were independent factors associated with dysarthria. In addition, PTV, R778L, and P992L were predominant in early-onset patients, whereas A874V was predominant in late-onset patients, and patients with R778L/A874V genotype displayed a higher age-at-onset than patients with R778L/R778L or R778L/P992L genotype.
Conclusions
Our work expanded the ATP7B variant spectrum and highlighted the differences among patients with WD in age-at-onset and ATP7B variants, which may provide some valuable insights into the diagnosis, counseling, and treatment of patients with WD.
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Wenbin Z, Yeqing H, Aiqun L, Mingfan H, Zhisheng W. A rare giant intracranial arachnoid cyst confused the diagnosis and treatment of Wilson disease. Transl Neurosci 2022; 13:52-56. [PMID: 35350656 PMCID: PMC8919839 DOI: 10.1515/tnsci-2022-0213] [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: 12/21/2021] [Revised: 02/12/2022] [Accepted: 02/14/2022] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Hepatolenticular degeneration (HLD), also known as Wilson disease (WD), is a rare autosomal-recessive hereditary disease, which is often missed and misdiagnosed because of its various clinical manifestations. And WD is even more rare with giant subarachnoid cysts. In this report, we will provide a case of WD with an intracranial arachnoid cyst (IAC). CASE DESCRIPTION A 27-year-old woman was hospitalized in a traditional Chinese medicine hospital in Guangzhou with the first manifestation of a "slight involuntary tremor of her left upper limb". There was no improvement after acupuncture treatment, and then she was transferred to another large general hospital in Guangzhou. MRI examination of the head showed "left frontal, parietal and temporal giant subarachnoid cyst" and the patient underwent "left frontotemporal arachnoid cyst celiac shunt operation." After the operation, the patient's left limb shaking remained unchanged. Subsequently, the patient was referred to another big hospital in Guangzhou, considered "Parkinson's disease," and given "Medopa, Antan" and other treatments. However, the patient's limb shaking continued to increase and gradually developed to the extremities. At last, the patient was referred to our hospital, combined with the medical history, neurological signs, and auxiliary examination results, improve the examination of corneal K-F ring, blood ceruloplasmin, gene screening, and other tests; the diagnosis was confirmed as hepatolenticular degeneration. CONCLUSION After expelling copper and symptomatic treatment, the condition is improved.
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Affiliation(s)
- Zhang Wenbin
- Department of Neurology, School of Clinical Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, 19 Nonglinxia Road, Guangzhou, 510080, China
| | - Huang Yeqing
- Department of Neurology, School of Clinical Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, 19 Nonglinxia Road, Guangzhou, 510080, China
| | - Liu Aiqun
- Department of Neurology, School of Clinical Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, 19 Nonglinxia Road, Guangzhou, 510080, China
| | - Hong Mingfan
- Department of Neurology, School of Clinical Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, 19 Nonglinxia Road, Guangzhou, 510080, China
| | - Wei Zhisheng
- Department of Neurology, School of Clinical Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, 19 Nonglinxia Road, Guangzhou, 510080, China
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Khan MQ, Chin JYL, Azhari H, Rosen CB, Leise MD. Pseudo-Wilsonian Crisis in a ATP7B Heterozygote. Liver Transpl 2022; 28:131-133. [PMID: 34388305 DOI: 10.1002/lt.26263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 07/16/2021] [Accepted: 08/06/2021] [Indexed: 01/13/2023]
Affiliation(s)
| | | | - Hassan Azhari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Charles B Rosen
- Division of Transplantation Surgery, Mayo Clinic, Rochester, MN
| | - Michael D Leise
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
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Couchonnal E, Bouchard S, Sandahl TD, Pagan C, Lion-François L, Guillaud O, Habes D, Debray D, Lamireau T, Broué P, Fabre A, Vanlemmens C, Sobesky R, Gottrand F, Bridoux-Henno L, Belmalih A, Poujois A, Brunet AS, Lachaux A, Bost M. ATP7B variant spectrum in a French pediatric Wilson disease cohort. Eur J Med Genet 2021; 64:104305. [PMID: 34400371 DOI: 10.1016/j.ejmg.2021.104305] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 06/12/2021] [Accepted: 08/12/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND/AIM The spectrum of ATP7B variants varies significantly according to geographic distribution, and there is insufficient data on the variants observed in the French population. METHODS Clinical data of 113 children included in the French WD national registry were gathered from March 01, 1995 to July 01, 2020. Data included epidemiological, clinical, laboratory, genetics. RESULTS Diagnosis was made at a mean age of 11.0 ± 4.1 years (range 1-18 years). At diagnosis, 91 patients (79.8 %) had hepatic manifestations, 18 (15.8 %) presented neurological manifestations, and 4 patients (3.5 %) were asymptomatic. Only 29 patients (25 %) were homozygous for a variant. We have found a total of 102 different variants including 14 novel variants. Recurrent variant p.His1069Gln was the most prevalent, n = 31 alleles (14,2%), with only seven homozygous; in contrast 55% of variants are identified in only one family. 45% were truncating variants. In respect of mutated exon, the three most prevalent were exon 14 (16.5%), exon 8 (13.8%), and exon 3 (11.5%). When considering patients with two Nonsense / Frameshift variants as a group and those with two Missense variants, we found significantly lower ceruloplasmin for the former: 2.8 ± 0.7 mg/dl vs 8.4 ± 5mg/dl (p<0.05). CONCLUSION p.His1069Gln is the most frequent variant (14,2%) and exons 14, 8, and 2 of the ATP7B gene account for 41.7% of total variants. However, there is significant heterogeneity in the French population concerning the other ATP7B variants. Nonsense / Frameshift variants were associated with lower ceruloplasmin levels.
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Affiliation(s)
- Eduardo Couchonnal
- Hospices Civils de Lyon. National Center for Wilson's Disease and Department of Pediatric Gastroenterology, Hepatology and Nutrition Children's Hospital of Lyon, France; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany.
| | | | - Thomas Damgaard Sandahl
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany; Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark
| | - Cecile Pagan
- Department of Biochemistry and Molecular Biology, LBMMS, Hospices Civils de Lyon, France
| | - Laurence Lion-François
- Hospices Civils de Lyon. National Center for Wilson's Disease and Department of Pediatric Gastroenterology, Hepatology and Nutrition Children's Hospital of Lyon, France; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany
| | - Olivier Guillaud
- Hospices Civils de Lyon. National Center for Wilson's Disease and Department of Pediatric Gastroenterology, Hepatology and Nutrition Children's Hospital of Lyon, France; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany
| | - Dalila Habes
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany; Pediatric Hepatology and Liver Transplantation Unit, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, Bicêtre Hospital, Assistance Publique - Hôpitaux de Paris, Le Kremlin-Bicêtre, France
| | - Dominique Debray
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany; Inserm U1193, Hepatinov, University of Paris Saclay, Orsay, France
| | - Thierry Lamireau
- Children's Hospital, Paediatric Gastroenterology Unit, Bordeaux, France
| | - Pierre Broué
- Children University Hospital, Metabolic Disease Department, Toulouse, France
| | - Alexandre Fabre
- APH, Timone Enfant, Service de Pédiatrie Multidisciplinaire, Marseille, France; Aix Marseille Univ, INSERM, MMG, Marseille, France
| | - Claire Vanlemmens
- University Hospital of Besancon, Paediatric Gastroenterology Unit, Besacon, France
| | - Rodolphe Sobesky
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany; Paul Brousse Hospital, Hepatobiliary Centre, Hepatobiliary Centre, France
| | - Frederic Gottrand
- Univ- Lille, CHU Lille, UMR1286 Department of Pediatric Gastroenterology Hepatology and Nutrition, Lille, France
| | | | - Abdelouahed Belmalih
- Hospices Civils de Lyon. National Center for Wilson's Disease and Department of Pediatric Gastroenterology, Hepatology and Nutrition Children's Hospital of Lyon, France; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany
| | - Aurelia Poujois
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany; French National Rare Disease Reference Centre "Wilson's Disease and Other Copper-related Rare Diseases", Rothschild Foundation Hospital, Neurology Department, Paris, France
| | - Anne Sophie Brunet
- Hospices Civils de Lyon. National Center for Wilson's Disease and Department of Pediatric Gastroenterology, Hepatology and Nutrition Children's Hospital of Lyon, France
| | - Alain Lachaux
- Hospices Civils de Lyon. National Center for Wilson's Disease and Department of Pediatric Gastroenterology, Hepatology and Nutrition Children's Hospital of Lyon, France; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany; Claude Bernard Lyon 1 University Lyon, France
| | - Muriel Bost
- Hospices Civils de Lyon. National Center for Wilson's Disease and Department of Pediatric Gastroenterology, Hepatology and Nutrition Children's Hospital of Lyon, France; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany; Department of Biochemistry and Molecular Biology, LBMMS, Hospices Civils de Lyon, France
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Zou J, Wang YH, Wang L, Chen RC. Liver Failure of Wilson's Disease With Manifestations Similar to Porphyria and Uncommon ATP7B Gene Mutation: A Case Report and Literature Review. Front Med (Lausanne) 2021; 8:702312. [PMID: 34381801 PMCID: PMC8350053 DOI: 10.3389/fmed.2021.702312] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 06/28/2021] [Indexed: 11/17/2022] Open
Abstract
Background: Wilson's disease (WD) is a rare condition; its diagnosis is challenging owing to a wide spectrum of ATP7B genotypes and variable clinical phenotypes, along with environmental factors. Few cases of WD with presentation of skin lesions and acute neurovisceral symptoms have been reported in the literature. To our knowledge, this is the first reported case of WD with an uncommon ATP7B gene mutation and rare symptoms of photosensitivity, sensation abnormality, and skin eruption occurring in a 19-year-old woman. Case presentation: We report the case of a 19-year-old woman with WD presenting with liver failure, skin manifestations, and acute neurovisceral symptoms.The rare mutation in intron 1 of ATP7B (c.51+2T > G) was further confirmed by gene sequencing. The patients' symptoms improved after administration of penicillamine and zinc therapy combined with plasma exchange. She received long-term penicillamine treatment, and her liver function was within the normal range at 1 year after discharge. However, she underwent liver transplantation at 1.5 years after discharge. Conclusions: We present a case of WD with a novel ATP7B gene mutation that may serve as a reference to generalists and specialists in hepatology or neurology of the rare clinical characteristics of WD, to prevent misdiagnosis and aid in the early diagnosis and treatment of the condition.
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Affiliation(s)
- Ju Zou
- Department of Infectious Disease, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, China
| | - Ying-Hao Wang
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ling Wang
- Department of Infectious Disease, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, China
| | - Ruo-Chan Chen
- Department of Infectious Disease, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, China
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21
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Investigation of the Wilson gene ATP7B transcriptional start site and the effect of core promoter alterations. Sci Rep 2021; 11:7674. [PMID: 33828154 PMCID: PMC8027023 DOI: 10.1038/s41598-021-87000-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 03/22/2021] [Indexed: 02/01/2023] Open
Abstract
Pathogenic genetic variants in the ATP7B gene cause Wilson disease, a recessive disorder of copper metabolism showing a significant variability in clinical phenotype. Promoter mutations have been rarely reported, and controversial data exist on the site of transcription initiation (the core promoter). We quantitatively investigated transcription initiation and found it to be located in immediate proximity of the translational start. The effects human single-nucleotide alterations of conserved bases in the core promoter on transcriptional activity were moderate, explaining why clearly pathogenic mutations within the core promoter have not been reported. Furthermore, the core promoter contains two frequent polymorphisms (rs148013251 and rs2277448) that could contribute to phenotypical variability in Wilson disease patients with incompletely inactivating mutations. However, neither polymorphism significantly modulated ATP7B expression in vitro, nor were copper household parameters in healthy probands affected. In summary, the investigations allowed to determine the biologically relevant site of ATP7B transcription initiation and demonstrated that genetic variations in this site, although being the focus of transcriptional activity, do not contribute significantly to Wilson disease pathogenesis.
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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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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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Zhang S, Li L, Wang J. Wilson disease patient with rare heterozygous mutations in ATP7B accompanied by distinctive nocturnal enuresis: A case report. Medicine (Baltimore) 2020; 99:e20997. [PMID: 32664103 PMCID: PMC7360279 DOI: 10.1097/md.0000000000020997] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
INTRODUCTION Wilson disease (WD) is an autosomal-recessive disorder of copper metabolism, which exhibits various symptoms due to the combination of environmental and genetic factors. Here, we report a WD patient who displayed distinctive symptom of nocturnal enuresis. PATIENT CONCERNS The patient was a 31-year old woman, who recently developed nocturnal enuresis, combined with hand tremors, trouble speaking, and panic disorder at night. DIAGNOSIS The patient had been diagnosed with WD by Kayser-Fleischer rings, abnormal copper metabolism, neuropsychiatric symptoms, and magnetic resonance imaging when she was 17. The diagnosis was further confirmed by genetic analysis, which revealed a compound heterozygous mutations in ATP7B gene (c.2195T>C and c.3044T>C). The patient exhibited nocturnal enuresis, but the ambulatory electroencephalogram, routine urinalysis, residual urine detection, color doppler ultrasound of kidney, ureter, and bladder all displayed no abnormality. INTERVENTIONS The patient was treated with sodium dimercaptosulphonate, supplemented with Glutathione and Encephalin-inosine. OUTCOMES The urinary copper excretion level decreased gradually, and the nocturnal enuresis was alleviated along with the neuropsychiatric symptoms by copper chelation therapy. CONCLUSION In this study, we proved that variants c.2195T>C and c.3044T>C is involved in pathogenesis of WD, and revealed that nocturnal enuresis may be a symptom of WD.
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Affiliation(s)
| | - Liangyong Li
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China
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Zhu Q, Zhu K, Wang J, Bian W, Lu J. Relationship between genetic mutations and clinical phenotypes in patients with Wilson disease. Medicine (Baltimore) 2019; 98:e18284. [PMID: 31804371 PMCID: PMC6919422 DOI: 10.1097/md.0000000000018284] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 09/24/2019] [Accepted: 10/06/2019] [Indexed: 11/26/2022] Open
Abstract
To study the relationship between genotype and clinical phenotype of major gene mutation sites in patients with Wilson disease (WD).Clinical and laboratory data were collected from 40 children with WD admitted to the hospital by high-pass sequencing. The basic clinical data of patients included the following: age, sex, first symptom, K-F ring, clinical classification, serum Ceruloplasmin (CP), 24 hours urine copper. High Frequency Mutations were identified in WD patients: Exon 8, Ar9778Leu, and study the relationship between high frequency mutation and clinical phenotype.The mutation frequency of 2333G>T(Arg778Leu) in Exon 8 was the highest (48%). The mutation frequency of Exon 13 at 2975C>T site was 29%. The age (t = 0.296, P = .768), sex (χ = 0.005, P = .944), first symptom (χ = 0.480, P = .449), K-F ring (χ = 0.321, P = .17), clinical classification (χ = 20.064, P > .969), serum CP levels (t = 0.007, P = .897) had no significant difference between Arg778Leu mutation group and non-Arg778Leu mutation group. Twenty-four-hour urinary copper levels (t = 12.134, P < .001,) in the Arg778Leu mutation group were higher than those in the Arg778Leu mutation group.Arg778Leu mutation is associated with 24 hours urinary copper. The study of the association between the type of gene mutation and the clinical phenotype has important implications for the occurrence regularity, pathogenesis, and disease progression in patients with WD.
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Affiliation(s)
- Qingwen Zhu
- Department of Prenatal screening and diagnosis center, Affiliated Maternity and Child Health Care Hospital of Nantong University, Nantong
| | - Keyu Zhu
- Department of Key Project of Gynecology, The Secondary Affiliated Hospital of Soochow University Orthopedics, Suzhou
| | - Jing Wang
- Department of Prenatal screening and diagnosis center, Affiliated Maternity and Child Health Care Hospital of Nantong University, Nantong
| | - Wenjun Bian
- Department of Prenatal screening and diagnosis center, Affiliated Maternity and Child Health Care Hospital of Nantong University, Nantong
| | - Jianxun Lu
- Department of Internal Medicine, The third people's Hospital of Nantong, Nantong, Jiangsu, China
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Genetic analysis of ATP7B in 102 south Indian families with Wilson disease. PLoS One 2019; 14:e0215779. [PMID: 31059521 PMCID: PMC6502322 DOI: 10.1371/journal.pone.0215779] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 04/08/2019] [Indexed: 01/02/2023] Open
Abstract
Wilson disease (WD) is an autosomal recessive disorder, characterized by excessive deposition of copper in various parts of the body, mainly in the liver and brain. It is caused by mutations in ATP7B. We report here the genetic analysis of 102 WD families from a south Indian population. Thirty-six different ATP7B mutations, including 13 novel ones [p.Ala58fs*19, p.Lys74fs*9, p.Gln281*, p.Pro350fs*12, p.Ser481*, p.Leu735Arg, p.Val752Gly, p.Asn812fs*2, p.Val845Ala, p.His889Pro, p.Ile1184fs*1, p.Val1307Glu and p.Ala1339Pro], were identified in 76/102 families. Interestingly, the mutation analysis of affected individuals in two families identified two different homozygous mutations in each family, and thus each affected individual from these families harbored two mutations in each ATP7B allele. Of 36 mutations, 28 were missense, thus making them the most prevalent mutations identified in the present study. Nonsense, insertion and deletion represented 3/36, 2/36 and 3/36 mutations, respectively. The haplotype analysis suggested founder effects for all the 14 recurrent mutations. Our study thus expands the mutational landscape of ATP7B with a total number of 758 mutations. The mutations identified during the present study will facilitate carrier and pre-symptomatic detection, and prenatal genetic diagnosis in affected families.
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Ferenci P, Stremmel W, Członkowska A, Szalay F, Viveiros A, Stättermayer AF, Bruha R, Houwen R, Pop TL, Stauber R, Gschwantler M, Pfeiffenberger J, Yurdaydin C, Aigner E, Steindl-Munda P, Dienes HP, Zoller H, Weiss KH. Age and Sex but Not ATP7B Genotype Effectively Influence the Clinical Phenotype of Wilson Disease. Hepatology 2019; 69:1464-1476. [PMID: 30232804 DOI: 10.1002/hep.30280] [Citation(s) in RCA: 105] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 09/12/2018] [Indexed: 02/05/2023]
Abstract
Wilson disease (WD) is an inherited disorder of hepatic copper metabolism with considerable variation in clinical presentations, the most common ones being liver disease and neuropsychiatric disturbances. This study investigated the clinical presentation in relation to mutations in a large cohort of patients with WD. A total of 1,357 patients (702 children, 655 adults; 1,172 index patients, 185 siblings, all with a Leipzig score ≥4, male/female: 679/678) were studied. The age and the symptoms at presentation were used as key phenotypic markers. Index patients were clinically classified as having either hepatic (n = 711) or neurologic disease (n = 461). Seven hundred fifteen (52.7%) patients had a liver biopsy at diagnosis. DNA was sequenced by the Genetic Analyzers ABI Prism 310 (Perkin Elmer) or 3500 (Applied Biosystems). Three hundred ninety-four different mutation combinations were detected. The most frequent mutation was H1069Q (c.3207C>A; allele frequency: 46.9%), followed by P767P-fs (c.2304dupC; 2.85%), P1134P-fs (c.3402delC; 2.8%), and R969Q (c.2755C>T; 2.18%). There was no correlation between mutations and individual clinical manifestation. There was a gender effect in index patients: Hepatic presentation was more common in females (male/female: 328/383) and neurologic presentation in males (259/202; P < 0.001). At diagnosis, 39.5% of children/adolescents (≤18 years) and 58% of adults already had cirrhosis. The presence of cirrhosis did not correlate with the genotype. Conclusion: These findings refine and extend our understanding of the natural history and individual spectrum/manifestations of WD. Initially, there is asymptomatic hepatic involvement, which may progress and become symptomatic. Neurologic symptoms present many years later.
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Affiliation(s)
- Peter Ferenci
- Department of Internal Medicine III, Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Wolfgang Stremmel
- Department of Internal Medicine IV, Medical University of Heidelberg, Heidelberg, Germany
| | - Anna Członkowska
- Second Department of Neurology, Institute of Psychiatry and Neurology, and Department of Pharmacology, Medical University of Warsaw, Poland
| | - Ferenc Szalay
- First Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - André Viveiros
- First Department of Internal Medicine, Medical University Innsbruck, Austria
| | | | - Radan Bruha
- Fourth Medical Department, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Roderick Houwen
- Wilhelmina Children's Hospital, University Medical Center Utrecht, the Netherlands
| | - Tudor Lucian Pop
- Second Pediatric Clinic, University of Medicine and Pharmacy "Iuliu Hatieganu" Cluj-Napoca, Romania
| | - Rudolf Stauber
- Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | | | - Jan Pfeiffenberger
- Department of Internal Medicine IV, Medical University of Heidelberg, Heidelberg, Germany
| | - Cihan Yurdaydin
- Department of Gastroenterology and Hepatology, Ankara University Medical School, Ankara, Turkey
| | - Elmar Aigner
- Department of Internal Medicine I, Paracelsus Medical University, Salzburg, Austria
| | - Petra Steindl-Munda
- Department of Internal Medicine III, Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Hans-Peter Dienes
- Department of Clinical Pathology, Medical University of Vienna, Austria
| | - Heinz Zoller
- First Department of Internal Medicine, Medical University Innsbruck, Austria
| | - Karl Heinz Weiss
- Department of Internal Medicine IV, Medical University of Heidelberg, Heidelberg, Germany
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Medici V, LaSalle JM. Genetics and epigenetic factors of Wilson disease. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:S58. [PMID: 31179295 PMCID: PMC6531661 DOI: 10.21037/atm.2019.01.67] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 01/25/2019] [Indexed: 12/13/2022]
Abstract
Wilson disease (WD) is a complex condition due to copper accumulation mainly in the liver and brain. The genetic base of WD is represented by pathogenic mutations of the copper-transporting gene ATP7B with consequent lack of copper excretion through the biliary tract. ATP7B is the only gene so far identified and known to be responsible for the development of the disease. Our understanding of the disease has been evolving as functional studies have associated specific disease-causing mutations with specific copper-transporter impairments. The most frequent variant in patients of European descent is the H1069Q missense mutation and it has been associated with protein misfolding, aberrant phosphorylation of the P-domain, and altered ATP binding orientation and affinity. Conversely, there is much less understanding of the relation between the genotype and the clinical manifestations of WD. WD is characterized by a highly varied and unpredictable presentation with different combined hepatic, neurological, and psychiatric symptoms. Several studies have attempted to correlate genotype and phenotype but the most recent evidences on larger populations failed to identify a relation between genotype and clinical presentations. Given that so far also modifier genes have not shown convincing association with WD, there is growing interest to identify epigenetic mechanisms of gene expression regulation as underlying the onset and progression of WD phenotype. Evidence from animal models indicated changes in methionine metabolism regulation with possible effects on DNA methylation. Mouse models of WD have indicated transcript level changes of genes related to DNA methylation in fetal and adult livers. And finally, evidence is accumulating regarding DNA methylation changes in patients with WD. It is unexplored how ATP7B genetic mutations combine with epigenetic changes to affect the phenotype. In conclusion, WD is a genetic disease with a complex regulation of its phenotype that includes molecular genetics and epigenetic mechanisms.
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Affiliation(s)
- Valentina Medici
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, California, USA
| | - Janine M. LaSalle
- Department of Medical Microbiology and Immunology, University of California Davis, Sacramento, California, 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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Parisi S, Polishchuk EV, Allocca S, Ciano M, Musto A, Gallo M, Perone L, Ranucci G, Iorio R, Polishchuk RS, Bonatti S. Characterization of the most frequent ATP7B mutation causing Wilson disease in hepatocytes from patient induced pluripotent stem cells. Sci Rep 2018; 8:6247. [PMID: 29674751 PMCID: PMC5908878 DOI: 10.1038/s41598-018-24717-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 04/09/2018] [Indexed: 12/27/2022] Open
Abstract
H1069Q substitution represents the most frequent mutation of the copper transporter ATP7B causing Wilson disease in Caucasian population. ATP7B localizes to the Golgi complex in hepatocytes but moves in response to copper overload to the endo-lysosomal compartment to support copper excretion via bile canaliculi. In heterologous or hepatoma-derived cell lines, overexpressed ATP7B-H1069Q is strongly retained in the ER and fails to move to the post-Golgi sites, resulting in toxic copper accumulation. However, this pathogenic mechanism has never been tested in patients’ hepatocytes, while animal models recapitulating this form of WD are still lacking. To reach this goal, we have reprogrammed skin fibroblasts of homozygous ATP7B-H1069Q patients into induced pluripotent stem cells and differentiated them into hepatocyte-like cells. Surprisingly, in HLCs we found one third of ATP7B-H1069Q localized in the Golgi complex and able to move to the endo-lysosomal compartment upon copper stimulation. However, despite normal mRNA levels, the expression of the mutant protein was only 20% compared to the control because of endoplasmic reticulum-associated degradation. These results pinpoint rapid degradation as the major cause for loss of ATP7B function in H1069Q patients, and thus as the primary target for designing therapeutic strategies to rescue ATP7B-H1069Q function.
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Affiliation(s)
- Silvia Parisi
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
| | | | - Simona Allocca
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Michela Ciano
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Anna Musto
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Maria Gallo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Lucia Perone
- Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
| | - Giusy Ranucci
- Department of Translational Medical Science, Section of Pediatric, University of Naples Federico II, Naples, Italy
| | - Raffaele Iorio
- Department of Translational Medical Science, Section of Pediatric, University of Naples Federico II, Naples, Italy
| | | | - Stefano Bonatti
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
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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: 34] [Impact Index Per Article: 4.9] [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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Abstract
Trace elements are chemical elements needed in minute amounts for normal physiology. Some of the physiologically relevant trace elements include iodine, copper, iron, manganese, zinc, selenium, cobalt and molybdenum. Of these, some are metals, and in particular, transition metals. The different electron shells of an atom carry different energy levels, with those closest to the nucleus being lowest in energy. The number of electrons in the outermost shell determines the reactivity of such an atom. The electron shells are divided in sub-shells, and in particular the third shell has s, p and d sub-shells. Transition metals are strictly defined as elements whose atom has an incomplete d sub-shell. This incomplete d sub-shell makes them prone to chemical reactions, particularly redox reactions. Transition metals of biologic importance include copper, iron, manganese, cobalt and molybdenum. Zinc is not a transition metal, since it has a complete d sub-shell. Selenium, on the other hand, is strictly speaking a nonmetal, although given its chemical properties between those of metals and nonmetals, it is sometimes considered a metalloid. In this review, we summarize the current knowledge on the inborn errors of metal and metalloid metabolism.
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Affiliation(s)
- Carlos R. Ferreira
- Division of Genetics and Metabolism, Children’s National Health System, Washington, DC, USA
- Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
- Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA
| | - William A. Gahl
- Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA
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Kathawala M, Hirschfield GM. Insights into the management of Wilson's disease. Therap Adv Gastroenterol 2017; 10:889-905. [PMID: 29147139 PMCID: PMC5673017 DOI: 10.1177/1756283x17731520] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 08/08/2017] [Indexed: 02/04/2023] Open
Abstract
Wilson's disease is a rare, inherited autosomal recessive disease of copper metabolism, in which the causative gene, ATP7B, results in absent or reduced function of the ATP7B transporter important for biliary excretion of copper and incorporation of copper into caeruloplasmin. Affected patients accumulate excessive copper within the liver, brain and other tissues. A disease mainly of children, adolescents and young adults; clinical features vary from the asymptomatic state to chronic liver disease, acute liver failure, and neuropsychiatric manifestations. Diagnosis requires a high index of suspicion and is based on a combination of clinical signs, biochemical tests, hepatic copper content assay and mutation analysis of the ATP7B gene; to date, there are more than 500 mutations of ATP7B in patients with Wilson's disease. Early recognition and treatment can result in an excellent prognosis whereas untreated disease is almost always fatal. Drug therapies include chelating agents, such as penicillamine or trientine, and zinc salts. Liver transplantation is curative correcting the underlying pathophysiology and is traditionally indicated in acute liver failure or end-stage liver disease refractory to medical therapy. This review provides an overview of various aspects of Wilson's disease including molecular basis of the disease, clinical features, diagnostic and management strategies with their current limitations.
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Affiliation(s)
- Mohmadshakil Kathawala
- Centre for Liver Research, NIHR Birmingham Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK
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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: 21] [Impact Index Per Article: 2.6] [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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Zarina A, Tolmane I, Kreile M, Chernushenko A, Cernevska G, Pukite I, Micule I, Krumina Z, Krumina A, Rozentale B, Piekuse L. Genetic variation spectrum in ATP7B gene identified in Latvian patients with Wilson disease. Mol Genet Genomic Med 2017; 5:405-409. [PMID: 28717664 PMCID: PMC5511797 DOI: 10.1002/mgg3.297] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 04/14/2017] [Accepted: 04/17/2017] [Indexed: 12/27/2022] Open
Abstract
Background Wilson disease (WD) is an autosomal recessive disorder of copper metabolism caused by allelic variants in ATP7B gene. More than 500 distinct variants have been reported, the most common WD causing allelic variant in the patients from Central, Eastern, and Northern Europe is H1069Q. Methods All Latvian patients with clinically confirmed WD were screened for the most common mutation p.H1069Q by PCR Bi‐PASA method. Direct DNA sequencing of gene ATP7B (all 21 exons) was performed for the patients with WD symptoms, being either heterozygous for H1069Q or without it on any allele. Results We identified 15 different allelic variants along with eight non‐disease‐causing allelic variants. Based on the gene molecular analysis and patients' clinical data variant p.His1069Gln was found in 66.9% of WD alleles. Wide clinical variability was observed among individuals with the same ATP7B genotype. The results of our study confirm that neurological manifestations of WD are typically present later than the liver disease but no significant association between the presence/absence of the most common genetic variant and mode of initial WD presentation or age at presentation was identified. Conclusions (1) The most prevalent mutation in Latvian patients with Wilson disease was c.3207C>A (p.His1069Gln); (2) No significant phenotype–genotype correlation was found in Latvian patients with Wilson disease; (3) The estimated prevalence of Wilson disease in Latvia is 1 of 24,000 cases which is higher than frequently quoted prevalence of 1: 30,000.
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Affiliation(s)
- Agnese Zarina
- Scientific Laboratory of Molecular GeneticsRīga Stradiņš UniversityRigaLatvia
| | - Ieva Tolmane
- Riga East Clinical University Hospitalstationary "Latvian Centre of Infectious Diseases"RigaLatvia.,Faculty of MedicineUniversity of LatviaRigaLatvia
| | - Madara Kreile
- Scientific Laboratory of Molecular GeneticsRīga Stradiņš UniversityRigaLatvia
| | - Aleksandrs Chernushenko
- Riga East Clinical University Hospitalstationary "Latvian Centre of Infectious Diseases"RigaLatvia
| | | | - Ieva Pukite
- Children's Clinical University HospitalRigaLatvia
| | - Ieva Micule
- Children's Clinical University HospitalRigaLatvia
| | - Zita Krumina
- Children's Clinical University HospitalRigaLatvia
| | - Astrida Krumina
- Scientific Laboratory of Molecular GeneticsRīga Stradiņš UniversityRigaLatvia
| | - Baiba Rozentale
- Riga East Clinical University Hospitalstationary "Latvian Centre of Infectious Diseases"RigaLatvia
| | - Linda Piekuse
- Scientific Laboratory of Molecular GeneticsRīga Stradiņš UniversityRigaLatvia
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Abstract
Wilson disease (WD) is an autosomal-recessive disorder of hepatocellular copper deposition caused by pathogenic variants in the copper-transporting gene, ATP7B. Early detection and treatment are critical to prevent lifelong neuropsychiatric, hepatic, and systemic disabilities. Due to the marked heterogeneity in age of onset and clinical presentation, the diagnosis of Wilson disease remains challenging to physicians today. Direct sequencing of the ATP7B gene is the most sensitive and widely used confirmatory testing method, and concurrent biochemical testing improves diagnostic accuracy. More than 600 pathogenic variants in ATP7B have been identified, with single-nucleotide missense and nonsense mutations being the most common, followed by insertions/deletions, and, rarely, splice site mutations. The prevalence of Wilson disease varies by geographic region, with higher frequency of certain mutations occurring in specific ethnic groups. Wilson disease has poor genotype-phenotype correlation, although a few possible modifiers have been proposed. Improving molecular genetic studies continue to advance our understanding of the pathogenesis, diagnosis, and screening for Wilson disease.
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Affiliation(s)
- Irene J Chang
- Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
| | - Si Houn Hahn
- Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, WA, USA.
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Chandhok G, Horvath J, Aggarwal A, Bhatt M, Zibert A, Schmidt HHJ. Functional analysis and drug response to zinc and D-penicillamine in stable ATP7B mutant hepatic cell lines. World J Gastroenterol 2016; 22:4109-4119. [PMID: 27122662 PMCID: PMC4837429 DOI: 10.3748/wjg.v22.i16.4109] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2015] [Revised: 01/24/2016] [Accepted: 02/22/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the effect of anti-copper treatment for survival of hepatic cells expressing different ATP7B mutations in cell culture.
METHODS: The most common Wilson disease (WD) mutations p.H1069Q, p.R778L and p.C271*, found in the ATP7B gene encoding a liver copper transporter, were studied. The mutations represent major genotypes of the United States and Europe, China, and India, respectively. A human hepatoma cell line previously established to carry a knockout of ATP7B was used to stably express WD mutants. mRNA and protein expression of mutant ATP7B, survival of cells, apoptosis, and protein trafficking were determined.
RESULTS: Low temperature increased ATP7B protein expression in several mutants. Intracellular ATP7B localization was significantly impaired in the mutants. Mutants were classified as high, moderate, and no survival based on their viability on exposure to toxic copper. Survival of mutant p.H1069Q and to a lesser extent p.C271* improved by D-penicillamine (DPA) treatment, while mutant p.R778L showed a pronounced response to zinc (Zn) treatment. Overall, DPA treatment resulted in higher cell survival as compared to Zn treatment; however, only combined Zn + DPA treatment fully restored cell viability.
CONCLUSION: The data indicate that the basic impact of a genotype might be characterized by analysis of mutant hepatic cell lines.
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Chen C, Shen B, Xiao JJ, Wu R, Duff Canning SJ, Wang XP. Currently Clinical Views on Genetics of Wilson's Disease. Chin Med J (Engl) 2016; 128:1826-30. [PMID: 26112727 PMCID: PMC4733722 DOI: 10.4103/0366-6999.159361] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Objective: The objective of this study was to review the research on clinical genetics of Wilson's disease (WD). Data Sources: We searched documents from PubMed and Wanfang databases both in English and Chinese up to 2014 using the keywords WD in combination with genetic, ATP7B gene, gene mutation, genotype, phenotype. Study Selection: Publications about the ATP7B gene and protein function associated with clinical features were selected. Results: Wilson's disease, also named hepatolenticular degeneration, is an autosomal recessive genetic disorder characterized by abnormal copper metabolism caused by mutations to the copper-transporting gene ATP7B. Decreased biliary copper excretion and reduced incorporation of copper into apoceruloplasmin caused by defunctionalization of ATP7B protein lead to accumulation of copper in many tissues and organs, including liver, brain, and cornea, finally resulting in liver disease and extrapyramidal symptoms. It is the most common genetic neurological disorder in the onset of adolescents, second to muscular dystrophy in China. Early diagnosis and medical therapy are of great significance for improving the prognosis of WD patients. However, diagnosis of this disease is usually difficult because of its complicated phenotypes. In the last 10 years, an increasing number of clinical studies have used molecular genetics techniques. Improved diagnosis and prediction of the progression of this disease at the molecular level will aid in the development of more individualized and effective interventions, which is a key to transition from molecular genetic research to the clinical study. Conclusions: Clinical genetics studies are necessary to understand the mechanism underlying WD at the molecular level from the genotype to the phenotype. Clinical genetics research benefits newly emerging medical treatments including stem cell transplantation and gene therapy for WD patients.
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Affiliation(s)
| | | | | | | | | | - Xiao-Ping Wang
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao-Tong University, Shanghai 200080, China
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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; 20:112-7. [PMID: 26799313 DOI: 10.1089/gtmb.2015.0213] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Hana Ljubić
- Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Mirjana Kalauz
- Department of Internal Medicine, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Srđana Telarović
- Department of Neurology, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Peter Ferenci
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Rajko Ostojić
- Department of Internal Medicine, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Maria Cristina Noli
- Department of Public Health and Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy
| | - Maria Barbara Lepori
- Department of Public Health and Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy
| | - Irena Hrstić
- Department of Internal Medicine, General Hospital Pula, Pula, Croatia
| | - Jurica Vuković
- Department of Pediatrics, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Marina Premužić
- Department of Internal Medicine, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Davor Radić
- Department of Internal Medicine, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Katja Grubelić Ravić
- Department of Internal Medicine, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Jadranka Sertić
- Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Ana Merkler
- Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Ana Acman Barišić
- Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb, Croatia
| | | | - Boris Vucelić
- Department of Internal Medicine, University Hospital Centre Zagreb, Zagreb, Croatia
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Squitti R, Siotto M, Arciello M, Rossi L. Non-ceruloplasmin bound copper and ATP7B gene variants in Alzheimer's disease. Metallomics 2016; 8:863-73. [DOI: 10.1039/c6mt00101g] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
ATP7B, a protein mainly expressed in the hepatocytes, is a copper chaperone that loads the metal into the serum copper–protein ceruloplasmin during its synthesis and also escorts superfluous copper into the bile, by a sophisticated trafficking mechanism.
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Affiliation(s)
- R. Squitti
- Molecular Markers Laboratory
- IRCCS Istituto Centro San Giovanni di Dio-Fatebenefratelli
- 25125 Brescia, Italy
| | - M. Siotto
- Don Carlo Gnocchi ONLUS Foundation
- Milan, Italy
| | - M. Arciello
- Department of Biology
- University of Rome Tor Vergata
- Rome, Italy
| | - L. Rossi
- Department of Biology
- University of Rome Tor Vergata
- Rome, Italy
- Consorzio Interuniversitario “Istituto Nazionale Biostrutture e Biosistemi” (I.N.B.B.)
- Rome, Italy
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Abstract
CONTEXT Geographic distribution of ATP7B mutations in different populations. OBJECTIVE To summarise common mutations in the ATP7B gene and graphically illustrate their prevalence in different populations. METHODS A literature search was done using PubMed and the Wilson Disease Mutation Database (http://www.wilsondisease.med.ualberta.ca/database). RESULTS p.His1069Gln is the most prevalent mutation seen in Europe. In the Mediterranean countries, the array of prevalent mutations is different from the rest of Europe. In Far East Asian countries, the mutation p.Arg778Leu is the most common. In India, no single mutation seems to be dominant, owing to the vast ethnic diversity of the country. The p.Cys271* mutation is dominant in the east, west and south, but not reported in the north. In the Middle East, data from Saudi Arabia shows the p.Gln1399Arg mutation as the most prevalent. In the US, the p.His1069Gln is dominant, whereas in Brazil the mutation c.3402delC dominates. CONCLUSION Clinical features in WD patients can be misleading and often absent. Genetic testing is used to confirm the diagnosis. However, owing to the large gene size and vast diversity in the mutations, genetic testing can be time-consuming and tedious. This study reviews ATP7B mutations seen in different populations and can help develop time-saving methods and expediate the process of genetic analysis of WD.
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Affiliation(s)
- Amanda Gomes
- a Department of Dietetics and Nutrition , Harokopio University of Athens , Athens , Greece and.,b Wilson Disease Clinic, Kokilaben Dhirubhai Ambani Hospital & Medical Research Institute , Mumbai , India
| | - George V Dedoussis
- a Department of Dietetics and Nutrition , Harokopio University of Athens , Athens , Greece and
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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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44
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Abstract
The copper metabolism disorder Wilson's disease was first defined in 1912. Wilson's disease can present with hepatic and neurological deficits, including dystonia and parkinsonism. Early-onset presentations in infancy and late-onset manifestations in adults older than 70 years of age are now well recognised. Direct genetic testing for ATP7B mutations are increasingly available to confirm the clinical diagnosis of Wilson's disease, and results from biochemical and genetic prevalence studies suggest that Wilson's disease might be much more common than previously estimated. Early diagnosis of Wilson's disease is crucial to ensure that patients can be started on adequate treatment, but uncertainty remains about the best possible choice of medication. Furthermore, Wilson's disease needs to be differentiated from other conditions that also present clinically with hepatolenticular degeneration or share biochemical abnormalities with Wilson's disease, such as reduced serum ceruloplasmin concentrations. Disordered copper metabolism is also associated with other neurological conditions, including a subtype of axonal neuropathy due to ATP7A mutations and the late-onset neurodegenerative disorders Alzheimer's disease and Parkinson's disease.
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Affiliation(s)
- Oliver Bandmann
- Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
| | - Karl Heinz Weiss
- University Hospital Heidelberg, Department of Internal Medicine IV, Heidelberg, Germany
| | - Stephen G Kaler
- Section on Translational Neuroscience, Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
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El-Mougy FA, Sharaf SAA, Elsharkawy MM, Mandour IA, El-Essawy RA, Eldin AM, Helmy HM, Soliman DH, Selim LH, Sharafeldin HM, Mogahed EA, El-Karaksy HM. Gene mutations in Wilson disease in Egyptian children: report on two novel mutations. Arab J Gastroenterol 2014; 15:114-8. [PMID: 25465132 DOI: 10.1016/j.ajg.2014.10.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Revised: 06/13/2014] [Accepted: 10/26/2014] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND STUDY AIMS Wilson disease (WD) is an autosomal recessive disorder, caused by defects in copper-transporting P-type adenosine triphosphatase (ATPase) encoded by the ATP7B gene, resulting in the deposition of copper in the liver and brain with significant disability or death if left untreated. An available regimen of treatment gives hope to those predisposed to the disease if diagnosed early. The objective of this study was to determine the frequency of the most common European mutation (p.H1069Q) in Egyptian children with WD, in addition to screening for previously reported mutations in the Egyptian patients in our selected group. PATIENTS AND METHODS Direct DNA sequencing was applied to exons (13, 14, 18, and 19) of the ATP7B gene for 19 patients previously diagnosed with WD. Then DNA sequencing and pedigree analysis were performed in the families of the patients showing variations in their results for the purpose of family screening and carrier detection. Six out of 19 patients were studied with their families (three families). RESULTS We identified five variants of which two were novel among the studied patients. One of the novel variants was synonymous substitution (p.A1074A) in 16% of patients and the other was predicted to be missense disease-causing mutations (p.T1076I) in 16% of patients, and three previously published mutations p.H1069Q were detected in 5% of patients, p.P1273Q in 10% of patients, and a silent variant p.A1003A in 26% of patients. CONCLUSION Screening for the two exons 14 and 18 of the ATP7B gene is important in Egyptian patients especially in suspected patients without hepatic manifestations.
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Affiliation(s)
- Fatma A El-Mougy
- Department of Clinical and Chemical Pathology, Kasr Al-Aini Hospital, Cairo University, Cairo, Egypt
| | - Sahar A A Sharaf
- Department of Clinical and Chemical Pathology, Kasr Al-Aini Hospital, Cairo University, Cairo, Egypt
| | - Marwa M Elsharkawy
- Department of Clinical and Chemical Pathology, Kasr Al-Aini Hospital, Cairo University, Cairo, Egypt.
| | - Iman A Mandour
- Department of Clinical and Chemical Pathology, Kasr Al-Aini Hospital, Cairo University, Cairo, Egypt
| | - Riham A El-Essawy
- Department of Clinical and Chemical Pathology, Kasr Al-Aini Hospital, Cairo University, Cairo, Egypt
| | - Abeer M Eldin
- Department of Clinical and Chemical Pathology, Kasr Al-Aini Hospital, Cairo University, Cairo, Egypt
| | - Heba M Helmy
- Department of Pediatrics, Cairo University Pediatric Hospital, Cairo, Egypt
| | - Dina H Soliman
- Department of Clinical and Chemical Pathology, Kasr Al-Aini Hospital, Cairo University, Cairo, Egypt
| | - Lamia H Selim
- Department of Clinical and Chemical Pathology, Kasr Al-Aini Hospital, Cairo University, Cairo, Egypt
| | - Heba M Sharafeldin
- Department of Clinical and Chemical Pathology, Kasr Al-Aini Hospital, Cairo University, Cairo, Egypt
| | - Engy A Mogahed
- Department of Pediatrics, Cairo University Pediatric Hospital, Cairo, Egypt
| | - Hanaa M El-Karaksy
- Department of Pediatrics, Cairo University Pediatric Hospital, Cairo, Egypt
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Usta J, Wehbeh A, Rida K, El-Rifai O, Estiphan TA, Majarian T, Barada K. Phenotype-genotype correlation in Wilson disease in a large Lebanese family: association of c.2299insC with hepatic and of p. Ala1003Thr with neurologic phenotype. PLoS One 2014; 9:e109727. [PMID: 25390358 PMCID: PMC4229086 DOI: 10.1371/journal.pone.0109727] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2014] [Accepted: 09/04/2014] [Indexed: 12/15/2022] Open
Abstract
Genotype phenotype correlations in Wilson disease (WD) are best established in homozygous patients or in compound heterozygous patients carrying the same set of mutations. We determined the clinical phenotype of patients with WD carrying the c.2298_2299insC in Exon 8 (c.2299insC) or the p. Ala1003Thr missense substitution in Exon 13 mutations in the homozygous or compound heterozygous state. We investigated 76 members of a single large Lebanese family. Their genotypes were determined, and clinical assessments were carried out for affected subjects. We also performed a literature search retrieving the phenotypes of patients carrying the same mutations of our patients in the homozygous or compound heterozygous state. There were 7 consanguineous marriages in this family and the prevalence of WD was 8.9% and of carriers of ATP7B mutation 44.7%. WD was confirmed in 9 out of 76 subjects. All 9 had the c.2299insC mutation, 5 homozygous and 4-compound heterozygous with p. Ala1003Thr. Six of our patients had hepatic, 2 had neurologic and 1 had asymptomatic phenotype. Based on our data and a literature review, clear phenotypes were reported for 38 patients worldwide carrying the c.2299insC mutation. About 53% of those have hepatic and 29% have neurologic phenotype. Furthermore, there were 10 compound heterozygous patients carrying the p. Ala1003Thr mutation. Among those, 80% having c.2299insC as the second mutation had hepatic phenotype, and all others had neurologic phenotype. We hereby report an association between the c.2299insC mutation and hepatic phenotype and between the p. Ala1003Thr mutation and neurologic phenotype.
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Affiliation(s)
- Julnar Usta
- Department of Biochemistry and Molecular Genetics; Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Antonios Wehbeh
- Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Khaled Rida
- Department of Biochemistry and Molecular Genetics; Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Omar El-Rifai
- Department of Biochemistry and Molecular Genetics; Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | | | - Tamar Majarian
- Department of Biochemistry and Molecular Genetics; Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Kassem Barada
- Division of Gastroenterology, Department of Internal Medicine, American University of Beirut Medical Center, Faculty of Medicine, Beirut, Lebanon
- * E-mail:
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Abstract
Wilson disease (WD) is an inherited disorder of chronic copper toxicosis characterized by excessive copper deposition in the body, primarily in the liver and the brain. It is a progressive disease and fatal if untreated. Excessive copper accumulation results from the inability of liver to excrete copper in bile. Copper is an essential trace metal and has a crucial role in many metabolic processes. Almost all of the body copper is protein bound. In WD, the slow but relentless copper accumulation overwhelms the copper chaperones (copper-binding proteins), resulting in high levels of free copper and copper-induced tissue injury. Liver is the central organ for copper metabolism, and copper is initially accumulated in the liver but over time spills to other tissues. WD has protean clinical manifestations mainly attributable to liver, brain, and osseomuscular impairment. Diagnosis of WD is challenging and based on combination of clinical features and laboratory tests. Identification of various high-frequency mutations identified in different population studies across the world has revived interest in developing DNA chips for rapid genetic diagnosis of WD. All symptomatic and all presymptomatic patients require lifelong decoppering with careful clinical tracking. Decoppering ensures that presymptomatic individuals remain symptom free. With judicious decoppering, given time, even patients with severe neurological disability improve and can return to normal life and resume school or work at par with their peers. Treatment regimens and tracking patients using the WD-specific Global Assessment Scale for WD (GAS for WD) are discussed.
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48
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Identification and characterization of a novel splice-site mutation in the Wilson disease gene. J Neurol Sci 2014; 345:154-8. [PMID: 25086856 DOI: 10.1016/j.jns.2014.07.031] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Revised: 06/14/2014] [Accepted: 07/14/2014] [Indexed: 11/22/2022]
Abstract
This study aimed to identify aberrant transcripts of the new splice-site mutation c.3244-2A>C in the Wilson disease (WD) gene (ATPase, Cu++ transporting, beta polypeptide, ATP7B) and discuss its genotype and clinical phenotype. DNA and RNA were extracted from peripheral blood lymphocytes, amplified by polymerase chain reaction (PCR) and nested reverse transcription PCR (RT-nested PCR) to characterize the aberrant transcripts. RT-nested PCR product sequencing comparison showed that c.3244-2A>C splice-site mutation caused aberrant transcripts and formatted a new splice acceptor. Patient carrying the splice-site mutation c.3244-2A>C presented early onset age, severe clinical manifestations, and poor prognosis. WD patients with the splice-site mutation show severe clinical manifestations, indicating that aberrant transcripts have important implications for WD phenotype.
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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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50
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Chandhok G, Schmitt N, Sauer V, Aggarwal A, Bhatt M, Schmidt HHJ. The effect of zinc and D-penicillamine in a stable human hepatoma ATP7B knockout cell line. PLoS One 2014; 9:e98809. [PMID: 24892424 PMCID: PMC4044041 DOI: 10.1371/journal.pone.0098809] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Accepted: 05/07/2014] [Indexed: 12/27/2022] Open
Abstract
Mutations in the copper (Cu) transporter gene ATP7B, the primary cause of Wilson disease (WD), result in high liver Cu and death of hepatocytes. Cu chelators and zinc salts are the two most important drugs used in the treatment of WD patients; however, the molecular mechanisms of the drugs with regard to ATP7B expression have not been determined. A targeted knockout of ATP7B (KO) was established in the most widely used human hepatoma cell line, HepG2 for molecular studies of the pathogenesis and treatment of the disease. KO cells showed similar growth, Cu uptake, release, and gene expression as compared to parental cells. However, in the presence of Cu, morphological changes, oxidative stress, apoptosis, and loss of viability were observed. Induction of metallothionein (MT1X) after Cu exposure was significantly reduced in KO cells. Following zinc treatment, MT1X expression was strongly induced and a high percentage of KO cells could be rescued from Cu induced toxicity. D-penicillamine treatment had a minor effect on the viability of KO cells whereas the parental cell line showed a pronounced improvement. Combined treatment displayed a highly synergistic effect in KO cells. The data suggest that zinc has a previously unrecognized effect on the viability of hepatocytes that lack ATP7B due to a high induction of MT1X expression that compensates low gene expression after Cu exposure. A combination therapy that simultaneously targets at MT1X induction and Cu chelation improves the overall survival of hepatocytes for most efficient therapy of patients having WD.
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Affiliation(s)
- Gursimran Chandhok
- Clinic for Transplantation Medicine, Münster University Hospital, Münster, Germany
- Wilson Disease Clinic, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Mumbai, India
| | - Nadine Schmitt
- Clinic for Transplantation Medicine, Münster University Hospital, Münster, Germany
| | - Vanessa Sauer
- Clinic for Transplantation Medicine, Münster University Hospital, Münster, Germany
| | - Annu Aggarwal
- Wilson Disease Clinic, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Mumbai, India
| | - Mohit Bhatt
- Wilson Disease Clinic, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Mumbai, India
| | - Hartmut H. J. Schmidt
- Clinic for Transplantation Medicine, Münster University Hospital, Münster, Germany
- * E-mail:
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