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Dong J, Xiang G, Xia X, Xu L, Wen P, Xu C, Xu Y, Su Y, Song Y, Tong H, Zhu Q, Han Y, Han Y, Cheng N, Wang H, Zhou H. Aberrant copper metabolism and hepatic inflammation cause neurological manifestations in a mouse model of Wilson's disease. J Neuroinflammation 2024; 21:235. [PMID: 39334421 PMCID: PMC11437830 DOI: 10.1186/s12974-024-03178-5] [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: 04/29/2024] [Accepted: 07/16/2024] [Indexed: 09/30/2024] Open
Abstract
Pathogenic germline mutations in the P-type copper-transporting ATPase (ATP7B) gene cause Wilson's disease (WD), a hereditary disorder characterized by disrupted copper metabolism. The Arg778Leu (R778L) mutation in exon 8 is prevalent among individuals with WD in East Asia and is associated with more severe phenotypes. In this study, we generated a WD mouse model harboring R778L mutation (R778L mice) using CRISPR/Cas9. R778L mice exhibit a range of pathological characteristics resembling those of patients with WD and the same point mutations, including aberrant copper metabolism, pathological cellular injury, inflammation, and severe hepatic fibrosis. At 3-5 months of age, these mice started to display neurological deficits in motor coordination and cognitive dysfunction, accompanied by increased expression of inflammatory cytokines in the central nervous system. Microglia in the striatum and cortex exhibit significant activation, shorter processes, and decreased branch points. However, the Cu2+ levels in the brain tissue of R778L mice did not differ significantly from those of wild-type mice. Notably, inhibition of hepatic inflammation with PJ34 or siNfkb markedly alleviated the deficiencies in cognitive performance and improved locomotor activity in R778L mice. Thus, this study establishes a novel murine model to investigate the pathophysiology of WD, highlights the liver-brain crosstalk responsible for neurological manifestations in individuals with WD caused by the R778L point mutation, and demonstrates the potential of modulating liver inflammation as a therapeutic strategy for alleviating the neurological manifestations of WD.
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Affiliation(s)
- Jianjian Dong
- Institute of Neurology, Anhui University of Chinese Medicine, 357, Changjiang Rd. Middle, Hefei, Anhui, 230061, China
- Center for Xin-An Medicine and Modernization of Traditional Chinese Medicine of IHM, Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Guanghai Xiang
- Key Laboratory of Immune Response and Immunotherapy, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, 230601, China
| | - Xiaoxue Xia
- Institute of Neurology, Anhui University of Chinese Medicine, 357, Changjiang Rd. Middle, Hefei, Anhui, 230061, China
| | - Lewen Xu
- Institute of Neurology, Anhui University of Chinese Medicine, 357, Changjiang Rd. Middle, Hefei, Anhui, 230061, China
| | - Peihua Wen
- Institute of Neurology, Anhui University of Chinese Medicine, 357, Changjiang Rd. Middle, Hefei, Anhui, 230061, China
| | - Chenchen Xu
- Institute of Neurology, Anhui University of Chinese Medicine, 357, Changjiang Rd. Middle, Hefei, Anhui, 230061, China
| | - Yin Xu
- Institute of Neurology, Anhui University of Chinese Medicine, 357, Changjiang Rd. Middle, Hefei, Anhui, 230061, China
| | - Yushuang Su
- School of Life Sciences, Anhui Medical University, Hefei, 230032, China
| | - Yanze Song
- Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 1 Beichen West Rd, Beijing, 100101, China
| | - Haiyang Tong
- High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
| | - Qingjun Zhu
- High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
| | - Yongzhu Han
- Institute of Neurology, Anhui University of Chinese Medicine, 357, Changjiang Rd. Middle, Hefei, Anhui, 230061, China
- Center for Xin-An Medicine and Modernization of Traditional Chinese Medicine of IHM, Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Yongsheng Han
- Institute of Neurology, Anhui University of Chinese Medicine, 357, Changjiang Rd. Middle, Hefei, Anhui, 230061, China
- Center for Xin-An Medicine and Modernization of Traditional Chinese Medicine of IHM, Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Nan Cheng
- Institute of Neurology, Anhui University of Chinese Medicine, 357, Changjiang Rd. Middle, Hefei, Anhui, 230061, China.
- Center for Xin-An Medicine and Modernization of Traditional Chinese Medicine of IHM, Anhui University of Chinese Medicine, Hefei, 230012, China.
| | - Haoyi Wang
- Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 1 Beichen West Rd, Beijing, 100101, China.
| | - Hong Zhou
- School of Life Sciences, Anhui Medical University, Hefei, 230032, China.
- School of Basic Medical Science, Anhui Medical University, Hefei, 230032, China.
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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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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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Diao SP, Zhuang YS, Huang YQ, Zhou ZH, Liu AQ, Hong MF. Analysis of risk factors for neurological symptoms in patients with purely hepatic Wilson's disease at diagnosis. BMC Neurol 2023; 23:89. [PMID: 36855079 PMCID: PMC9972690 DOI: 10.1186/s12883-023-03105-w] [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: 10/07/2022] [Accepted: 02/02/2023] [Indexed: 03/02/2023] Open
Abstract
OBJECTIVE To analyze and explore the risk factors for neurological symptoms in patients with purely hepatic Wilson's disease (WD) at diagnosis. METHODS This retrospective study was conducted at the First Affiliated Hospital of the Guangdong Pharmaceutical University on 68 patients with purely hepatic WD aged 20.6 ± 7.2 years. The physical examinations, laboratory tests, color Doppler ultrasound of the liver and spleen, and magnetic resonance imaging (MRI) of the brain were performed. RESULTS The elevated alanine transaminase (ALT) and aspartate transaminase (AST) levels and 24-h urinary copper level were higher in the purely hepatic WD who developed neurological symptoms (NH-WD) group than those in the purely hepatic WD (H-WD) group. Adherence to low-copper diet, and daily oral doses of penicillamine (PCA) and zinc gluconate (ZG) were lower in the NH-WD group than those in the H-WD group. Logistic regression analysis showed that insufficient doses of PCA and ZG were associated with the development of neurological symptoms in patients with purely hepatic WD at diagnosis. CONCLUSION The development of neurological symptoms in patients with purely hepatic WD was closely associated with insufficient doses of PCA and ZG, and the inferior efficacy of copper-chelating agents. During the course of anti-copper treatment, the patient's medical status and the efficacy of copper excretion should be closely monitored.
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Affiliation(s)
- Sheng-Peng Diao
- grid.412601.00000 0004 1760 3828Department of Neurology, The First Affiliated Hospital, Jinan University, Guangzhou, 610630 Guangdong China ,grid.477976.c0000 0004 1758 4014Department of Neurology, College of Clinical Medicine, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, 510062 Guangdong China
| | - Yang-Sha Zhuang
- grid.477976.c0000 0004 1758 4014Department of Neurology, College of Clinical Medicine, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, 510062 Guangdong China
| | - Ye-Qing Huang
- grid.477976.c0000 0004 1758 4014Department of Neurology, College of Clinical Medicine, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, 510062 Guangdong China
| | - Zhi-Hua Zhou
- grid.477976.c0000 0004 1758 4014Department of Neurology, College of Clinical Medicine, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, 510062 Guangdong China
| | - Ai-Qun Liu
- grid.477976.c0000 0004 1758 4014Department of Neurology, College of Clinical Medicine, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, 510062 Guangdong China
| | - Ming-Fan Hong
- Department of Neurology, The First Affiliated Hospital, Jinan University, Guangzhou, 610630, Guangdong, China. .,Department of Neurology, College of Clinical Medicine, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, 510062, Guangdong, China.
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Dong Y, Wu ZY. Challenges and suggestions for precise diagnosis and treatment of Wilson's disease. World J Pediatr 2021; 17:561-565. [PMID: 34714531 DOI: 10.1007/s12519-021-00475-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 10/13/2021] [Indexed: 01/06/2023]
Affiliation(s)
- Yi Dong
- Department of Neurology, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, China.,Department of Medical Genetics, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, China
| | - Zhi-Ying Wu
- Department of Neurology, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, China. .,Department of Medical Genetics, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, China.
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Copper Toxicity Is Not Just Oxidative Damage: Zinc Systems and Insight from Wilson Disease. Biomedicines 2021; 9:biomedicines9030316. [PMID: 33804693 PMCID: PMC8003939 DOI: 10.3390/biomedicines9030316] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/13/2021] [Accepted: 03/17/2021] [Indexed: 12/13/2022] Open
Abstract
Essential metals such as copper (Cu) and zinc (Zn) are important cofactors in diverse cellular processes, while metal imbalance may impact or be altered by disease state. Cu is essential for aerobic life with significant functions in oxidation-reduction catalysis. This redox reactivity requires precise intracellular handling and molecular-to-organismal levels of homeostatic control. As the central organ of Cu homeostasis in vertebrates, the liver has long been associated with Cu storage disorders including Wilson Disease (WD) (heritable human Cu toxicosis), Idiopathic Copper Toxicosis and Endemic Tyrolean Infantile Cirrhosis. Cu imbalance is also associated with chronic liver diseases that arise from hepatitis viral infection or other liver injury. The labile redox characteristic of Cu is often discussed as a primary mechanism of Cu toxicity. However, work emerging largely from the study of WD models suggests that Cu toxicity may have specific biochemical consequences that are not directly attributable to redox activity. This work reviews Cu toxicity with a focus on the liver and proposes that Cu accumulation specifically impacts Zn-dependent processes. The prospect that Cu toxicity has specific biochemical impacts that are not entirely attributable to redox may promote further inquiry into Cu toxicity in WD and other Cu-associated disorders.
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Dong Y, Wang RM, Yang GM, Yu H, Xu WQ, Xie JJ, Zhang Y, Chen YC, Ni W, Wu ZY. Role for Biochemical Assays and Kayser-Fleischer Rings in Diagnosis of Wilson's Disease. Clin Gastroenterol Hepatol 2021; 19:590-596. [PMID: 32485301 DOI: 10.1016/j.cgh.2020.05.044] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 05/17/2020] [Accepted: 05/22/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Wilson disease is an autosomal recessive disorder that impairs copper homeostasis and is caused by homozygous or compound heterozygous mutations in ATP7B, which encodes a copper-transporting P-type ATPase. Patients have variable clinical manifestations and laboratory test results, resulting in diagnostic dilemmas. We aimed to identify factors associated with symptoms and features of Wilson disease from a large cohort, over 15 years. METHODS We collected data from 715 patients (529 with symptoms, 146 without symptoms, and 40 uncategorized) and a genetic confirmation of Wilson's disease (mean age of diagnosis, 18.84 years), recruited from 3 hospitals in China from 2004 through 2019. We analyzed clinical data along with serum levels of ceruloplasmin (available from 636 patients), 24-hr urinary copper excretion (collected from 131 patients), Kayser-Fleisher rings (copper accumulation in eyes, with neurologic data from 355 patients), and magnetic resonance imaging (MRI) abnormalities. Differences among the groups were analyzed using 1-way analysis of variance followed by Tukey multiple comparison test. RESULTS Of the 529 patients with symptoms, 121 had hepatic features, 355 had neurologic features, 28 had osteomuscular features (premature osteoarthritis, skeletal deformities, and pathological bone fractures), and 25 had psychiatric symptoms. Age of onset was significantly younger in patients with hepatic (16.94 ± 1.03 years; P = .0105) or osteomuscular features (13 ± 1.33 years; P = .0001) than patients with neurological features (19.48 ± 0.46 years). Serum levels of ceruloplasmin differed among asymptomatic patients and patients with osteomuscular or neurologic symptoms of Wilson disease. Serum levels of ceruloplasmin ranged from 18.93 mg/L to approximately 120.00 mg/L (quantiles of 0.025 to approximately 0.975). Fifty-one of 131 patients (39%) had urinary copper excretion levels below 100 μg/24 hr; there was significant variation in levels of urinary copper excretion between patients older than 14 years vs 14 years or younger. Of the 355 patients with neurologic features, 244 patients (69%) had abnormal findings from MRI and Kayser-Fleisher rings; only 1 patient with abnormal findings from brain MRI was negative for Kayser-Fleisher rings. CONCLUSIONS Serum level of ceruloplasmin, 24-hour urinary copper excretion, and Kayser-Fleisher rings can be used to identify patients who might have Wilson disease. Patients with serum levels of ceruloplasmin below 120 mg/L and children with urinary copper excretion above 40 μg should undergo genetic testing for Wilson's disease. Patients with movement disorders and brain MRI abnormalities without Kayser-Fleisher rings are not likely to have Wilson disease.
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Affiliation(s)
- Yi Dong
- Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Rou-Min Wang
- Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Guo-Min Yang
- Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Hao Yu
- Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Wan-Qing Xu
- Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Juan-Juan Xie
- Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Yue Zhang
- Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China
| | - Yu-Chao Chen
- Department of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Wang Ni
- Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhi-Ying Wu
- Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China.
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Appenzeller-Herzog C, Mathes T, Heeres MLS, Weiss KH, Houwen RHJ, Ewald H. Comparative effectiveness of common therapies for Wilson disease: A systematic review and meta-analysis of controlled studies. Liver Int 2019; 39:2136-2152. [PMID: 31206982 DOI: 10.1111/liv.14179] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 05/16/2019] [Accepted: 06/04/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Wilson disease (WD) is a rare disorder of copper metabolism. The objective of this systematic review was to determine the comparative effectiveness and safety of common treatments of WD. METHODS We included WD patients of any age or stage and the study drugs D-penicillamine, zinc salts, trientine and tetrathiomolybdate. The control could be placebo, no treatment or any other treatment. We included prospective, retrospective, randomized and non-randomized studies. We searched Medline and Embase via Ovid, the Cochrane Central Register of Controlled Trials, and screened reference lists of included articles. Where possible, we applied random-effects meta-analyses. RESULTS The 23 included studies reported on 2055 patients and mostly compared D-penicillamine to no treatment, zinc, trientine or succimer. One study compared tetrathiomolybdate and trientine. Post-decoppering maintenance therapy was addressed in one study only. Eleven of 23 studies were of low quality. When compared to no treatment, D-penicillamine was associated with a lower mortality (odds ratio 0.013; 95% CI 0.0010 to 0.17). When compared to zinc, there was no association with mortality (odds ratio 0.73; 95% CI 0.16 to 3.40) and prevention or amelioration of clinical symptoms (odds ratio 0.84; 95% CI 0.48 to 1.48). Conversely, D-penicillamine may have a greater impact on side effects and treatment discontinuations than zinc. CONCLUSIONS There are some indications that zinc is safer than D-penicillamine therapy while being similarly effective in preventing or reducing hepatic or neurological WD symptoms. Study quality was low warranting cautious interpretation of our findings.
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Affiliation(s)
| | - Tim Mathes
- Institute for Research in Operative Medicine, Faculty of Health, School of Medicine, Witten/Herdecke University, Cologne, Germany
| | - Marlies L S Heeres
- Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Karl Heinz Weiss
- Department of Internal Medicine IV, Medical University of Heidelberg, Heidelberg, Germany
| | - Roderick H J Houwen
- Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Hannah Ewald
- University Medical Library, University of Basel, Basel, Switzerland.,Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland
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Eda K, Mizuochi T, Iwama I, Inui A, Etani Y, Araki M, Hara S, Kumagai H, Hagiwara SI, Murayama K, Murakami J, Shimizu N, Kodama H, Yasuda R, Takaki Y, Yamashita Y. Zinc monotherapy for young children with presymptomatic Wilson disease: A multicenter study in Japan. J Gastroenterol Hepatol 2018; 33:264-269. [PMID: 28452067 DOI: 10.1111/jgh.13812] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 04/16/2017] [Accepted: 04/24/2017] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Few studies of zinc monotherapy for presymptomatic Wilson disease have focused on young children. We therefore evaluated long-term efficacy and safety of zinc monotherapy for such children and established benchmarks for maintenance therapy. METHODS We retrospectively and prospectively examined children under 10 years old with presymptomatic Wilson disease who received zinc monotherapy from time of diagnosis at 12 participating pediatric centers in Japan. RESULTS Twenty-four patients met entry criteria. Aspartate aminotransferase and alanine aminotransferase decreased significantly beginning 1 month after initiation of treatment and usually remained under 50 U/L from 1 to 8 years of treatment. Twenty four-hour urinary copper decreased significantly at 6 months and usually remained under 75 μg/day and between 1 and 3 μg/kg/day for the remainder of the study. All patients continued to take zinc, and none became symptomatic. In patients under 6 years old who received 50 mg/day of zinc as an initial dose, aspartate aminotransferase and alanine aminotransferase significantly decreased at 1 month after initiation of treatment, as did γ-glutamyltransferase and 24-h urinary copper at 6 months. CONCLUSIONS To our knowledge, this is the first multicenter study of zinc monotherapy for young children with presymptomatic Wilson disease. Such monotherapy proved highly effective and safe. Maintaining normal transaminase values (or values under 50 U/L when normalization is difficult) and 24-h urinary copper excretion between 1 and 3 μg/kg/day and under 75 μg/day is a reasonable goal. An initial dose of 50 mg/day is appropriate for patients under 6 years old.
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Affiliation(s)
- Keisuke Eda
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan
| | - Tatsuki Mizuochi
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan
| | - Itaru Iwama
- Department of Pediatrics, Okinawa Chubu Hospital, Uruma, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Japan
| | - Yuri Etani
- Department of Pediatric Gastroenterology, Nutrition, and Endocrinology, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan
| | - Mariko Araki
- Department of Pediatrics, Kochi Medical School, Kochi University, Nankoku, Japan
| | - Shinya Hara
- Department of Pediatrics, Toyota Memorial Hospital, Toyota, Japan
| | - Hideki Kumagai
- Department of Pediatrics, Jichi Medical University, Shimotsuke, Japan
| | - Shin-Ichiro Hagiwara
- Division of General Pediatrics, Saitama Children's Medical Center, Saitama, Japan
| | - Kei Murayama
- Department of Metabolism, Chiba Children's Hospital, Chiba, Japan
| | - Jun Murakami
- Division of Pediatrics and Perinatology, Faculty of Medicine, Tottori University, Yonago, Japan
| | - Norikazu Shimizu
- Department of Pediatrics, Toho University School of Medicine, Ohashi Medical Center, Tokyo, Japan
| | - Hiroko Kodama
- Department of Pediatrics, Teikyo University School of Medicine, Tokyo, Japan
| | - Ryosuke Yasuda
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan
| | - Yugo Takaki
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan
| | - Yushiro Yamashita
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan
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To U, Schilsky ML. Introduction to Copper Metabolism and Wilson Disease. CLINICAL GASTROENTEROLOGY 2018. [DOI: 10.1007/978-3-319-91527-2_1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Sun YM, Dong Y, Wang J, Lu JH, Chen Y, Wu JJ. A novel mutation of VAPB in one Chinese familial amyotrophic lateral sclerosis pedigree and its clinical characteristics. J Neurol 2017; 264:2387-2393. [PMID: 28993872 DOI: 10.1007/s00415-017-8628-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 09/20/2017] [Accepted: 09/21/2017] [Indexed: 12/13/2022]
Abstract
The mutation of vesicle-associated membrane protein-associated protein B (VAPB) was proved to cause family amyotrophic lateral sclerosis (FALS). Only two mutations of VAPB associated with ALS have been reported (p.Pro56Ser and p.Thr46Ile). Here we reported a Chinese Han FALS family caused by a novel VAPB point mutation. The clinical materials of one Chinese Han FALS family were collected. The genetic analysis was carried out by target sequencing and further verified by Sanger sequencing. One novel mutation of c.167C>A (p.Pro56His) on VAPB was found in the proband. The age at onset of the proband was 48 with the onset symptoms of weakness in the right arm, followed by progressive limb and trunk weakness with decreased deep-tendon reflexes, muscular cramps and fasciculation. But the disease duration was more than 15 years. He was under the tracheotomy for 1 year at last visit. Electromyography showed widespread acute and chronic neurogenic damages. His mother presented weakness in her limbs in 50 s and died 15 years later. One of his younger sisters diagnosed as ALS for 6 years also carried the same mutation. She presented the similar symptoms on 41. No dominant upper motor neuron sign was showed. The clinical features were similar to the patients carrying the known mutation of p.Pro56Ser. A novel mutation of VAPB was found in one Chinese Han FALS pedigree. The affected patients presented a much slower progression and the lesions were limited in lower motor neurons.
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Affiliation(s)
- Yi-Min Sun
- Department of Neurology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai, 200040, China
| | - Yi Dong
- Department of Neurology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai, 200040, China
| | - Jian Wang
- Department of Neurology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai, 200040, China
| | - Jia-Hong Lu
- Department of Neurology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai, 200040, China
| | - Yan Chen
- Department of Neurology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai, 200040, China.
| | - Jian-Jun Wu
- Department of Neurology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai, 200040, China.
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Abstract
Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism. Its incidence is higher in China than in western countries. ATP7B is the causative gene and encodes a P-type ATPase, which participates in the synthesis of holoceruloplasmin and copper excretion. Disease-causing variants of ATP7B disrupt the normal structure or function of the enzyme and cause copper deposition in multiple organs, leading to diverse clinical manifestations. Given the variety of presentations, misdiagnosis is not rare. Genetic diagnosis plays an important role and has gradually become a routine test in China. The first Chinese spectrum of disease-causing mutations of ATP7B has been established. As a remediable hereditary disorder, most WD patients have a good prognosis with an early diagnosis and chelation treatment. However, clinical trials are relatively few in China, and most treatments are based on the experience of experts and evidences from other countries. It is necessary to study and develop appropriate regimens specific for Chinese WD patients.
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Affiliation(s)
- Juan-Juan Xie
- Department of Neurology and Research Center of Neurology in the Second Affiliated Hospital, and the Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, 310009, China
| | - Zhi-Ying Wu
- Department of Neurology and Research Center of Neurology in the Second Affiliated Hospital, and the Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, 310009, China.
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Cheng N, Wang H, Wu W, Yang R, Liu L, Han Y, Guo L, Hu J, Xu L, Zhao J, Han Y, Liu Q, Li K, Wang X, Chen W. Spectrum of ATP7B mutations and genotype-phenotype correlation in large-scale Chinese patients with Wilson Disease. Clin Genet 2017; 92:69-79. [PMID: 27982432 DOI: 10.1111/cge.12951] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2016] [Revised: 11/17/2016] [Accepted: 12/03/2016] [Indexed: 01/17/2023]
Abstract
Wilson disease (WD), an inherited disorder associated with ATP7B gene, has a wide spectrum of genotypes and phenotypes. In this study, we developed a rapid multiplex PCR-MassArray method for detecting 110 mutant alleles of interest, and used it to examine genomic DNA from 1222 patients and 110 healthy controls. In patients not found to have any mutation in the 110 selected alleles, PCR-Sanger sequencing was used to examine the ATP7B gene. We identified 88 mutations, including 9 novel mutations. Our analyses revealed p.Arg778Leu, p.Arg919Gly and p.Thr935Met showed some correlations to phenotype. The p.Arg778Leu was related to younger onset age and lower levels of ceruloplasmin (Cp) and serum copper, while p.Arg919Gly and p.Thr935Met both indicated higher Cp levels. Besides, the p.Arg919Gly was related to neurological subtype, and p.Thr935Met showed significant difference in the percentage of combined neurological and visceral subtype. Moreover, for ATP7B mutations, the more severe impact on ATP7B protein was, the younger onset age and lower Cp level presented. The feasibility of presymptomatic DNA diagnosis and predicting clinical manifestation or severity of WD would be facilitated with identified mutations and genotype-phenotype correlation precisely revealed in the study.
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Affiliation(s)
- N Cheng
- Hospital Affiliated to Institute of Neurology, Anhui University of Traditional Chinese Medicine, Hefei, China.,Center of Medical Physics and Technology, Hefei Institute of Physical Science, Chinese Academy of Sciences, Hefei, China
| | - H Wang
- Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - W Wu
- Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - R Yang
- Hospital Affiliated to Institute of Neurology, Anhui University of Traditional Chinese Medicine, Hefei, China
| | - L Liu
- Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Y Han
- Hospital Affiliated to Institute of Neurology, Anhui University of Traditional Chinese Medicine, Hefei, China
| | - L Guo
- Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - J Hu
- Hospital Affiliated to Institute of Neurology, Anhui University of Traditional Chinese Medicine, Hefei, China
| | - L Xu
- Research Department, Beijing Macro & Micro Test Biotech Co., Ltd, Beijing, China
| | - J Zhao
- Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Y Han
- Hospital Affiliated to Institute of Neurology, Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Q Liu
- Research Department, Beijing Macro & Micro Test Biotech Co., Ltd, Beijing, China
| | - K Li
- Hospital Affiliated to Institute of Neurology, Anhui University of Traditional Chinese Medicine, Hefei, China
| | - X Wang
- Hospital Affiliated to Institute of Neurology, Anhui University of Traditional Chinese Medicine, Hefei, China
| | - W Chen
- Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
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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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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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Zinc mono-therapy in pre-symptomatic Chinese children with Wilson disease: a single center, retrospective study. PLoS One 2014; 9:e86168. [PMID: 24475083 PMCID: PMC3901685 DOI: 10.1371/journal.pone.0086168] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2013] [Accepted: 12/06/2013] [Indexed: 01/02/2023] Open
Abstract
Background There is no official consensus regarding zinc therapy in pre-symptomatic children with Wilson Disease (WD); more data is needed. Objective To investigate the safety and efficacy of zinc gluconate therapy for Chinese children with pre-symptomatic WD. Methods We retrospectively analyzed pre-symptomatic children receiving zinc gluconate in a single Chinese center specialized in pediatric hepatology. Short-term follow-up data on safety and efficacy were presented, and effects of different zinc dosages were compared. Results 30 children (21 males) aged 2.7 to 16.8 years were followed for up to 4.4 years; 26 (87%) children had abnormal ALT at baseline. Most patients (73%) received higher than the currently recommended dose of elemental zinc. Zinc gluconate significantly reduced mean ALT (p<0.0001), AST (p<0.0001), GGT (p<0.0001) levels after 1 month, and urinary copper excretion after 6 months (p<0.0054). Mean direct bilirubin levels dropped significantly at 1 month (p = 0.0175), 3 months (p = 0.0010), and 6 months (p = 0.0036). Serum zinc levels gradually increased and reached a significantly higher level after 6 months (p<0.0026), reflecting good compliance with the therapy. Complete blood count parameters did not change throughout the analysis period. 8 children experienced mild and transient gastrointestinal side effects. The higher zinc dose did not affect treatment response and was not associated with different or increased side effects when compared to conventional zinc dose. Conclusion In our cohort, zinc gluconate therapy for Chinese children with pre-symptomatic WD was effective, and higher initial dose of elemental zinc had the same level of efficacy as the conventional dose.
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Kumar MK, Kumar V, Singh PK. Wilson's Disease with Neurological Presentation, without Hepatic Involvement in Two Siblings. J Clin Diagn Res 2013; 7:1476-8. [PMID: 23998100 PMCID: PMC3749670 DOI: 10.7860/jcdr/2013/5974.3188] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2013] [Accepted: 05/13/2013] [Indexed: 11/24/2022]
Abstract
Wilson's Disease (WD) is a rare, autosomal, recessive, inborn error of the copper metabolism, which is caused by a mutation in the copper-transporting gene, ATP7B. The presentation is usually neurologic or hepatic, which is seen in 40% of the patients. The diagnosis depends primarily on the clinical features, the biochemical parameters and the presence of the Kayser - Fleischer ring. Here, we are reporting two siblings who were affected by Wilson's disease, with only neurological manifestations, without any hepatic involvement.
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Affiliation(s)
| | - Vijay Kumar
- Assistant Professor, Department of Biochemistry
| | - Praphul Kumar Singh
- MBBS, DCH, Clinical Tutor, Department of Pediatrics, Narayan Medical College and Hospital, Jamuhar, Sasaram, Bihar, India
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Dong QY, Wu ZY. Advance in the pathogenesis and treatment of Wilson disease. Transl Neurodegener 2012; 1:23. [PMID: 23210912 PMCID: PMC3526418 DOI: 10.1186/2047-9158-1-23] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2012] [Accepted: 11/21/2012] [Indexed: 02/06/2023] Open
Abstract
Wilson disease is an autosomal recessive disorder of copper metabolism. Diagnosis depends primarily on clinical features, biochemical parameters and the presence of the Kayser-Fleischer ring. Genetic analysis for mutations within ATP7B is a convincing diagnostic tool. The traditional treatment for WD includes chelation of excessive copper accumulation and reduction of copper intake. Medical therapy is effective but WD is not yet curable. Liver transplantation is especially helpful for patients who fail to respond to medical therapy or present with fulminant liver failure, although evaluation of its long-term effect are still in need.
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Affiliation(s)
- Qin-Yun Dong
- Department of Neurology and Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, 12 Wulumuqi Zhong Road, Shanghai, 200040, China
| | - Zhi-Ying Wu
- Department of Neurology and Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, 12 Wulumuqi Zhong Road, Shanghai, 200040, China
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Zinc monotherapy from time of diagnosis for young pediatric patients with presymptomatic Wilson disease. J Pediatr Gastroenterol Nutr 2011; 53:365-7. [PMID: 21970993 DOI: 10.1097/mpg.0b013e31821d5abe] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
In 4 young pediatric patients with presymptomatic Wilson disease, we found zinc monotherapy beginning at time of diagnosis to be safe and highly effective for follow-up intervals between 1 and 2 years. Such maintenance therapy with zinc can maintain urinary copper excretion between 1 and 3 μg · kg(-1) · day.
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Wang LH, Huang YQ, Shang X, Su QX, Xiong F, Yu QY, Lin HP, Wei ZS, Hong MF, Xu XM. Mutation analysis of 73 southern Chinese Wilson's disease patients: identification of 10 novel mutations and its clinical correlation. J Hum Genet 2011; 56:660-5. [PMID: 21796144 DOI: 10.1038/jhg.2011.76] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
This study was designed to investigate the molecular basis and the correlation between genotype and phenotype in the southern Chinese patients with Wilson's disease (WD). Genotypes of the ATP7B gene in 73 WD patients were examined by denaturing high-performance liquid chromatography (DHPLC) and DNA sequencing. A total of 38 different disease-causing mutations were identified, including 10 novel mutations: missense mutations (p.Gln707Arg, p.Cys1079Phe, p.Gly1149Glu, p.Ser855Tyr, p.Ala874Pro and p.Ser921Arg), nonsense mutation (p.Arg1228Stop), splice-site mutations (2121+3A>T and 3244-2A>G) and frameshift mutation (1875_1876insAATT). We found that a pair of siblings carried the same genotype but different clinical type, and two patients were found to have three mutations. In addition, we compared the clinical data for p.Arg778Leu homozygotes and compound heterozygotes. Our research has enriched the mutation spectrum of the ATP7B gene in the Chinese population and can serve as the basis for genetic counseling and clinical/prenatal diagnosis to prevent WD in China.
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Affiliation(s)
- Li-Hua Wang
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
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Lee BH, Kim JH, Lee SY, Jin HY, Kim KJ, Lee JJ, Park JY, Kim GH, Choi JH, Kim KM, Yoo HW. Distinct clinical courses according to presenting phenotypes and their correlations to ATP7B mutations in a large Wilson's disease cohort. Liver Int 2011; 31:831-9. [PMID: 21645214 DOI: 10.1111/j.1478-3231.2011.02503.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION AND AIMS Wide phenotypic and genotypic heterogeneities in Wilson's disease (WD) have been reported, hampering the study of their correlations. The goal of this study was to identify the factors related to these diversities. METHODS Clinical courses and molecular genetic characteristics were analysed in 237 unrelated Korean WD families. The average follow-up period was 8.2 ± 5.8 years. RESULTS Presenting phenotypes were classified as H1 (12.2%), H2 (42.4%), N1 (21.6%), N2 (0.4%), NX (0.4%), presymptomatic (22.4%) and other (0.4%), modifying the guidelines by Ferenci and colleagues. Age at presentation was youngest and cirrhosis was rarest in the presymptomatic group. Decompensated cirrhosis was the highest in the H1 group. Favourable outcome was rarest in the N1 group. Forty-seven (11 novel) ATP7B mutations were identified in 85% of the 474 alleles. Multiplex ligation-dependent probe amplification assays in ATP7B and analyses of ATOX1 and COMMD1 genes identified no additional mutations. Yeast complementation assays demonstrated functional perturbation of the seven novel missense mutants. Five major mutations, p.Arg778Leu, p.Ala874Val, p.Asn1270Ser, p.Lys838SerfsX35 and p.Leu1083Phe, accounted for 63% of the alleles. H1 was more common, age at presentation was younger and N1+N2+NX tended to be less common in patients with nonsense, frame shifting or splicing mutations than in those with missense mutations alone. Patients with both mutations in the transduction (Td) or the ATP hinge domain showed presymptomatic or hepatic manifestations but no neurological manifestation. CONCLUSIONS The presenting phenotype strongly affects the clinical outcome of WD, and is related to the ATP7B mutation type and location, providing an evidence for genotype-phenotype correlations in WD.
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Affiliation(s)
- Beom H Lee
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
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Linn FHH, Houwen RHJ, van Hattum J, van der Kleij S, van Erpecum KJ. Long-term exclusive zinc monotherapy in symptomatic Wilson disease: experience in 17 patients. Hepatology 2009; 50:1442-52. [PMID: 19731238 DOI: 10.1002/hep.23182] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
UNLABELLED Exclusive monotherapy with zinc in symptomatic Wilson disease is controversial. Seventeen symptomatic patients with Wilson disease were treated with zinc only. The mean age at diagnosis and start of treatment was 18 years (range 13-26) with approximately half presenting as adolescents. Presentation was exclusively hepatic, exclusively neurologic, and combined in seven, five, and five patients, respectively. The median follow-up was 14 years (range 2-30). At baseline, two of the 12 patients with hepatic disease exhibited decompensated cirrhosis, five exhibited compensated cirrhosis, and five had less severe disease. Both patients with decompensated cirrhosis improved to a compensated state after initiation of therapy. Two of the five patients with initial compensated cirrhosis progressed to decompensated state, and three remain stable. Three of the five patients with moderate or mild liver disease remain stable and two improved. Apart from decreasing bilirubin levels, no significant changes occurred in the liver biochemistry or function during long-term follow-up. Nine of 10 neurologic patients improved markedly and one deteriorated. Two patients with exclusively neurologic presentation developed liver disease during zinc treatment. Two patients with exclusively hepatic presentation developed mild neurologic symptoms. According to 24-hour urinary copper excretions (213 +/- 38 versus 91 +/- 23 microg: P = 0.01) and serum non-ceruloplasmin-bound copper concentrations (11 +/- 2 versus 7 +/- 1 microg/dL: P = 0.1) at the end of follow-up, the efficacy of decoppering was less in the exclusively hepatic than in the neurologic group. The prescribed zinc dose and 24-hour urinary zinc excretions tended to be less in the exclusively hepatic group. CONCLUSION The outcome of exclusive zinc therapy is generally good in cases of neurologic disease. A less satisfactory outcome in hepatic disease may relate to less efficient decoppering.
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Affiliation(s)
- Francisca H H Linn
- Department of Neurology, University Medical Center, Utrecht, The Netherlands
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Wiggelinkhuizen M, Tilanus MEC, Bollen CW, Houwen RHJ. Systematic review: clinical efficacy of chelator agents and zinc in the initial treatment of Wilson disease. Aliment Pharmacol Ther 2009; 29:947-58. [PMID: 19210288 DOI: 10.1111/j.1365-2036.2009.03959.x] [Citation(s) in RCA: 94] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND No consensus is available on the optimal initial treatment in Wilson disease. AIM To assess systematically the available literature of treatment in newly presenting patients with a presymptomatic, hepatic or neurological presentation of Wilson disease. METHODS A systematic literature search of the MEDLINE, EMBASE and COCHRANE databases was performed. Original studies on clinical efficacy of D-penicillamine, trientine, tetrathiomolybdate or zinc monotherapy as initial treatment in Wilson disease were included. A descriptive analysis of the relevant published data was performed. RESULTS One randomized trial and 12 observational studies met the inclusion criteria. These studies were quite heterogeneous and generally of low validity. Nevertheless, according to currently available data, patients with hepatic presentation of Wilson disease are probably most effectively treated by D-penicillamine. Zinc seems to be preferred above d-penicillamine for treatment of presymptomatic and neurological patients, as in these subgroups, the tolerance profile is in favour of zinc, while no obvious differences in clinical efficacy could be observed. CONCLUSIONS There is lack of high-quality evidence to estimate the relative treatment effects of the available drugs in Wilson disease. Therefore, multicentre prospective randomized controlled comparative trials are necessary.
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Affiliation(s)
- M Wiggelinkhuizen
- Department of Paediatric Gastroenterology, University Medical Centre Utrecht, Utrecht, The Netherlands
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Ye S, Gong L, Shui QX, Zhou LF. Wilson disease: Identification of two novel mutations and clinical correlation in Eastern Chinese patients. World J Gastroenterol 2007; 13:5147-50. [PMID: 17876883 PMCID: PMC4434647 DOI: 10.3748/wjg.v13.i38.5147] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study mutations in the P-type ATPase (ATP7B) gene responsible for Wilson disease (WD) in the Eastern Chinese population, and the possible correlation of specific mutations with clinical characteristics.
METHODS: Mutations of the ATP7B gene were sought by means of direct sequencing in 50 Eastern Chinese WD patients of Han ethnic origin.
RESULTS: Two novel mutations, Asp96Gly and Asp196Glu, were first identified. We also compared the characterization of mutations in ATP7B with the clinical findings, and a significant correlation with hepatic manifestations between patients carrying the Arg778Leu mutation and those without was found.
CONCLUSION: Gene sequencing analysis was shown to have a high detection rate and accuracy. It may become the first priority in screening of WD patients.
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Affiliation(s)
- Sheng Ye
- Department of Pediatrics, Child Hospital, Zhejiang University, Hangzhou 310005, Zhejiang Province, China
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Lutsenko S, Barnes NL, Bartee MY, Dmitriev OY. Function and regulation of human copper-transporting ATPases. Physiol Rev 2007; 87:1011-46. [PMID: 17615395 DOI: 10.1152/physrev.00004.2006] [Citation(s) in RCA: 596] [Impact Index Per Article: 33.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Copper-transporting ATPases (Cu-ATPases) ATP7A and ATP7B are evolutionarily conserved polytopic membrane proteins with essential roles in human physiology. The Cu-ATPases are expressed in most tissues, and their transport activity is crucial for central nervous system development, liver function, connective tissue formation, and many other physiological processes. The loss of ATP7A or ATP7B function is associated with severe metabolic disorders, Menkes disease, and Wilson disease. In cells, the Cu-ATPases maintain intracellular copper concentration by transporting copper from the cytosol across cellular membranes. They also contribute to protein biosynthesis by delivering copper into the lumen of the secretory pathway where metal ion is incorporated into copper-dependent enzymes. The biosynthetic and homeostatic functions of Cu-ATPases are performed in different cell compartments; targeting to these compartments and the functional activity of Cu-ATPase are both regulated by copper. In recent years, significant progress has been made in understanding the structure, function, and regulation of these essential transporters. These studies raised many new questions related to specific physiological roles of Cu-ATPases in various tissues and complex mechanisms that control the Cu-ATPase function. This review summarizes current data on the structural organization and functional properties of ATP7A and ATP7B as well as their localization and functions in various tissues, and discusses the current models of regulated trafficking of human Cu-ATPases.
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Affiliation(s)
- Svetlana Lutsenko
- Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, Oregon 97239, USA.
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Wan L, Tsai CH, Tsai Y, Hsu CM, Lee CC, Tsai FJ. Mutation analysis of Taiwanese Wilson disease patients. Biochem Biophys Res Commun 2006; 345:734-8. [PMID: 16696937 DOI: 10.1016/j.bbrc.2006.04.136] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2006] [Accepted: 04/20/2006] [Indexed: 11/17/2022]
Abstract
Wilson disease (WD) is an autosomal recessive disorder of copper metabolism, which is caused by mutation in copper-transporting ATPase (ATP7B). In the present study, we report a molecular diagnosis method to screen the WD chromosome in patients or in heterozygotic carriers in Taiwan. Exons 8, 11, 12, 13, 16, 17, and 18 of ATP7B are selected for the screening of mutations. The most common mutation, Arg778Leu or Arg778Gln, was first screened by PCR-RFLP then we combined single-stranded conformation polymorphism (SSCP) analysis followed by direct DNA sequencing on the DNA fragments with mobility shift on SSCP analysis. The diagnostic rate was compared with standard ATP7B whole gene sequencing analysis. Ten different mutations were identified among 29 WD patients; among them four were novel (Ala1168Pro, Thr1178Ala, Ala1193Pro, and Pro1273Gln). The false positive rates were tested against 100 normal individuals and listed as follows: exon 8: 5%; exon 11: 4%; exon 12: 6%; exon 13: 5%; exon 16: 5%; exon 17: 3%; exon 18: 4%. The Arg778Leu mutation exhibited the highest allelic frequency (43.1%). The detection rate of WD chromosomes is 65.52%, which is as sensitive as whole gene sequencing scanning. According to our results, WD chromosomes in Taiwan are predominantely located at exons 8, 11, 12, 13, 16, 17, and 18. The standard sequencing analysis on the entire gene is time consuming. We recommend screening these 7 exons first on those individuals who have a higher risk in having WD, before whole gene and promoter sequencing analysis in Taiwan.
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Affiliation(s)
- Lei Wan
- Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
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Abstract
Wilson's disease is an inherited copper toxicosis caused by defective putative copper transporting ATPase in the liver. Because of impaired biliary secretion, copper remains in the liver, resulting in chronic hepatic lesions including fatty metamorphosis, chronic hepatitis and cirrhosis. In the latter stage, extrapyramidal syndromes may develop with and without symptomatic hepatic lesions. Acute liver damage associated with hemolysis and deep jaundice may be the first manifestation. The majority of patients show hypoceruloplasminemia, which has been used as a screening test for the disease. A large number of mutations in the ATP7B gene have been reported. Thus, genetic diagnosis might be limitedly used to presymptomatic diagnosis of siblings when mutations are identified in an index patient. Introduction of penicillamine caused a revolution in the treatment of patients. Another chelater, trientine, is now available for those intolerant of penicillamine. Tetrathiomolibdate and zinc acetate are additional alternatives currently being tested. Hypoceruloplasminemia and further reduction after chelation therapy may be associated with iron overload. This complication is closely related with impaired transport of ferrous ion due to ferroxidase deficiency. Noncompliance and teratogenicity are other major concerns because any treatment with the agents listed above is a life long regimen. Despite various side effects of penicillamine, its teratogenicity is negligible. These data indicate that penicillamine is the first choice of drug for this disease.
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Affiliation(s)
- Hisao Hayashi
- Department of Medicine, Faculty of Pharmaceutical Sciences of Hokuriku University, Kanazawa 920-1181, Japan.
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