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Ghosh U, Sen Sarma M, Samanta A. Challenges and dilemmas in pediatric hepatic Wilson's disease. World J Hepatol 2023; 15:1109-1126. [PMID: 37970614 PMCID: PMC10642431 DOI: 10.4254/wjh.v15.i10.1109] [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: 07/31/2023] [Revised: 09/23/2023] [Accepted: 10/08/2023] [Indexed: 10/24/2023] Open
Abstract
Wilson disease is an autosomal recessive disorder affecting the ATP7B gene located on chromosome 13q. This leads to copper deposition in various organs, most importantly in the liver and brain. The genetic mutations are vast, well reported in the West but poorly documented in developing countries. Hence the diagnosis is made with a constellation of clinico-laboratory parameters which have significant overlap with other liver diseases and often pose a significant dilemma for clinicians. Diagnostic scoring systems are not fool-proof. The availability and affordability of chelators in developing countries impact the drug compliance of patients. While D-penicillamine is a potent drug, its side effects lead to drug discontinuation. Trientine is cost-prohibitive in developing countries. There is no single test to assess the adequacy of chelation. Exchangeable urinary copper is an essential upcoming diagnostic and prognostic tool. In the presence of cirrhosis, hypersplenism clouds the assessment of myelosuppression of drugs. Similarly, it may be difficult to distinguish disease tubulopathy from drug-induced glomerulonephritis. Neurological worsening due to chelators may appear similar to disease progression. Presentation as fulminant hepatic failure requires rapid workup. There is a limited window of opportunity to salvage these patients with the help of plasmapheresis and other liver-assisted devices. This review addresses the challenges and clinical dilemmas faced at beside in developing countries.
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Affiliation(s)
- Upasana Ghosh
- Department of Pediatric Gastroenterology, Sanjay Gandhi Post graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Moinak Sen Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India.
| | - Arghya Samanta
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
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Huong NTM, Hoa NPA, Ngoc ND, Mai NTP, Yen PH, Anh HTV, Hoa G, Dien TM. Mutation spectrum of ATP7B gene in pediatric patients with Wilson disease in Vietnam. Mol Genet Metab Rep 2022; 31:100861. [PMID: 35782615 PMCID: PMC9248214 DOI: 10.1016/j.ymgmr.2022.100861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 03/08/2022] [Accepted: 03/09/2022] [Indexed: 12/08/2022] Open
Abstract
Background Wilson disease (WD) is caused by mutations in the copper-transporting P-type adenosine triphosphatase encoded by the ATP7B gene. In this study, we screened and identified the ATP7B mutations among unrelated Vietnamese pediatric patients. Methods One-hundred-thirteen pediatric patients with clinically diagnosed WD were recruited. DNA samples were extracted from peripheral blood. Mutations in the ATP7B gene were identified by Sanger sequencing. Results Approximately 98% of the clinically diagnosed WD patients carried ATP7B mutations. A total of 35 different ATP7B variants were detected, including five novel mutations (L658P, L792P, T977K, IVS4 + 1G > A and IVS20 + 4A > G). Remarkably, this study revealed that S105* was the most prevalent variant (32.27%), followed by L1371P (9.09%), I1148T (7.27%), R778L (6.36%), T850I (5.45%), V176Sfs*28 and IVS14-2A > G (4.55%). Most ATP7B mutations were located in the exon 2 (37.73%), exon 16 (10.00%), exon 8 (9.55%), exon 20 (9.09%), exon 10 and exon 18 (5.45%), exon 14 (5.00%), exon 13 and intron 14 (4.55%). We developed a streamlined procedure to quickly characterize mutations in the ATP7B gene in the Vietnamese children, starting with sequencing exon 2 and subsequently to exons 8,10,13-16,18, and 20 to allow quick diagnosis of clinically suspected patients. Conclusion The mutational spectrum and hotspots of ATP7B gene in the Vietnamese population were fairly different from other East Asian populations. A streamlined procedure was developed to screen exon 2 in ATP7B gene among suspected WD patients to reduce genetically diagnostic cost, to facilitate early detection and intervention in countries with limited resources.
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Affiliation(s)
| | | | - Ngo Diem Ngoc
- Department of Human Genetics, National Children's Hospital, Hanoi, Viet Nam
| | | | - Pham Hai Yen
- Department of Hepatology, National Children's Hospital, Hanoi, Viet Nam
| | - Hoàng Thị Vân Anh
- Department of Hepatology, National Children's Hospital, Hanoi, Viet Nam
| | - Giang Hoa
- Gene Solutions, Ho Chi Minh City, Viet Nam
- Medical Genetics Institutes, Ho Chi Minh City, Viet Nam
| | - Tran Minh Dien
- Department of Human Genetics, National Children's Hospital, Hanoi, Viet Nam
- Department of Hepatology, National Children's Hospital, Hanoi, Viet Nam
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Xu L, Liu B, Liu Z, Tang N, She C, Wang J, Zang B, Yang Y. Co-occurrence of Wilson's disease and systemic lupus erythematosus: a case report and literature review. BMC Gastroenterol 2021; 21:229. [PMID: 34020599 PMCID: PMC8139024 DOI: 10.1186/s12876-021-01814-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Accepted: 05/16/2021] [Indexed: 11/17/2022] Open
Abstract
Background Wilsons disease (WD) is a rare autosomal recessive disease associated with defective biliary excretion of copper. The simultaneous occurrence of WD and systemic lupus erythematosus (SLE) has seldom been reported. Therefore, this study aimed to report the co-occurrence of SLE and WD with hepatic involvement in a patient so as to improve the understanding of the coexistence of these two conditions. Case presentation A 35-year-old woman with SLE was found to have liver fibrosis during a routinely abdominal ultrasound examination. Her laboratory evaluation showed low serum ceruloplasmin and high 24h urine copper levels. The slit-lamp examination revealed the presence of KayseriFleischer ring in her cornea. Liver biopsy demonstrated the enlargement of the portal area with hyperplasia of the fibrous tissue, infiltration of lymphoid plasma cells, swelling of hepatocytes, and steatosis, demonstrating liver fibrosis. Ensuing genetic testing confirmed the diagnosis of WD. Conclusions Clinicians should bear in mind that unexplained liver fibrosis in patients with SLE may be related to WD, so as to avoid a missed or delayed diagnosis.
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Affiliation(s)
- Lishan Xu
- Department of Rheumatology, The Affiliated Hospital of Qingdao University, Qingdao, 260071, China
| | - Bin Liu
- Department of Rheumatology, The Affiliated Hospital of Qingdao University, Qingdao, 260071, China.
| | - Zhaoyang Liu
- Department of Rheumatology, The Affiliated Hospital of Qingdao University, Qingdao, 260071, China
| | - Ning Tang
- Department of Rheumatology, The Affiliated Hospital of Qingdao University, Qingdao, 260071, China
| | - Chunhui She
- Department of Rheumatology, The Affiliated Hospital of Qingdao University, Qingdao, 260071, China
| | - Jing Wang
- Department of Rheumatology, The Affiliated Hospital of Qingdao University, Qingdao, 260071, China
| | - Bo Zang
- Department of Rheumatology, The Affiliated Hospital of Qingdao University, Qingdao, 260071, China
| | - Yifei Yang
- Department of Rheumatology, The Affiliated Hospital of Qingdao University, Qingdao, 260071, China
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Canine Models for Copper Homeostasis Disorders. Int J Mol Sci 2016; 17:196. [PMID: 26861285 PMCID: PMC4783930 DOI: 10.3390/ijms17020196] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2015] [Revised: 01/21/2016] [Accepted: 01/25/2016] [Indexed: 12/23/2022] Open
Abstract
Copper is an essential trace nutrient metal involved in a multitude of cellular processes. Hereditary defects in copper metabolism result in disorders with a severe clinical course such as Wilson disease and Menkes disease. In Wilson disease, copper accumulation leads to liver cirrhosis and neurological impairments. A lack in genotype-phenotype correlation in Wilson disease points toward the influence of environmental factors or modifying genes. In a number of Non-Wilsonian forms of copper metabolism, the underlying genetic defects remain elusive. Several pure bred dog populations are affected with copper-associated hepatitis showing similarities to human copper metabolism disorders. Gene-mapping studies in these populations offer the opportunity to discover new genes involved in copper metabolism. Furthermore, due to the relatively large body size and long life-span of dogs they are excellent models for development of new treatment strategies. One example is the recent use of canine organoids for disease modeling and gene therapy of copper storage disease. This review addresses the opportunities offered by canine genetics for discovery of genes involved in copper metabolism disorders. Further, possibilities for the use of dogs in development of new treatment modalities for copper storage disorders, including gene repair in patient-derived hepatic organoids, are highlighted.
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Ni W, Dong QY, Zhang Y, Wu ZY. Zinc monotherapy and a low-copper diet are beneficial in patients with Wilson disease after liver transplantation. CNS Neurosci Ther 2013; 19:905-7. [PMID: 24119323 PMCID: PMC6493497 DOI: 10.1111/cns.12167] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2013] [Revised: 07/30/2013] [Accepted: 08/03/2013] [Indexed: 01/02/2023] Open
Affiliation(s)
- Wang Ni
- 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, Shanghai, China
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Mufamadi MS, Choonara YE, Kumar P, Modi G, Naidoo D, Ndesendo VMK, du Toit LC, Iyuke SE, Pillay V. Surface-Engineered Nanoliposomes by Chelating Ligands for Modulating the Neurotoxicity Associated with β-Amyloid Aggregates of Alzheimer’s disease. Pharm Res 2012; 29:3075-89. [DOI: 10.1007/s11095-012-0770-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2011] [Accepted: 04/30/2012] [Indexed: 11/28/2022]
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Shimizu N, Fujiwara J, Ohnishi S, Sato M, Kodama H, Kohsaka T, Inui A, Fujisawa T, Tamai H, Ida S, Itoh S, Ito M, Horiike N, Harada M, Yoshino M, Aoki T. Effects of long-term zinc treatment in Japanese patients with Wilson disease: efficacy, stability, and copper metabolism. Transl Res 2010; 156:350-7. [PMID: 21078496 DOI: 10.1016/j.trsl.2010.08.007] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2010] [Revised: 08/23/2010] [Accepted: 08/26/2010] [Indexed: 02/07/2023]
Abstract
Wilson disease is an autosomal recessive disorder with copper metabolism. In Japan, the standard treatment is the administration of copper chelating agents, such as D-penicillamine and trientine. In this study, the authors used zinc acetate to treat Japanese patients with Wilson disease and investigated its efficacy. The 37 patients that comprise this study were found to have Wilson disease using clinical and biochemical tests and were administrated zinc acetate for 48 weeks. The authors followed the clinical symptoms and laboratory findings of the patients by assessing their complete blood counts, biochemical findings, as well as the results of urinalysis and special laboratory tests for copper and zinc metabolism. We also examined side effects of the treatment. Zinc acetate did not aggravate the hepatic or neurological symptoms of any of the patients. Blood biochemical analysis also did not reveal elevation of alanine aminotransferase, aspartate aminotransferase, and γ-glutamyltranspeptidase levels. Zinc treatment did not aggravate the patients' clinical signs and/or laboratory findings. However, it did improve some clinical symptoms of the Wilson disease patients. Although this agent had some side effects, none of them were severe. The authors measured spot urinary copper excretion, which gave an indication of the efficacy of treatment and of the sufficient dosage of zinc. We recommend maintaining a spot urinary copper excretion less than 0.075-μg/mg creatinine. The authors conclude that zinc acetate is an effective and safe treatment for Japanese patients with Wilson disease.
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Affiliation(s)
- Norikazu Shimizu
- Department of Pediatrics, Toho University School of Medicine, Ohashi Medical Center, 2-17-6 Ohashi, Meguro-ku, Tokyo, Japan.
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Lu J, Poppitt SD, Othman AA, Sunderland T, Ruggiero K, Willett MS, Diamond LE, Garcia WD, Roesch BG, Cooper GJS. Pharmacokinetics, pharmacodynamics, and metabolism of triethylenetetramine in healthy human participants: an open-label trial. J Clin Pharmacol 2010; 50:647-58. [PMID: 20145262 DOI: 10.1177/0091270009349379] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The selective Cu(II)-chelator, triethylenetetramine (TETA), is undergoing clinical trials for the treatment of heart failure in patients with diabetes. Recently, the authors showed that 2 acetylated metabolites, N(1)-acetyltriethylenetetramine (MAT) and N(1),N(10)-diacetyltriethylenetetramine (DAT), are formed in humans following oral TETA administration. Thus, it became necessary to determine whether the N-acetyltransferase (NAT) 2 phenotype has any effects on the pharmacological properties and safety profile of TETA. Twelve fast and 12 slow NAT2-phenotype healthy participants were recruited. After oral drug administration, the authors collected plasma and urine samples, measured plasma concentrations of TETA and its 2 metabolites along with concomitant urinary copper concentrations, and performed safety tests. They present, for the first time, the complete 24-hour pharmacokinetic profiles of TETA, MAT, and DAT in humans. There was no evidence for clear-cut differences in pharmacokinetic profiles between fast and slow acetylators. Pharmacodynamic analysis showed no significant differences in cupruresis between the 2 NAT2 phenotypes. Safety results were consistent with TETA being well tolerated, and no significant differences in safety profiles were observed between the 2 phenotypes. Based on these data, NAT2 phenotype does not affect TETA's pharmacokinetic, pharmacodynamic, or safety profiles. TETA may be acetylated via an alternative mechanism, such as that catalyzed by spermidine/spermine N(1)-acetyltranferase.
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Affiliation(s)
- Jun Lu
- School of Biological Sciences, Faculty of Science, University of Auckland, Auckland 1142, New Zealand
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Nakayama K, Kubota M, Katoh Y, Sawada Y, Saito A, Nishimura K, Katsura E, Ichihara N, Suzuki T, Kouguchi H, Tamura M, Honma H, Kanzaki S, Itami H, Ohtake A, Kobayashi K, Ariga T, Fujieda K, Shimizu N, Aoki T. Early and presymptomatic detection of Wilson's disease at the mandatory 3-year-old medical health care examination in Hokkaido Prefecture with the use of a novel automated urinary ceruloplasmin assay. Mol Genet Metab 2008; 94:363-7. [PMID: 18424137 DOI: 10.1016/j.ymgme.2008.03.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2007] [Revised: 03/10/2008] [Accepted: 03/10/2008] [Indexed: 01/30/2023]
Abstract
Wilson's disease (WND) is an autosomal recessive disorder of copper (Cu) accumulation leading to liver and/or brain damage. Oral chelating agents and diet are effective in treating WND. However, once irreversible damage has occurred, the effect of treatment is diminished and the patient's quality of life is compromised. For these reasons an effective method for screening has been needed for early detection of presymptomatic patients. We conducted an early and presymptomatic detection of WND using a novel automated assay of ceruloplasmin (Cp) concentration in urine and selected the mandatory medical health care examination for 3-year-old children in Hokkaido Prefecture (the largest administrative division in Japan) as a sampling point. We measured urinary Cp concentrations in 11,362 children using an immunological latex agglutination assay kit developed by us. Among these children we identified a positive case with markedly reduced urinary Cp concentration. Detailed medical examination provided no clinical manifestations to support the diagnosis of WND, although serum Cp and Cu levels were remarkably low in this case. Therefore, we analyzed the WND gene in order to confirm the diagnosis. Sequence analysis revealed that the case was compound heterozygous for the WND gene mutations 2871del.C and D1296N. According to the Ferenci scoring system for WND diagnosis, the case was established as a WND patient at the presymptomatic stage. Consequently, the patient has maintained a good quality of life under medical treatment with polaprezinc administration to date. Our investigation suggests that the screening system for WND using the automated urinary assay at the mandatory medical health care examination for 3-year-old children is a noninvasive and efficient method for the early and presymptomatic diagnosis of WND.
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Affiliation(s)
- Kenji Nakayama
- Hokkaido Institute of Public Health, North 19 West 12, Kita-ku, Sapporo 060-0819, Hokkaido, Japan.
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Erol I, Alehan F, Ozcay F, Canan O, Haberal M. Neurologic complications of liver transplantation in pediatric patients with the hepatic form of Wilson's disease. J Child Neurol 2008; 23:293-300. [PMID: 18079318 DOI: 10.1177/0883073807309233] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The literature contains very little documentation on neurologic complications in liver transplant recipients for Wilson's disease. We retrospectively reviewed 17 consecutive cases of pediatric liver transplantation for the hepatic form of Wilson's disease to assess the types of neurologic complications that occurred, the incidence of those problems, and associated factors in this patient group. The patients were 12 boys and 5 girls; indications for liver transplantation were fulminant hepatic failure in 3 patients and chronic hepatic failure in 14 patients. Neurologic complications were observed in 10 of the 17 patients as 16 episodes. The most common neurologic complications were seizure (7 episodes in 6 patients) and sudden-onset headache (5 episodes in 4 patients). Tacrolimus was identified as the only possible cause of headache in 3 episodes. Encephalitis was the cause in 1 and intracranial hemorrhage was the cause in the other headache episode. We also noted 1 episode of tremor, 1 episode of acute dystonic reaction, 1 episode of diffuse encephalopathy, and 1 episode of common peroneal nerve palsy. Immunosuppressive agents were the primary cause of 12 of the 16 episodes of neurologic complications. Uremia with hypertension, compression of the right common peroneal nerve, encephalitis, and intracranial hemorrhages attributable to coagulopathy caused 1 neurologic episode each. Neurologic complications in patients with the hepatic form of Wilson's disease were frequent during the first 30 days after pediatric liver transplantation but did not affect survival. Transplantation teams should be aware of the high incidence of neurologic complications in pediatric patients with the hepatic form of Wilson's disease.
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Affiliation(s)
- Ilknur Erol
- Baskent University Faculty of Medicine, Department of Pediatrics, Pediatric Neurology Division, 6. Cadde 72/3 Bahcelievler, Ankara, Turkey.
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Kobayashi S, Kodama H, Inuzuka R, Mori Y, Yanagawa Y. Combination treatment with penicillamine and trientine in a patient with Wilson's disease. Pediatr Int 2005; 47:589-91. [PMID: 16190972 DOI: 10.1111/j.1442-200x.2005.02106.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Shigetoshi Kobayashi
- Department of Pediatrics, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan.
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Wang XH, Cheng F, Zhang F, Li XC, Kong LB, Li GQ, Li J, Qian XF. Living-related liver transplantation for Wilson's disease. Transpl Int 2005; 18:651-656. [PMID: 15910288 DOI: 10.1111/j.1432-2277.2004.00074.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Orthotopic liver transplantation has been applied to the treatment of Wilson's disease (WD), living-related liver transplantation (LRLT) has also been indicated for WD with increasing frequency. Between January 2001 and November 2003, 22 LRLTs were performed on patients (19 pediatric, three adults) with WD in liver transplantation center. Two patients were transplanted because of a presentation coexistent with fulminant hepatic failure. Twenty presented with chronic advanced liver disease with (n = 9) or without (n = 11) associated neurologic manifestations. All the recipients had low serum ceruloplasmin levels with a mean value of 12.8 +/- 3.2 mg/dl before transplantation and increased to an average of 26.0 +/- 3.6 mg/dl after LRLT at the latest evaluation. The survival patients with neurologic manifestations such as tremor, dysarthia, dysphagia, dystonia and sialorrhea had improved after LRLT. This suggests that LRLT not only resolves the hepatic but also ameliorates the neurologic consequences of WD.
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Affiliation(s)
- Xue-hao Wang
- Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
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Pellecchia MT, Criscuolo C, Longo K, Campanella G, Filla A, Barone P. Clinical presentation and treatment of Wilson's disease: a single-centre experience. Eur Neurol 2003; 50:48-52. [PMID: 12824712 DOI: 10.1159/000070858] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2002] [Accepted: 02/25/2003] [Indexed: 11/19/2022]
Abstract
Thirty patients with Wilson's disease (WD) were observed at a movement disorder clinic between 1970 and 2000. Disease onset was at the mean age (SD) of 14.5 (+/-5.9) years. Presentation with hepatic disease occurred in 12 of 30 patients and with neurologic disease in 15. Three patients were asymptomatic at the time of diagnosis. The mean (SD) delay to diagnosis was 5.9 (+/-5.7) years. Five patients diagnosed in an advanced stage of disease died before initiating treatment. Eighteen patients were followed and treated with D-penicillamine alone or in combination with zinc sulphate. Treatment improved most of neurological symptoms. Dystonic postures, behavioural disturbances and dysarthria were the most resistant neurological signs. 'Pseudo-sclerotic' neurologic involvement predicted a good outcome, whereas hepatic onset and 'classic' neurologic involvement were associated with a poorer prognosis. Two of the 18 treated patients died of hepatic failure due to voluntary discontinuation of therapy. Both D-penicillamine and zinc sulphate were well tolerated. No teratogenic effect of D-penicillamine was observed throughout 5 pregnancies. Our results suggest that D-penicillamine or a combination of D-penicillamine and zinc sulphate is a safe and effective long-term treatment in patients with WD.
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Affiliation(s)
- M T Pellecchia
- Department of Neurological Sciences, University Federico II, Naples, Italy.
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Giles NM, Watts AB, Giles GI, Fry FH, Littlechild JA, Jacob C. Metal and redox modulation of cysteine protein function. CHEMISTRY & BIOLOGY 2003; 10:677-93. [PMID: 12954327 DOI: 10.1016/s1074-5521(03)00174-1] [Citation(s) in RCA: 331] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
In biological systems, the amino acid cysteine combines catalytic activity with an extensive redox chemistry and unique metal binding properties. The interdependency of these three aspects of the thiol group permits the redox regulation of proteins and metal binding, metal control of redox activity, and ligand control of metal-based enzyme catalysis. Cysteine proteins are therefore able to act as "redox switches," to sense concentrations of oxidative stressors and unbound zinc ions in the cytosol, to provide a "storage facility" for excess metal ions, to control the activity of metalloproteins, and to take part in important regulatory and signaling pathways. The diversity of cysteine's multiple roles in vivo is equally as fascinating as it is promising for future biochemical and pharmacological research.
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Affiliation(s)
- Niroshini M Giles
- School of Biological and Chemical Sciences, University of Exeter, Stocker Road, EX4 4QD, Exeter, United Kingdom
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Sutcliffe RP, Maguire DD, Muiesan P, Dhawan A, Mieli-Vergani G, O'Grady JG, Rela M, Heaton ND. Liver transplantation for Wilson's disease: long-term results and quality-of-life assessment. Transplantation 2003; 75:1003-6. [PMID: 12698088 DOI: 10.1097/01.tp.0000055830.82799.b1] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Wilson's disease associated with severe liver disease is effectively cured by orthotopic liver transplantation (OLT). However, there are also anecdotal reports of improved or resolved neurologic symptoms after OLT in patients with stable or normal liver function. Side effects with conventional chelating agents are common, and it has been suggested that OLT should be considered in patients with severe progressive neurologic symptoms. However, the decision to apply this therapeutic modality to a subgroup of patients without significant liver disease is a quality-of-life issue. METHODS Long-term follow-up and quality-of-life data were obtained prospectively for 24 patients who underwent OLT between 1988 and 2000 for Wilson's disease associated with severe liver disease. In long-term survivors, quality of life was assessed using the 36-Item Short Form 36 Health Survey Questionnaire. RESULTS One patient who had multiorgan failure before OLT died within 24 hr of surgery and two patients died within 1 year because of immunosuppressant-related complications. There have been no deaths or graft loss in patients who have undergone transplantation since 1994, and after a median follow-up of 92 months, all survivors have satisfactory graft function (5-year patient and graft survival, 87.5%), with quality-of-life scores (assessed in 86% of survivors) comparable to age- and sex-matched controls from the general population. CONCLUSIONS The authors' results suggest that liver transplantation can be safely performed in patients with Wilson's disease, with excellent long-term results and quality of life. Further study of the utility of liver transplantation in the management of patients with severe neurologic symptoms is justified.
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Affiliation(s)
- Robert P Sutcliffe
- Institute of Liver Studies, Liver Transplant Unit, Kings College Hospital, London SE5 9RS, United Kingdom
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Nakano Y, Nohta H, Yoshida H, Saita T, Fujito H, Mori M, Yamaguchi M. Liquid chromatographic determination of triethylenetetramine in human and rabbit sera based on intramolecular excimer-forming fluorescence derivatization. J Chromatogr B Analyt Technol Biomed Life Sci 2002; 774:165-72. [PMID: 12076686 DOI: 10.1016/s1570-0232(02)00185-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
A highly selective and simple fluorimetric liquid chromatographic method for the determination of triethylenetetramine (TETA), a therapeutic drug for Wilson's disease, in human and rabbit sera is described. This method is based on intramolecular excimer-forming fluorescence derivatization, which allows spectrofluorometric discrimination of polyamino compounds from monoamino species, followed by liquid chromatography. TETA and 1,6-hexanediamine (internal standard) were converted to the corresponding excimer-forming derivatives with a pyrene reagent, 4-(1-pyrene)butyric acid N-hydroxysuccinimide ester. The derivatives were separated within 20 min on a reversed-phase column using isocratic elution and detected spectofluorometrically at 480 nm with excitation at 345 nm. This method was successfully applied to the monitoring of TETA in human and rabbit sera with a simple pretreatment. The detection limit for TETA in serum was 18 ng/ml (0.13 nmol/ml) corresponding to 0.2 pmol on column at a signal-to-noise ratio of 3.
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Affiliation(s)
- Yukitaka Nakano
- Faculty of Hospital Pharmacy, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan
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18
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Bono W, Moutie O, Benomar A, Aïdi S, el Alaoui-Faris M, Yahyaoui M, Chkili T. [Wilson's disease. Clinical presentation, treatment and evolution in 21 cases]. Rev Med Interne 2002; 23:419-31. [PMID: 12064213 DOI: 10.1016/s0248-8663(02)00589-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
PURPOSE Wilson's disease is characterized by neuropsychiatric symptoms with frequent extrapyramidal and intellectual presentations. They have an insidious evolution that leads to a late diagnosis and less therapeutic effectiveness in the advanced forms. METHODS We report 21 cases of Wilson's disease with neurological complications, emphasizing clinical semiology, diagnostic means and problems of the therapeutics in our country. RESULTS The average age at the beginning of the disease was 17.6 years, with a female prevalence (8/13). The signs at first were mostly all neurological (71.4%), then psychiatric (19%) or hepatic (19%). The most common neurological signs were dystonia of members (81%), dysarthria (76%), tremors (76%) or disorders of motoricity (71.4%). Sometimes there were sialorrhea or disorders of the handwriting. The Kayser-Fleischer ring was present in 19 patients. Eighteen patients had clinical and/or biological hepatic involvement. The diagnosis was confirmed by biochemical examinations, which found a low rate of copper in blood, a sinking rate of ceruloplasmin and a very high rate of urinary copper. The cerebral computer tomography shows a cortical and/or subcortical atrophy (37%), and/or a low density of the central grey cores (35%). The treatment was based on D-penicillamine and/or zinc sulfate, according to the availability of the drugs. The evolution was favourable among 18 patients (85%) and not good in 42.8% of the cases. Six of the first patients had poor evolution after many years of follow-up. Finally, only 12 patients (57%) had a very good outcome. The family investigation made among 17 patients revealed 13 family cases. The only predictive factor of a poor evolution was the therapeutic noncompliance (P = 0.006). CONCLUSIONS The neurological presentations are traditional during the Wilson's disease, but are often ignored. We must suspect the disease in children when faced with disorders of handwriting or school failures and in the adult, when faced with neurological symptoms in a patient having a hepatic disease. We must not hesitate to consider it even given purely psychiatric signs, and we had better know to seek the neurological ones.
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Affiliation(s)
- W Bono
- Service de neurologie, hôpital des spécialités, CHU Ibn Sina, Rabat, Maroc.
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19
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Hermes-Lima M, Gonçalves MS, Andrade RG. Pyridoxal isonicotinoyl hydrazone (PIH) prevents copper-mediated in vitro free radical formation. Mol Cell Biochem 2001; 228:73-82. [PMID: 11855743 DOI: 10.1023/a:1013348005312] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Pyridoxal isonicotinoyl hydrazone (PIH) is an iron chelator with antioxidant activity, low toxicity and is useful in the experimental treatment of iron-overload diseases. Previous studies on x-ray diffraction have revealed that PIH also forms a complex with Cu(II). Since the main drug of choice for the treatment of Wilson's disease, d-penicillamine, causes a series of side effects, there is an urgent need for the development of alternative copper chelating agents for clinical use. These chelators must also have antioxidant activity because oxidative stress is associated with brain and liver copper-overload. In this work we tested the ability of PIH to prevent in vitro free radical formation mediated by Cu(II), ascorbate and dissolved O2. Degradation of 2-deoxyribose mediated by 10 microM Cu(II) and 3 mM ascorbate was fully inhibited by 10 microM PIH (I50 = 6 microM) or 20 microM d-penicillamine (I50 = 10 microM). The antioxidant efficiency of PIH remained unchanged with increasing concentrations (from 1 to 15 mM) of the hydroxyl radical detector molecule, 2-deoxyribose, indicating that PIH does not act as a hydroxyl scavenger. On the other hand, the efficiency of PIH (against copper-mediated 2-deoxyribose degradation and ascorbate oxidation) was inversely proportional to the Cu(II) concentration, suggesting a competition between PIH and ascorbate for complexation with Cu(lI). An almost full inhibitory effect by PIH was observed when the ratio PIH:copper was 1:1. A similar result was obtained with the measurement of copper plus ascorbate-mediated O2 uptake. Moreover, spectral studies of the copper and PIH interaction showed a peak at 455 nm and also indicated the formation of a stable Cu(II) complex with PIH with a 1:1 ratio. These data demonstrated that PIH prevents hydroxyl radical formation and oxidative damage to 2-deoxyribose by forming a complex with Cu(II) that is not reactive with ascorbate (first step of the reactions leading to hydroxyl radical formation from Cu(II), ascorbate and O2) and does not participate in Haber-Weiss reactions.
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Affiliation(s)
- M Hermes-Lima
- Departamento de Biologia Celular, Instituto de Quimica, Universidade de Brasilia, DF, Brazil.
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20
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Floris G, Medda R, Padiglia A, Musci G. The physiopathological significance of ceruloplasmin. A possible therapeutic approach. Biochem Pharmacol 2000; 60:1735-41. [PMID: 11108788 DOI: 10.1016/s0006-2952(00)00399-3] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
This article reviews and comments on the physiological roles of ceruloplasmin (Cp). We show that, in addition to its ascertained involvement in iron homeostasis, the protein, by virtue of its unique structure among multicopper oxidases, is likely involved in other processes of both an enzymatic and a nonenzymatic nature. In particular, based on the analysis of the kinetic parameters, on the one hand, and of the side-products of the oxidation, on the other, we propose that the long-recognized ability of Cp to interact with and oxidize non-iron substrates may be of physiological relevance. The striking example of 6-hydroxydopamine oxidation is presented, where we show that the catalytic action is carried out readily under physiological conditions, without release of potentially toxic oxygen intermediates.
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Affiliation(s)
- G Floris
- Department of Sciences Applied to Biosystems, University of Cagliari, Cagliari, Italy
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21
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Abstract
Zn is an essential trace element for all organisms. In human subjects body growth and development is strictly dependent on Zn. The nervous, reproductive and immune systems are particularly influenced by Zn deficiency, as well as by increased levels of Zn. The relationship between Zn and the immune system is complex, since there are four different types of influence associated with Zn. (1) The dietary intake and the resorption of Zn depends on the composition of the diet and also on age and disease status. (2) Zn is a cofactor in more than 300 enzymes influencing various organ functions having a secondary effect on the immune system. (3) Direct effects of Zn on the production, maturation and function of leucocytes. (4) Zn influences the function of immunostimulants used in the experimental systems. Here we summarize all four types of influence on the immune function. Nutritional aspects of Zn, the physiology of Zn, the influence of Zn on enzymes and cellular functions, direct effects of Zn on leucocytes at the cellular and molecular level, Zn-altered function of immunostimulants and the therapeutic use of Zn will be discussed in detail.
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Affiliation(s)
- L Rink
- Institute of Immunology and Transfusion Medicine, University of Lübeck School of Medicine, Ratzeburger Allee 160, D-23538 Lübeck, Germany.
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