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1
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Lee YT, Wu FY, Chang YS. Epidemiology and effect of psychiatric comorbidities on survival rates in patients with systemic sclerosis: A nationwide population-based cohort study. J Affect Disord 2025; 382:518-524. [PMID: 40274124 DOI: 10.1016/j.jad.2025.04.104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 04/09/2025] [Accepted: 04/19/2025] [Indexed: 04/26/2025]
Abstract
BACKGROUND Systemic sclerosis (SSc) is a chronic, disabling connective tissue disease with a considerable psychological burden. While studies suggest a higher prevalence of psychiatric disorders in SSc, most have small sample sizes. METHODS Using Taiwan's National Health Insurance Research Database, we identified 3270 SSc patients from the catastrophic illness registry and matched them 1:4 by age and sex with 13,080 controls. We compared the incidence rate ratios (IRRs) of new psychiatric disorder diagnoses between the two groups and analyzed risk factors using a Cox proportional hazards model. Kaplan-Meier analysis and log-rank test were used to compare survival in SSc patients with and without psychiatric conditions (matched at a 1:4 ratio by age, sex and CCI). We compared psychiatric disorder incidence rates. RESULTS The SSc group had a significantly higher incidence of psychiatric disorders than controls (IRR = 1.66, p < 0.001). In SSc patients, treatment with an oral daily steroid dose of ≥7.5 mg (hazard ratio [HR] = 1.71, p = 0.010), intravenous steroid pulse therapy (HR = 2.34, p < 0.0042), or D-penicillamine (HR = 1.60, p < 0.001) served as an independent risk factor for psychiatric comorbidities. SSc patients with psychiatric comorbidities had significantly lower survival rates than those without. CONCLUSIONS Patients with SSc are at an increased risk of psychiatric comorbidities, which can negatively affect their survival rates. Treatment with a daily oral steroid dose of ≥7.5 mg, intravenous steroid pulse therapy, or D-penicillamine is a risk factor for psychiatric comorbidities in SSc.
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Affiliation(s)
- Yao-Tung Lee
- Department of Psychiatry and Psychosomatic Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan; Department of Psychiatry, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; Graduate School of Criminology, National Taipei University, New Taipei City, Taiwan.
| | - Fang-Yi Wu
- Department of Data Science, American University College of Arts and Sciences, Washington, DC, USA
| | - Yu-Sheng Chang
- Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
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2
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Minemura M, Fukuda R, Tajiri K, Muraishi N, Murayama A, Hayashi Y, Takahara T, Noguchi A, Yasuda I. Wilson's Disease Suspected to Involve a Novel Genetic Mutation of ATP7B Gene, Requiring a Differential Diagnosis with Non-alcoholic Steatohepatitis. Intern Med 2025; 64:375-379. [PMID: 38960689 PMCID: PMC11867747 DOI: 10.2169/internalmedicine.3673-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 05/19/2024] [Indexed: 07/05/2024] Open
Abstract
A 19-year-old Japanese man was referred for a further evaluation of liver dysfunction. Despite the absence of symptoms or obesity, the liver biopsy results were consistent with non-alcoholic steatohepatitis. Subsequent investigations revealed low serum ceruloplasmin, increased urinary copper excretion, and a known mutation c.3809A>G (p.Asn1270Ser) in the copper-transporting enzyme P-type ATPase (ATP7B) gene, leading to a diagnosis of Wilson's disease. A previously unreported variant, i.e., c.3866A>T (p.Asp1289Val) was detected on the patient's other allele and was considered a novel mutation, classified as 'likely pathogenic' according to the American College of Medical Genetics guidelines.
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Affiliation(s)
- Masami Minemura
- Department of Gastroenterology, Toyama University Hospital, Japan
- Department of Community Medical Support, Toyama University Hospital, Japan
| | - Rei Fukuda
- Department of Clinical Genetics, Toyama University Hospital, Japan
| | - Kazuto Tajiri
- Department of Gastroenterology, Toyama University Hospital, Japan
| | - Nozomu Muraishi
- Department of Gastroenterology, Toyama University Hospital, Japan
| | - Aiko Murayama
- Department of Gastroenterology, Toyama University Hospital, Japan
| | - Yuka Hayashi
- Department of Gastroenterology, Toyama University Hospital, Japan
| | - Terumi Takahara
- Department of Gastroenterology, Toyama University Hospital, Japan
| | - Akira Noguchi
- Department of Diagnostic Pathology, Toyama University Hospital, Japan
| | - Ichiro Yasuda
- Department of Gastroenterology, Toyama University Hospital, Japan
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3
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Kirss S, Reinapu A, Kabin E, Smirnova J, Tõugu V, Palumaa P. α-Lipoic acid: a potential regulator of copper metabolism in Alzheimer's disease. Front Mol Biosci 2024; 11:1451536. [PMID: 39290994 PMCID: PMC11405343 DOI: 10.3389/fmolb.2024.1451536] [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: 06/19/2024] [Accepted: 08/20/2024] [Indexed: 09/19/2024] Open
Abstract
Alzheimer's disease (AD) is characterized by classic hallmarks such as amyloid plaques and neurofibrillary tangles, however, intensive research has broadened its scope to explore additional underlying mechanisms. Notably, disruptions in metal homeostasis, particularly involving copper, have gained significant attention. In AD pathology, an imbalance is evident: there is an excess of extracellular copper alongside a deficiency in intracellular copper in brain tissue. Our previous work demonstrated that α-lipoic acid (LA) can effectively shift copper from the extracellular space to the intracellular environment in a neuronal cell model. However, the precise mechanism of action and role of LA in copper metabolism remained elusive. In this study, we compared the cellular effects of LA with those of different synthetic copper-binding ligands: diethyldithiocarbamate (DETC), clioquinol (CQ), D-penicillamine (D-PA) and elesclomol (ES). Using differentiated SH-SY5Y cell culture as a neuronal model, we found that, unlike other synthetic compounds, natural ligand LA is not toxic in the presence of extracellular copper, even at high doses. LA gradually increased intracellular copper levels over 24 h. In contrast, DETC, CQ, and ES acted as fast copper ionophores, potentially explaining their higher toxicity compared to LA. D-PA did not facilitate copper uptake into cells. We demonstrated that a slow increase of LA inside the cells is enhanced in the presence of copper. Furthermore, the ability of LA to modulate the equilibrium of extra- and intracellular copper was evident when we added copper isotope 65Cu. The ratio of copper isotopes changed rapidly, reflecting the impact of LA on the equilibrium of copper distribution without affecting the copper transport network. Our results provide compelling evidence that α-lipoic acid holds promise as a non-toxic agent capable of normalizing copper metabolism in Alzheimer's disease.
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Affiliation(s)
- Sigrid Kirss
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
| | - Anette Reinapu
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
| | - Ekaterina Kabin
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
| | - Julia Smirnova
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
| | - Vello Tõugu
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
| | - Peep Palumaa
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
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4
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Lee EJ, Woo MH, Moon JS, Ko JS. Efficacy and safety of D-penicillamine, trientine, and zinc in pediatric Wilson disease patients. Orphanet J Rare Dis 2024; 19:261. [PMID: 38982450 PMCID: PMC11234817 DOI: 10.1186/s13023-024-03271-1] [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: 10/29/2023] [Accepted: 07/01/2024] [Indexed: 07/11/2024] Open
Abstract
OBJECTIVES Wilson disease (WD) is a rare genetic disease affecting copper metabolism and the biliary tract's copper excretion. Lifelong medication is necessary to prevent liver failure, neurological complications, and death. Although D-penicillamine (DPA), trientine, and zinc are used to treat WD, there is limited research on the long-term outcomes of these drugs, especially in children. This study aimed to evaluate the efficacy and safety of DPA, trientine, and zinc in patients diagnosed with WD during childhood. METHODS Ninety out of 92 patients were included in the analysis, excluding two patients who underwent liver transplantation without drug treatment due to an acute liver failure diagnosis. Treatment outcomes and reasons for discontinuation of therapy in 148 treatment blocks (37 DPA, 50 trientine, and 61 zinc) were analyzed using Kaplan-Meier analysis. RESULTS The median age at diagnosis was 8.3 years. There was a statistically significant difference in drug changes due to treatment ineffectiveness among the three drugs: trientine (22/50, 44%), zinc (15/61, 25%), and DPA (2/37, 5%) (all p < 0.05). Regarding drug changes due to adverse effects, the rate was the highest for DPA, followed by zinc and trientine. There were significant differences between DPA and zinc, zinc and trientine (all p < 0.05), but no significant difference was observed between DPA and zinc (p = 0.22). CONCLUSIONS In pediatric WD, DPA, zinc, and trientine have therapeutic effects in that order. However, DPA and zinc are associated with more adverse effects compared to trientine.
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Affiliation(s)
- Eun Joo Lee
- Department of Pediatrics, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Min Hyung Woo
- Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Jin Soo Moon
- Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Jae Sung Ko
- Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea.
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Kirk FT, Munk DE, Swenson ES, Quicquaro AM, Vendelbo MH, Larsen A, Schilsky ML, Ott P, Sandahl TD. Effects of tetrathiomolybdate on copper metabolism in healthy volunteers and in patients with Wilson disease. J Hepatol 2024; 80:586-595. [PMID: 38081365 DOI: 10.1016/j.jhep.2023.11.023] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 11/08/2023] [Accepted: 11/23/2023] [Indexed: 01/19/2024]
Abstract
BACKGROUND & AIMS In Wilson disease (WD), copper accumulates in the liver and brain causing disease. Bis-choline tetrathiomolybdate (TTM) is a potent copper chelator that may be associated with a lower risk of inducing paradoxical neurological worsening than conventional therapy for neurologic WD. To better understand the mode of action of TTM, we investigated its effects on copper absorption and biliary excretion. METHODS In a double-blind randomized setting, hepatic 64Cu activity was examined after orally administered 64Cu by PET/CT in 16 healthy volunteers before and after seven days of TTM treatment (15 mg/d) or placebo. Oral 64Cu was administered one hour after the final TTM dose. Changes in hepatic 64Cu activity reflected changes in intestinal 64Cu uptake. Additionally, in four patients with WD, the distribution of 64Cu in venous blood, liver, gallbladder, kidney, and brain was followed after i.v. 64Cu dosing for up to 68 hours before and after seven days of TTM (15 mg/day), using PET/MRI. Increased gallbladder 64Cu activity was taken as evidence of increased biliary 64Cu excretion. RESULTS In healthy volunteers, TTM reduced intestinal 64Cu uptake by 82% 15 hours after the oral 64Cu dose. In patients with WD, gallbladder 64Cu activity was negligible before and after TTM, while TTM effectively retained 64Cu in the blood, significantly reduced hepatic 64Cu activity at all time-points and significantly reduced cerebral 64Cu activity two hours after the intravenous 64Cu dose. CONCLUSIONS While we did not show an increase in biliary excretion of 64Cu following TTM administration, we demonstrated that TTM effectively inhibited most intestinal 64Cu uptake and retained 64Cu in the blood stream, limiting the exposure of organs like the liver and brain to 64Cu. IMPACT AND IMPLICATIONS Bis-choline tetrathiomolybdate (TTM) is an investigational copper chelator being developed for the treatment of Wilson disease. In animal models of Wilson disease, TTM has been shown to facilitate biliary copper excretion. In the present human study, TTM surprisingly did not facilitate biliary copper excretion but instead reduced intestinal copper uptake to a clinically significant degree. Our study builds on our understanding of human copper metabolism and the mechanism of action of TTM.
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Affiliation(s)
- Frederik Teicher Kirk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
| | - Ditte Emilie Munk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | | | | | - Mikkel Holm Vendelbo
- Department of Nuclear Medicine & PET-center, Aarhus University Hospital, Aarhus, Denmark; Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Agnete Larsen
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Michael L Schilsky
- Department of Medicine, Section of Digestive Diseases, and Department of Surgery, Section of Transplant and Immunology, Yale School of Medicine, New Haven, CT, USA
| | - Peter Ott
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
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Litwin T, Członkowska A, Smolinski L. Early neurological worsening in Wilson disease: The need for an evidence-based definition. J Hepatol 2023; 79:e241-e242. [PMID: 37392837 DOI: 10.1016/j.jhep.2023.06.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 06/15/2023] [Indexed: 07/03/2023]
Affiliation(s)
- Tomasz Litwin
- Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland.
| | - Anna Członkowska
- Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Lukasz Smolinski
- Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
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7
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Cazzoli R, Zamborlin A, Ermini ML, Salerno A, Curcio M, Nicoletta FP, Iemma F, Vittorio O, Voliani V, Cirillo G. Evolving approaches in glioma treatment: harnessing the potential of copper metabolism modulation. RSC Adv 2023; 13:34045-34056. [PMID: 38020008 PMCID: PMC10661684 DOI: 10.1039/d3ra06434d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 11/10/2023] [Indexed: 12/01/2023] Open
Abstract
The key properties and high versatility of metal nanoparticles have shed new perspectives on cancer therapy, with copper nanoparticles gaining great interest because of the ability to couple the intrinsic properties of metal nanoparticles with the biological activities of copper ions in cancer cells. Copper, indeed, is a cofactor involved in different metabolic pathways of many physiological and pathological processes. Literature data report on the use of copper in preclinical protocols for cancer treatment based on chemo-, photothermal-, or copper chelating-therapies. Copper nanoparticles exhibit anticancer activity via multiple routes, mainly involving the targeting of mitochondria, the modulation of oxidative stress, the induction of apoptosis and autophagy, and the modulation of immune response. Moreover, compared to other metal nanoparticles (e.g. gold, silver, palladium, and platinum), copper nanoparticles are rapidly cleared from organs with low systemic toxicity and benefit from the copper's low cost and wide availability. Within this review, we aim to explore the impact of copper in cancer research, focusing on glioma, the most common primary brain tumour. Glioma accounts for about 80% of all malignant brain tumours and shows a poor prognosis with the five-year survival rate being less than 5%. After introducing the glioma pathogenesis and the limitation of current therapeutic strategies, we will discuss the potential impact of copper therapy and present the key results of the most relevant literature to establish a reliable foundation for future development of copper-based approaches.
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Affiliation(s)
- Riccardo Cazzoli
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales Sydney NSW Australia
| | - Agata Zamborlin
- NEST-Scuola Normale Superiore Piazza San Silvestro 12 - 56127 Pisa Italy
- Center for Nanotechnology Innovation, Istituto Italiano di Tecnologia Piazza San Silvestro 12 - 56127 Pisa Italy
| | - Maria Laura Ermini
- Center for Nanotechnology Innovation, Istituto Italiano di Tecnologia Piazza San Silvestro 12 - 56127 Pisa Italy
| | - Antonietta Salerno
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales Sydney NSW Australia
| | - Manuela Curcio
- Department of Pharmacy Health and Nutritional Science, University of Calabria 87036 Rende Italy +39 0984493208
| | - Fiore Pasquale Nicoletta
- Department of Pharmacy Health and Nutritional Science, University of Calabria 87036 Rende Italy +39 0984493208
| | - Francesca Iemma
- Department of Pharmacy Health and Nutritional Science, University of Calabria 87036 Rende Italy +39 0984493208
| | - Orazio Vittorio
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales Sydney NSW Australia
- School of Biomedical Sciences, University of New South Wales Sydney NSW Australia
| | - Valerio Voliani
- Center for Nanotechnology Innovation, Istituto Italiano di Tecnologia Piazza San Silvestro 12 - 56127 Pisa Italy
- Department of Pharmacy, School of Medical and Pharmaceutical Sciences, University of Genoa Viale Cembrano 4 - 16148 Genoa Italy
| | - Giuseppe Cirillo
- Department of Pharmacy Health and Nutritional Science, University of Calabria 87036 Rende Italy +39 0984493208
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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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Kabin E, Dong Y, Roy S, Smirnova J, Smith JW, Ralle M, Summers K, Yang H, Dev S, Wang Y, Devenney B, Cole RN, Palumaa P, Lutsenko S. α-lipoic acid ameliorates consequences of copper overload by up-regulating selenoproteins and decreasing redox misbalance. Proc Natl Acad Sci U S A 2023; 120:e2305961120. [PMID: 37751556 PMCID: PMC10556618 DOI: 10.1073/pnas.2305961120] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 08/18/2023] [Indexed: 09/28/2023] Open
Abstract
α-lipoic acid (LA) is an essential cofactor for mitochondrial dehydrogenases and is required for cell growth, metabolic fuel production, and antioxidant defense. In vitro, LA binds copper (Cu) with high affinity and as an endogenous membrane permeable metabolite could be advantageous in mitigating the consequences of Cu overload in human diseases. We tested this hypothesis in 3T3-L1 preadipocytes with inactivated Cu transporter Atp7a; these cells accumulate Cu and show morphologic changes and mitochondria impairment. Treatment with LA corrected the morphology of Atp7a-/- cells similar to the Cu chelator bathocuproinedisulfonate (BCS) and improved mitochondria function; however, the mechanisms of LA and BCS action were different. Unlike BCS, LA did not decrease intracellular Cu but instead increased selenium levels that were low in Atp7a-/- cells. Proteome analysis confirmed distinct cell responses to these compounds and identified upregulation of selenoproteins as the major effect of LA on preadipocytes. Upregulation of selenoproteins was associated with an improved GSH:GSSG ratio in cellular compartments, which was lowered by elevated Cu, and reversal of protein oxidation. Thus, LA diminishes toxic effects of elevated Cu by improving cellular redox environment. We also show that selenium levels are decreased in tissues of a Wilson disease animal model, especially in the liver, making LA an attractive candidate for supplemental treatment of this disease.
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Affiliation(s)
- Ekaterina Kabin
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn12618, Estonia
- Department of Physiology, Johns Hopkins Medical Institutes, Baltimore, MD21205
| | - Yixuan Dong
- Department of Physiology, Johns Hopkins Medical Institutes, Baltimore, MD21205
| | - Shubhrajit Roy
- Department of Physiology, Johns Hopkins Medical Institutes, Baltimore, MD21205
| | - Julia Smirnova
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn12618, Estonia
| | - Joshua W. Smith
- Mass Spectrometry and Proteomics Core, Johns Hopkins Medical Institutes, Baltimore, MD21205
| | - Martina Ralle
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR97201
| | - Kelly Summers
- Department of Physiology, Johns Hopkins Medical Institutes, Baltimore, MD21205
| | - Haojun Yang
- Department of Physiology, Johns Hopkins Medical Institutes, Baltimore, MD21205
| | - Som Dev
- Department of Physiology, Johns Hopkins Medical Institutes, Baltimore, MD21205
| | - Yu Wang
- Department of Physiology, Johns Hopkins Medical Institutes, Baltimore, MD21205
| | - Benjamin Devenney
- Department of Physiology, Johns Hopkins Medical Institutes, Baltimore, MD21205
| | - Robert N. Cole
- Mass Spectrometry and Proteomics Core, Johns Hopkins Medical Institutes, Baltimore, MD21205
| | - Peep Palumaa
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn12618, Estonia
| | - Svetlana Lutsenko
- Department of Physiology, Johns Hopkins Medical Institutes, Baltimore, MD21205
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Voicu V, Tataru CP, Toader C, Covache-Busuioc RA, Glavan LA, Bratu BG, Costin HP, Corlatescu AD, Ciurea AV. Decoding Neurodegeneration: A Comprehensive Review of Molecular Mechanisms, Genetic Influences, and Therapeutic Innovations. Int J Mol Sci 2023; 24:13006. [PMID: 37629187 PMCID: PMC10455143 DOI: 10.3390/ijms241613006] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 08/17/2023] [Accepted: 08/18/2023] [Indexed: 08/27/2023] Open
Abstract
Neurodegenerative disorders often acquire due to genetic predispositions and genomic alterations after exposure to multiple risk factors. The most commonly found pathologies are variations of dementia, such as frontotemporal dementia and Lewy body dementia, as well as rare subtypes of cerebral and cerebellar atrophy-based syndromes. In an emerging era of biomedical advances, molecular-cellular studies offer an essential avenue for a thorough recognition of the underlying mechanisms and their possible implications in the patient's symptomatology. This comprehensive review is focused on deciphering molecular mechanisms and the implications regarding those pathologies' clinical advancement and provides an analytical overview of genetic mutations in the case of neurodegenerative disorders. With the help of well-developed modern genetic investigations, these clinically complex disturbances are highly understood nowadays, being an important step in establishing molecularly targeted therapies and implementing those approaches in the physician's practice.
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Affiliation(s)
- Victor Voicu
- Pharmacology, Toxicology and Clinical Psychopharmacology, “Carol Davila” University of Medicine and Pharmacy in Bucharest, 020021 Bucharest, Romania;
- Medical Section within the Romanian Academy, 010071 Bucharest, Romania
| | - Calin Petre Tataru
- Department of Opthamology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Central Military Emergency Hospital “Dr. Carol Davila”, 010825 Bucharest, Romania
| | - Corneliu Toader
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (R.-A.C.-B.); (L.A.G.); (B.-G.B.); (H.P.C.); (A.D.C.); (A.V.C.)
- Department of Vascular Neurosurgery, National Institute of Neurology and Neurovascular Diseases, 077160 Bucharest, Romania
| | - Razvan-Adrian Covache-Busuioc
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (R.-A.C.-B.); (L.A.G.); (B.-G.B.); (H.P.C.); (A.D.C.); (A.V.C.)
| | - Luca Andrei Glavan
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (R.-A.C.-B.); (L.A.G.); (B.-G.B.); (H.P.C.); (A.D.C.); (A.V.C.)
| | - Bogdan-Gabriel Bratu
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (R.-A.C.-B.); (L.A.G.); (B.-G.B.); (H.P.C.); (A.D.C.); (A.V.C.)
| | - Horia Petre Costin
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (R.-A.C.-B.); (L.A.G.); (B.-G.B.); (H.P.C.); (A.D.C.); (A.V.C.)
| | - Antonio Daniel Corlatescu
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (R.-A.C.-B.); (L.A.G.); (B.-G.B.); (H.P.C.); (A.D.C.); (A.V.C.)
| | - Alexandru Vlad Ciurea
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (R.-A.C.-B.); (L.A.G.); (B.-G.B.); (H.P.C.); (A.D.C.); (A.V.C.)
- Neurosurgery Department, Sanador Clinical Hospital, 010991 Bucharest, Romania
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11
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Mohr I, Pfeiffenberger J, Eker E, Merle U, Poujois A, Ala A, Weiss KH. Neurological worsening in Wilson disease - clinical classification and outcome. J Hepatol 2023; 79:321-328. [PMID: 37116715 DOI: 10.1016/j.jhep.2023.04.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 04/02/2023] [Accepted: 04/11/2023] [Indexed: 04/30/2023]
Abstract
BACKGROUND & AIMS Prevention of neurological worsening (NW) under therapy is an unmet need in the management of Wilson disease (WD). In this study, we aimed to characterize the occurrence, associated outcomes and potential reversibility of NW in WD. METHODS From a total cohort of 457 patients with WD, 128 patients with WD and neurological features at any time point (all Caucasian, 63 females, median age at diagnosis 22 years) were identified by chart review at University Hospital Heidelberg and grouped according to initial presentation. The timing and occurrence of NW was assessed following a structured clinical examination during clinical visits. RESULTS Early NW (within the first 3 months of therapy) was observed in 30 out of 115 (26.1%) patients with neurological or mixed presentation and never in patients with a purely hepatic or asymptomatic presentation (0%). Late NW (after >12 months) was seen in a further 23 (20%) with neurological or mixed presentation and in 13 out of 294 (4.4%) patients with a hepatic or asymptomatic presentation. The median time from start of treatment to late NW was 20 months. Only three patients experienced NW between 3 and 12 months. NW was observed with D-penicillamine, trientine and zinc therapy and was reversible in 15/30 (50%) with early NW and in 29/36 (81%) with late NW. CONCLUSIONS In this study, we identified two peaks in NW: an early (≤3 months) treatment-associated peak and a late (>12 months of treatment) adherence-associated peak. Early paradoxical NW was attributed to treatment initiation and pre-existing neurological damage, and was not observed in those with a hepatic or asymptomatic presentation. Late NW is likely to be associated with non-adherence. IMPACT AND IMPLICATIONS In patients with Wilson disease, defined as an excess accumulation of copper which can damage the liver, brain and other vital organs, neurological worsening can occur despite chelation therapy. The study identifies different patterns of 'early' (<3 months) vs. 'late' (>12 months) neurological worsening in relation to initiation of chelation therapy and establishes possible causes and the potential for reversibility. These data should be useful for counseling patients and for guiding the optimal management of chelation therapy.
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Affiliation(s)
- Isabelle Mohr
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany
| | - Jan Pfeiffenberger
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany
| | - Ecem Eker
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany
| | - Uta Merle
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany
| | - Aurélia Poujois
- Department of Neurology, Rare Disease Reference Centre "Wilson's Disease and Other Copper-Related Rare Diseases", Rothschild Foundation Hospital, Paris, France
| | - Aftab Ala
- Department of Clinical and Experimental Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK; Department of Gastroenterology and Hepatology, Royal Surrey NHS Foundation Trust, Guildford, UK; Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK
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12
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Zimny S, Bourhis H, Weber S, Reiter FP, Hohenester S, Kraft E, Mohr I, Merle U, Weiss KH, Denk G. Medical care of patients with Wilson disease in Germany: a multidisciplinary survey among university centers. Orphanet J Rare Dis 2023; 18:122. [PMID: 37226184 DOI: 10.1186/s13023-023-02731-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 05/14/2023] [Indexed: 05/26/2023] Open
Abstract
BACKGROUND Wilson disease (WD) is a rare, hereditary disorder of copper metabolism. Due to its variable symptoms and manifestations, diagnosis remains challenging. Affected patients must obtain lifelong medical treatment, as the disease is fatal if untreated. Patients require continuous monitoring, but little is known about the care of these patients in Germany. Therefore, we analyzed the medical care of WD patients at German university centers. We sent a questionnaire containing 20 questions to a total of 108 departments of pediatrics, neurology and gastroenterology in 36 university hospitals. Our questions referred to the characteristics of WD patients at the different sites and internal procedures regarding diagnosis, therapy and follow-up. A descriptive statistical analysis was performed. RESULTS Sixty-three departments (58%) returned our questionnaire. In total, approximately one-third of the estimated WD patients in Germany are seen annually in the outpatient clinics of these departments (approx. 950 patients). There are only a few departments which treat patients in a multidisciplinary setting (12%). Our survey revealed that for diagnosis, 51% of all departments used an algorithm based on the Leipzig score as recommended by international guidelines. Most departments apply essential parameters recommended by WD guidelines. Routine monitoring is performed at least biannually by 84% of the departments, and standard investigations for monitoring are regularly applied. A routine family screening is performed by 84% of all departments. A reduction in medical therapy during pregnancy is recommended by 46% of the departments. Only 14% suggested that WD patients should not breastfeed. Liver transplantation (LT) due to WD is a rare but repeatedly occurring event. Most departments of gastroenterology (72%) reported at least one patient with LT within the last decade. CONCLUSIONS Medical care of WD patients at German university centers follows the recommendations set forth by international guidelines, but only a few centers treat significant numbers of patients. The surveillance of patients does not follow specified standards, but most departments adhere to the accepted guidelines. The formation of central units and networks in a multidisciplinary setting should be evaluated to improve the care of WD patients.
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Affiliation(s)
- Sebastian Zimny
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany.
| | - Hélène Bourhis
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
| | - Sabine Weber
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
| | - Florian Paul Reiter
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
- Department of Medicine II, University Hospital Würzburg, Oberdürrbacher Straße 6, 97080, Würzburg, Germany
| | - Simon Hohenester
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
| | - Eduard Kraft
- Department of Physical Medicine and Rehabilitation, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
| | - Isabelle Mohr
- Department of Internal Medicine IV, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Uta Merle
- Department of Internal Medicine IV, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Karl Heinz Weiss
- Internal Medicine, Salem Medical Center, Zeppelinstraße 11 - 33, 69121, Heidelberg, Germany
| | - Gerald Denk
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
- Transplant Center, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
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13
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Joshi SP, Thomas M, Yoganathan S, Danda S, Chandran M, Jasper A. Clinico-Etiological Spectrum and Functional Outcomes of Children with Pre-Status Dystonicus and Status Dystonicus (SD): A Descriptive Study. Ann Indian Acad Neurol 2023; 26:268-274. [PMID: 37538432 PMCID: PMC10394458 DOI: 10.4103/aian.aian_660_22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 03/05/2023] [Accepted: 03/09/2023] [Indexed: 08/05/2023] Open
Abstract
Background Status dystonicus (SD) is a life-threatening movement disorder emergency characterized by increasingly frequent and severe episodes of generalized dystonia, requiring urgent hospital admission. The diverse clinico-etiological spectrum, high risk of recurrence, and residual disabilities complicate functional outcomes. Aim We aim to describe the clinico-etiological spectrum, radiology, therapeutic options, and follow-up of patients with pre-status dystonicus (pre-SD) and SD. Methodology A cross-sectional retrospective study was carried out in a tertiary care referral center. The clinical, laboratory, and radiology data of all patients aged less than 18 years with pre-SD and SD from January 2010 to December 2020 were collected. The Dystonia Severity Assessment Plan (DSAP) scale for grading severity and the modified Rankin Scale (mRS) for assessing outcome were used at the last follow-up visit. Results Twenty-eight patients (male:female: 2.1:1) experiencing 33 episodes of acute dystonia exacerbation were identified. The median age at the onset of dystonia and SD presentation was 8.71 (range: 0.25-15.75) and 9.12 (range: 1-16.75) years, respectively. Four patients experienced more than one episode of SD. The etiological spectrum of SD includes metabolic (Wilson's disease-13, L-aromatic amino acid decarboxylase deficiency-one, and Gaucher's disease-one), genetic (neurodegeneration with brain iron accumulation-three and KMT2B and THAP 1 gene-related-one each), structural-three, post-encephalitic sequelae (PES)-four, and immune-mediated (anti-NMDA receptor encephalitis-one). Five patients had pre-SD (DSAP grade 3), and 23 patients had established SD (DSAP grade 4-17 and DSAP grade 5-six). The Rapid escalation of chelation therapy precipitated SD in 11 patients with Wilson's disease. Febrile illness or pneumonia precipitated SD in nine patients. Twenty-three episodes of SD required midazolam infusion in addition to anti-dystonic medications. The median duration of hospital stay was 10 days (range: 3-29). Twenty-three patients had resolution of SD but residual dystonia persisted, while two patients had no residual dystonia at follow-up. Three patients succumbed owing to refractory SD and its complications. Conclusion Early identification of triggers, etiology, and appropriate management are essential to calm the dystonic storm.
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Affiliation(s)
- Shridhar P. Joshi
- Paediatric Neurology Unit, Departments of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India
| | - Maya Thomas
- Paediatric Neurology Unit, Departments of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India
| | - Sangeetha Yoganathan
- Paediatric Neurology Unit, Departments of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India
| | - Sumita Danda
- Medical Genetics, Christian Medical College, Vellore, Tamil Nadu, India
| | - Mahalakshmi Chandran
- Neurochemistry Laboratory, Christian Medical College, Vellore, Tamil Nadu, India
| | - Anitha Jasper
- Radiodiagnosis, Christian Medical College, Vellore, Tamil Nadu, India
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14
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Garza NM, Swaminathan AB, Maremanda KP, Zulkifli M, Gohil VM. Mitochondrial copper in human genetic disorders. Trends Endocrinol Metab 2023; 34:21-33. [PMID: 36435678 PMCID: PMC9780195 DOI: 10.1016/j.tem.2022.11.001] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 10/28/2022] [Accepted: 11/04/2022] [Indexed: 11/24/2022]
Abstract
Copper is an essential micronutrient that serves as a cofactor for enzymes involved in diverse physiological processes, including mitochondrial energy generation. Copper enters cells through a dedicated copper transporter and is distributed to intracellular cuproenzymes by copper chaperones. Mitochondria are critical copper-utilizing organelles that harbor an essential cuproenzyme cytochrome c oxidase, which powers energy production. Mutations in copper transporters and chaperones that perturb mitochondrial copper homeostasis result in fatal genetic disorders. Recent studies have uncovered the therapeutic potential of elesclomol, a copper ionophore, for the treatment of copper deficiency disorders such as Menkes disease. Here we review the role of copper in mitochondrial energy metabolism in the context of human diseases and highlight the recent developments in copper therapeutics.
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Affiliation(s)
- Natalie M Garza
- Department of Biochemistry and Biophysics, MS 3474, Texas A&M University, College Station, TX 77843, USA
| | - Abhinav B Swaminathan
- Department of Biochemistry and Biophysics, MS 3474, Texas A&M University, College Station, TX 77843, USA
| | - Krishna P Maremanda
- Department of Biochemistry and Biophysics, MS 3474, Texas A&M University, College Station, TX 77843, USA
| | - Mohammad Zulkifli
- Department of Biochemistry and Biophysics, MS 3474, Texas A&M University, College Station, TX 77843, USA
| | - Vishal M Gohil
- Department of Biochemistry and Biophysics, MS 3474, Texas A&M University, College Station, TX 77843, USA.
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15
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Schilsky ML, Roberts EA, Bronstein JM, Dhawan A, Hamilton JP, Rivard AM, Washington MK, Weiss KH, Zimbrean PC. A multidisciplinary approach to the diagnosis and management of Wilson disease: 2022 Practice Guidance on Wilson disease from the American Association for the Study of Liver Diseases. Hepatology 2022:01515467-990000000-00207. [PMID: 36151586 DOI: 10.1002/hep.32801] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 09/13/2022] [Indexed: 01/18/2023]
Affiliation(s)
- Michael L Schilsky
- Medicine and Surgery , Yale University School of Medicine , New Haven , Connecticut , USA
| | - Eve A Roberts
- Paediatrics, Medicine, Pharmacology and Toxicology , University of Toronto , Toronto , Ontario , Canada
| | - Jeff M Bronstein
- Neurology , University of California Los Angeles , Los Angeles , California , USA
| | - Anil Dhawan
- Paediatric Liver, GI and Nutrition Centre and MowatLabs , King's College Hospital , London , UK
| | - James P Hamilton
- Medicine , Johns Hopkins University School of Medicine , Baltimore , Maryland , USA
| | - Anne Marie Rivard
- Food and Nutrition Services , Yale New Haven Hospital , New Haven , Connecticut , USA
| | - Mary Kay Washington
- Pathology, Immunology and Microbiology , Vanderbilt University Medical Center , Nashville , Tennessee , USA
| | | | - Paula C Zimbrean
- Psychiatry , Yale University School of Medicine , New Haven , Connecticut , USA
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16
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Avan A, Członkowska A, Gaskin S, Granzotto A, Sensi SL, Hoogenraad TU. The Role of Zinc in the Treatment of Wilson’s Disease. Int J Mol Sci 2022; 23:ijms23169316. [PMID: 36012580 PMCID: PMC9409413 DOI: 10.3390/ijms23169316] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/09/2022] [Accepted: 08/15/2022] [Indexed: 02/06/2023] Open
Abstract
Wilson’s disease (WD) is a hereditary disorder of copper metabolism, producing abnormally high levels of non-ceruloplasmin-bound copper, the determinant of the pathogenic process causing brain and hepatic damage and dysfunction. Although the disease is invariably fatal without medication, it is treatable and many of its adverse effects are reversible. Diagnosis is difficult due to the large range and severity of symptoms. A high index of suspicion is required as patients may have only a few of the many possible biomarkers. The genetic prevalence of ATP7B variants indicates higher rates in the population than are currently diagnosed. Treatments have evolved from chelators that reduce stored copper to zinc, which reduces the toxic levels of circulating non-ceruloplasmin-bound copper. Zinc induces intestinal metallothionein, which blocks copper absorption and increases excretion in the stools, resulting in an improvement in symptoms. Two meta-analyses and several large retrospective studies indicate that zinc is equally effective as chelators for the treatment of WD, with the advantages of a very low level of toxicity and only the minor side effect of gastric disturbance. Zinc is recommended as a first-line treatment for neurological presentations and is gaining acceptance for hepatic presentations. It is universally recommended for lifelong maintenance therapy and for presymptomatic WD.
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Affiliation(s)
- Abolfazl Avan
- Department of Public Health, School of Medicine, Mashhad University of Medical Sciences, Mashhad 93518-88415, Iran
- Correspondence:
| | - Anna Członkowska
- 2nd Department of Neurology, Institute of Psychiatry and Neurology, 02-957 Warsaw, Poland
| | - Susan Gaskin
- Department of Civil Engineering, McGill University, Montreal, QC H3A 0C3, Canada
| | - Alberto Granzotto
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Department of Neuroscience, Imaging, and Clinical Sciences (DNISC), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Sue and Bill Gross Stem Cell Research Center, University of California-Irvine, Irvine, CA 92697, USA
| | - Stefano L. Sensi
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Department of Neuroscience, Imaging, and Clinical Sciences (DNISC), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Institute for Advanced Biomedical Technologies (ITAB), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Tjaard U. Hoogenraad
- Department of Neurology, University Medical Centre Utrecht, 3584 CX Utrecht, The Netherlands
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17
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Kamila G, Chakrabarty B. Management of Wilson Disease: The Quest Continues. Ann Indian Acad Neurol 2022; 25:585-586. [PMID: 36211138 PMCID: PMC9540928 DOI: 10.4103/aian.aian_961_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 11/16/2021] [Indexed: 11/07/2022] Open
Affiliation(s)
- Gautam Kamila
- Department of Pediatrics, Child Neurology Division, AIIMS, New Delhi, India
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18
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Lynch EN, Campani C, Innocenti T, Dragoni G, Forte P, Galli A. Practical insights into chronic management of hepatic Wilson’s disease. World J Clin Cases 2022; 10:4334-4347. [PMID: 35663095 PMCID: PMC9125272 DOI: 10.12998/wjcc.v10.i14.4334] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 10/07/2021] [Accepted: 03/26/2022] [Indexed: 02/06/2023] Open
Abstract
Wilson’s disease (WD) is a rare inherited disorder of human copper metabolism, with an estimated prevalence of 1:30000-1:50000 and a broad spectrum of hepatic and neuropsychiatric manifestations. In healthy individuals, the bile is the main route of elimination of copper. In WD patients, copper accumulates in the liver, it is released into the bloodstream, and is excreted in urine. Copper can also be accumulated in the brain, kidneys, heart, and osseous matter and causes damage due to direct toxicity or oxidative stress. Hepatic WD is commonly but not exclusively diagnosed in childhood or young adulthood. Adherent, non-cirrhotic WD patients seem to have a normal life expectancy. Nevertheless, chronic management of patients with Wilson’s disease is challenging, as available biochemical tests have many limitations and do not allow a clear identification of non-compliance, overtreatment, or treatment goals. To provide optimal care, clinicians should have a complete understanding of these limitations and counterbalance them with a thorough clinical assessment. The aim of this review is to provide clinicians with practical tools and suggestions which may answer doubts that can arise during chronic management of patients with hepatic WD. In particular, it summarises current knowledge on Wilson’s disease clinical and biochemical monitoring and treatment. It also analyses available evidence on pregnancy and the role of low-copper diet in WD. Future research should focus on trying to provide new copper metabolism tests which could help to guide treatment adjustments.
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Affiliation(s)
- Erica Nicola Lynch
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Claudia Campani
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Tommaso Innocenti
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Gabriele Dragoni
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
- Department of Medical Biotechnologies, University of Siena, Siena 53100, Italy
| | - Paolo Forte
- Division of Gastroenterology, University Hospital “Careggi”, Florence 50134, Italy
| | - Andrea Galli
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
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19
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Hou H, Chen D, Liu J, Feng L, Zhang J, Liang X, Xu Y, Li X. Clinical and Genetic Analysis in Neurological Wilson’s Disease Patients With Neurological Worsening Following Chelator Therapy. Front Genet 2022; 13:875694. [PMID: 35444691 PMCID: PMC9013891 DOI: 10.3389/fgene.2022.875694] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 03/21/2022] [Indexed: 12/04/2022] Open
Abstract
Objectives: None of the previous studies have focused on the genetic effect on neurological worsening in neurological Wilson’s disease (WD) patients following chelator therapy. We aimed to evaluate the clinical and genetic role in the occurrence of neurological worsening. Methods: We retrospectively reviewed the medical records of neurological WD patients who received initial chelator therapy and genetic test. Clinical, laboratory, and genetic data were collected. The genotype was classified into two types: 1) severe mutation genotype: patients who carried at least one of the following three types of mutations: frameshift mutation, splicing mutation, or nonsense mutation; 2) non-severe mutation genotype: patients who only carried missense mutations. Then, the clinical features and genotype of the patients with and without neurological worsening were investigated. Results: Forty-seven neurological WD patients were identified with a median age at onset of 16.17 years (range 7.75–47 years) and 35 (74.5%) males. The mean interval from onset to diagnosis was 0.6 years (range: 0.5 months-6.25 years). Neurological deterioration was observed in 29 patients (61.7%) and the other 18 patients (38.3%) were stable or improved during anti-copper treatment. The neurological worsening was completely irreversible in 6 cases (20.7%) and partially irreversible in 16 cases (55.2%). The common deteriorated symptoms were as follows: rigidity in 20 cases (69%), speech difficulties in 20 cases (69%)), walking difficulties in 13 cases (44.8%), dysphagia in 9 cases (31%), and salivation in 9 cases (31%). The patients with neurological worsening had significantly younger age (p = 0.028), shorter delayed diagnosis time (p = 0.011), higher rate of dystonia (p = 0.003), and severe mutation genotype (p = 0.036), compared to those without neurological worsening. Conclusion: We found that younger age of onset, the presence of dystonia, and genotype with severe mutations may be predictive of neurological worsening in the neurological WD patients that received chelator therapy. For those patients, chelator therapy should be given with caution and needs closer observation during follow-up.
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Affiliation(s)
- Haiman Hou
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Dingbang Chen
- Department of Neurology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Junxiu Liu
- The First People’s Hospital of Zhongshan City, Zhongshan, China
| | - Li Feng
- Department of Neurology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Jiwei Zhang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiuling Liang
- Department of Neurology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yuming Xu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Yuming Xu, ; Xunhua Li,
| | - Xunhua Li
- Department of Neurology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- *Correspondence: Yuming Xu, ; Xunhua Li,
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20
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Padovani D, Galardon E. Molecular Basis for the Interaction of Catalase with d-Penicillamine: Rationalization of Some of Its Deleterious Effects. Chem Res Toxicol 2022; 35:412-421. [PMID: 35191669 DOI: 10.1021/acs.chemrestox.1c00313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
d-Penicillamine (d-Pen) is a sulfur compound used in the management of rheumatoid arthritis, Wilson's disease (WD), and alcohol dependence. Many side effects are associated with its use, particularly after long-term treatment. However, the molecular basis for such side effects is poorly understood. Based on the well-known oxidase activity of hemoproteins and the participation of catalase in cellular H2O2 redox signaling, we posit that d-Pen could inactivate catalase, thus disturbing H2O2 levels. Herein, we report on the molecular basis that could partly explain the side effects associated with this drug compound, and we demonstrate that it induces the formation of compound II, a temporarily inactive state of the enzyme, through two distinct mechanisms. Initially, d-Pen reacts with native catalase and/or iron metal ions, used to mimic non-heme iron overload observed in long-term treated WD patients, to generate thiyl radicals. These radicals partake in a futile redox cycle, thus producing superoxide radical anions O2•- and hydrogen peroxide H2O2. Then, either H2O2 unexpectedly reacts with reduced CAT-Fe(II) to produce compound II or both aforementioned reactive oxygen species intervene in compound II generation through compound I formation and then reduction. These findings support the evidence that d-Pen could perturb H2O2 redox homeostasis through transient but recurring catalase inactivation, which may in part rationalize some deleterious effects observed with this therapeutic agent, as discussed.
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Affiliation(s)
- Dominique Padovani
- UMR 8601, LCBPT, CNRS-Université de Paris, 45 rue des Sts Pères, 75006 Paris, France
| | - Erwan Galardon
- UMR 8601, LCBPT, CNRS-Université de Paris, 45 rue des Sts Pères, 75006 Paris, France
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21
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Kumar S, Patra BR, Irtaza M, Rao PK, Giri S, Darak H, Gopan A, Kale A, Shukla A. Adverse Events with D-penicillamine Therapy in Hepatic Wilson's Disease: A Single-Center Retrospective Audit. Clin Drug Investig 2022; 42:177-184. [PMID: 35102516 DOI: 10.1007/s40261-022-01117-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/12/2022] [Indexed: 12/22/2022]
Abstract
UNLABELLED BACKGROUND AND OBJECTIVE: There are limited data on the adverse events of D-penicillamine in Wilson's disease (WD) that can result in dose modification or treatment discontinuation. The objective of this study was to observe the adverse events related to D-penicillamine in patients with hepatic WD. METHODS A retrospective audit of prospectively registered hepatic WD patients at a tertiary care center between December 2006 and January 2020 was carried out. Demographic variables, laboratory parameters, and details of treatment were noted. Adverse events (AEs) related to D-penicillamine treatment, the timing and management of these AEs were analysed. RESULTS The study included 112 patients with hepatic WD on D-penicillamine. D-penicillamine intolerance was seen in 28/112 (25%) over 179 person-years. Of the 28 AEs, severe AEs leading to permanent D-penicillamine discontinuation occurred in 16 (57%) [never reintroduced 12 (43%), discontinued after intolerant to rechallenge, 4 (14%)], temporary cessation followed by reintroduction to initial dose 13 (46%) and continuation with reduced dose in 3 (11%) patients. Overall, most common AEs were hematological [16, 57% (pancytopenia n = 8, bicytopenia n = 5 and hemolytic anemia n = 3)] while renal adverse events (n = 7, 25%) constituted the most common indication for permanent discontinuation. Cytopenias developed beyond 12 months of D-penicillamine initiation whereas hemolytic anemia developed within first 3 months. Following D-penicillamine discontinuation in 25 patients, it was reintroduced to initial dose in 13/25 (52%), switched to trientine due to neurological worsening in 2/25 (8%) and switched to zinc in 10/25 (40%). In patients with reintroduction, gradual dose escalation was tolerated in 9/13 (69%) with a recurrence of AEs leading to permanent discontinuation in 4/13 (31%). CONCLUSION D-penicillamine treatment is associated with significant AEs mainly related to blood, kidney, and skin. Temporary cessation of drug with reintroduction at a lower dose is an effective and safe option.
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Affiliation(s)
- Sanjay Kumar
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Gastroenterology office, 9th floor, New Building, Parel, Mumbai, 400012, India
| | - Biswa Ranjan Patra
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Gastroenterology office, 9th floor, New Building, Parel, Mumbai, 400012, India
| | - Mohammed Irtaza
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Gastroenterology office, 9th floor, New Building, Parel, Mumbai, 400012, India
| | - Praveen Kumar Rao
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Gastroenterology office, 9th floor, New Building, Parel, Mumbai, 400012, India
| | - Suprabhat Giri
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Gastroenterology office, 9th floor, New Building, Parel, Mumbai, 400012, India
| | - Harish Darak
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Gastroenterology office, 9th floor, New Building, Parel, Mumbai, 400012, India
| | - Amrit Gopan
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Gastroenterology office, 9th floor, New Building, Parel, Mumbai, 400012, India
| | - Aditya Kale
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Gastroenterology office, 9th floor, New Building, Parel, Mumbai, 400012, India
| | - Akash Shukla
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Gastroenterology office, 9th floor, New Building, Parel, Mumbai, 400012, India.
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22
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Ghasemi AS, Makiabadi B, Zakarianezhad M, Soltani A, Ashrafi F, Mashhadban F. Experimental and theoretical studies of the interaction of Penicillamine with SWCNT (6,0) as a drug delivery system. INORG NANO-MET CHEM 2022. [DOI: 10.1080/24701556.2021.2025101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
| | - Batoul Makiabadi
- Department of Chemical Engineering, Sirjan University of Technology, Sirjan, Iran
| | | | - Alireza Soltani
- Golestan Rheumatology Research Center, Golestan University of Medical Sciences, Gorgan, Iran
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23
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Borchard S, Raschke S, Zak KM, Eberhagen C, Einer C, Weber E, Müller SM, Michalke B, Lichtmannegger J, Wieser A, Rieder T, Popowicz GM, Adamski J, Klingenspor M, Coles AH, Viana R, Vendelbo MH, Sandahl TD, Schwerdtle T, Plitz T, Zischka H. Bis-choline tetrathiomolybdate prevents copper-induced blood-brain barrier damage. Life Sci Alliance 2021; 5:5/3/e202101164. [PMID: 34857647 PMCID: PMC8675913 DOI: 10.26508/lsa.202101164] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 11/16/2021] [Accepted: 11/17/2021] [Indexed: 11/24/2022] Open
Abstract
The blood–brain barrier endothelial cell monolayer becomes permeable to elevated copper loosely bound to albumin, which can be avoided by a high-affinity copper chelator but not by D-penicillamine. In Wilson disease, excessive copper accumulates in patients’ livers and may, upon serum leakage, severely affect the brain according to current viewpoints. Present remedies aim at avoiding copper toxicity by chelation, for example, by D-penicillamine (DPA) or bis-choline tetrathiomolybdate (ALXN1840), the latter with a very high copper affinity. Hence, ALXN1840 may potentially avoid neurological deterioration that frequently occurs upon DPA treatment. As the etiology of such worsening is unclear, we reasoned that copper loosely bound to albumin, that is, mimicking a potential liver copper leakage into blood, may damage cells that constitute the blood-brain barrier, which was found to be the case in an in vitro model using primary porcine brain capillary endothelial cells. Such blood–brain barrier damage was avoided by ALXN1840, plausibly due to firm protein embedding of the chelator bound copper, but not by DPA. Mitochondrial protection was observed, a prerequisite for blood–brain barrier integrity. Thus, high-affinity copper chelators may minimize such deterioration in the treatment of neurologic Wilson disease.
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Affiliation(s)
- Sabine Borchard
- Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Stefanie Raschke
- Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.,TraceAge-Deutsche Forschungsgemeinschaft Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly (Forschungsgruppe 2558), Berlin-Potsdam-Jena-Wuppertal, Germany
| | - Krzysztof M Zak
- Institute of Structural Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Carola Eberhagen
- Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Claudia Einer
- Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Elisabeth Weber
- Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Sandra M Müller
- Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
| | - Bernhard Michalke
- Research Unit Analytical BioGeoChemistry, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Josef Lichtmannegger
- Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Albrecht Wieser
- Institute of Radiation Medicine, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Tamara Rieder
- Technical University Munich, School of Medicine, Institute of Toxicology and Environmental Hygiene, Munich, Germany
| | - Grzegorz M Popowicz
- Institute of Structural Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Jerzy Adamski
- Research Unit Molecular Endocrinology and Metabolism, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.,Lehrstuhl für Experimentelle Genetik, Technical University Munich, Freising-Weihenstephan, Germany.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Martin Klingenspor
- Chair of Molecular Nutritional Medicine, Technical University of Munich, School of Life Sciences Weihenstephan, Freising, Germany.,Else-Kröner Fresenius Center for Nutritional Medicine, Technical University of Munich, Freising, Germany
| | | | - Ruth Viana
- Alexion AstraZeneca Rare Disease, Boston, MA, USA
| | - Mikkel H Vendelbo
- Department of Nuclear Medicine and Positron Emission Tomography Centre, Aarhus University Hospital, Aarhus, Denmark.,Department of Biomedicine, Aarhus University, Aarhus C, Denmark
| | - Thomas D Sandahl
- Medical Department Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Tanja Schwerdtle
- Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.,TraceAge-Deutsche Forschungsgemeinschaft Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly (Forschungsgruppe 2558), Berlin-Potsdam-Jena-Wuppertal, Germany
| | | | - Hans Zischka
- Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany .,Technical University Munich, School of Medicine, Institute of Toxicology and Environmental Hygiene, Munich, Germany
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24
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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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25
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Wang M, Zhang R, Dehaen W, Fang Y, Qian S, Ren Y, Cheng F, Guo Y, Guo C, Li Y, Deng Y, Cao Z, Peng C. Specific recognition, intracellular assay and detoxification of fluorescent curcumin derivative for copper ions. JOURNAL OF HAZARDOUS MATERIALS 2021; 420:126490. [PMID: 34252661 DOI: 10.1016/j.jhazmat.2021.126490] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 06/15/2021] [Accepted: 06/17/2021] [Indexed: 06/13/2023]
Abstract
Recognition and excretion of metal ions play an important role in the diagnosis and treatment of various diseases and poisoning. Although copper (Cu) is a cofactor of many key enzymes in the human body, its accumulation caused by genetic ATP7B mutation or environmental pollution can lead to hepatotoxicity, renal failure, Wilson's disease, inflammation, and even Parkinson's disease (PD) and Alzheimer's disease (AD). Therefore, in this work, a difluoroboron curcumin derivative (DF-Cur) was used for the specific recognition of copper ions (Cu2+). DF-Cur could be further used to as a rapid diagnostic agent for the copper detection in cells and zebrafish at the nanomolar level. DF-Cur could significantly reduce the toxic damage caused by high Cu2+ dose. Inductively coupled plasma-mass spectrometry (ICP-MS) analysis indicated that DF-Cur could promote the excretion of copper ions in the urine and bile and reduce the accumulation of copper ions in vivo. In addition, DF-Cur could selectively detect cholesterol in the blood and adipose tissue in vivo by fluorescent staining. These results demonstrated that this molecule might represent a new and promising diagnostic and therapeutic agent to combat diseases related to copper ions accumulation.
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Affiliation(s)
- Miao Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Ruoqi Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Wim Dehaen
- Department of Chemistry, KU Leuven, Celestijnenlaan 200f-bus 02404, 3001 Leuven, Belgium
| | - Yuyu Fang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Chemistry, KU Leuven, Celestijnenlaan 200f-bus 02404, 3001 Leuven, Belgium.
| | - Shan Qian
- Department of Pharmaceutical Engineering, School of Food and Bioengineering, Xihua University, Chengdu 610039, China
| | - Yali Ren
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Fang Cheng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yuying Guo
- Department of Pharmaceutical Engineering, School of Food and Bioengineering, Xihua University, Chengdu 610039, China
| | - Chuanjie Guo
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yuzhi Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yun Deng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Zhixing Cao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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26
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García-Cortés M, Ortega-Alonso A, Andrade RJ. Safety of treating acute liver injury and failure. Expert Opin Drug Saf 2021; 21:191-203. [PMID: 34254839 DOI: 10.1080/14740338.2021.1955854] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Acute liver injury and progression to acute liver failure can be life-threatening conditions that require prompt careful clinical assessment and therapeutic management. AREAS COVERED The aim of this article is to review the safety and side effect profile of pharmacological therapies used in the treatment of acute liver injury with specific focus on hepatic toxicity. We performed an extensive literature search with the terms 'acute liver injury,' 'acute liver failure,' 'therapy,' 'safety,' 'adverse reactions' and 'drug induced liver injury.' A thorough discussion of the main drugs and devices used in patients with acute liver injury and acute liver failure, its safety profile and the management of complications associated to therapy of these conditions is presented. EXPERT OPINION Several pharmacological approaches are used in acute liver injury and acute liver failure in an empirical basis. Whilst steroids are frequently tried in serious drug-induced liver injury there is concern on a potential harmful effect of these agents because of the higher mortality in patients receiving the drug; hence, statistical approaches such as propensity score matching might help resolve this clinical dilemma. Likewise, properly designed clinical trials using old and new drugs for subjects with serious drug-induced liver injury are clearly needed.
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Affiliation(s)
- Miren García-Cortés
- Servicio De Aparato Digestivo, Instituto De Investigación Biomédica De Málaga-IBIMA. Hospital Universitario Virgen De La Victoria, Universidad De Málaga, Centro De Investigación Biomédica En Red De Enfermedades Hepáticas Y Digestivas CIBERehd, Málaga, Spain
| | - Aida Ortega-Alonso
- Servicio De Aparato Digestivo, Instituto De Investigación Biomédica De Málaga-IBIMA. Hospital Universitario Virgen De La Victoria, Universidad De Málaga, Centro De Investigación Biomédica En Red De Enfermedades Hepáticas Y Digestivas CIBERehd, Málaga, Spain
| | - Raúl J Andrade
- Servicio De Aparato Digestivo, Instituto De Investigación Biomédica De Málaga-IBIMA. Hospital Universitario Virgen De La Victoria, Universidad De Málaga, Centro De Investigación Biomédica En Red De Enfermedades Hepáticas Y Digestivas CIBERehd, Málaga, Spain
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27
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Michniewicz F, Saletta F, Rouaen JRC, Hewavisenti RV, Mercatelli D, Cirillo G, Giorgi FM, Trahair T, Ziegler D, Vittorio O. Copper: An Intracellular Achilles' Heel Allowing the Targeting of Epigenetics, Kinase Pathways, and Cell Metabolism in Cancer Therapeutics. ChemMedChem 2021; 16:2315-2329. [PMID: 33890721 DOI: 10.1002/cmdc.202100172] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Indexed: 02/06/2023]
Abstract
Copper is an essential transition metal frequently increased in cancer known to strongly influence essential cellular processes. Targeted therapy protocols utilizing both novel and repurposed drug agents initially demonstrate strong efficacy, before failing in advanced cancers as drug resistance develops and relapse occurs. Overcoming this limitation involves the development of strategies and protocols aimed at a wider targeting of the underlying molecular changes. Receptor Tyrosine Kinase signaling pathways, epigenetic mechanisms and cell metabolism are among the most common therapeutic targets, with molecular investigations increasingly demonstrating the strong influence each mechanism exerts on the others. Interestingly, all these mechanisms can be influenced by intracellular copper. We propose that copper chelating agents, already in clinical trial for multiple cancers, may simultaneously target these mechanisms across a wide variety of cancers, serving as an excellent candidate for targeted combination therapy. This review summarizes the known links between these mechanisms, copper, and copper chelation therapy.
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Affiliation(s)
- Filip Michniewicz
- Children's Cancer Institute, Lowy Cancer Research Centre, School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia
| | - Federica Saletta
- Children's Cancer Institute, Lowy Cancer Research Centre, School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia
| | - Jourdin R C Rouaen
- Children's Cancer Institute, Lowy Cancer Research Centre, School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia
| | - Rehana V Hewavisenti
- Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
| | - Daniele Mercatelli
- Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy
| | - Giuseppe Cirillo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy
| | - Federico M Giorgi
- Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy
| | - Toby Trahair
- Children's Cancer Institute, Lowy Cancer Research Centre, School of Women's and Children's Health, University of New South Wales, Sydney, Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia
| | - David Ziegler
- Children's Cancer Institute, Lowy Cancer Research Centre, School of Women's and Children's Health, University of New South Wales, Sydney, Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia
| | - Orazio Vittorio
- Children's Cancer Institute, Lowy Cancer Research Centre, School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia
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28
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Pugliese M, Biondi V, Gugliandolo E, Licata P, Peritore AF, Crupi R, Passantino A. D-Penicillamine: The State of the Art in Humans and in Dogs from a Pharmacological and Regulatory Perspective. Antibiotics (Basel) 2021; 10:antibiotics10060648. [PMID: 34071639 PMCID: PMC8229433 DOI: 10.3390/antibiotics10060648] [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: 03/30/2021] [Revised: 05/18/2021] [Accepted: 05/26/2021] [Indexed: 11/16/2022] Open
Abstract
Chelant agents are the mainstay of treatment in copper-associated hepatitis in humans, where D-penicillamine is the chelant agent of first choice. In veterinary medicine, the use of D-penicillamine has increased with the recent recognition of copper-associated hepatopathies that occur in several breeds of dogs. Although the different regulatory authorities in the world (United States Food and Drugs Administration-U.S. FDA, European Medicines Agency-EMEA, etc.) do not approve D-penicillamine for use in dogs, it has been used to treat copper-associated hepatitis in dogs since the 1970s, and is prescribed legally by veterinarians as an extra-label drug to treat this disease and alleviate suffering. The present study aims to: (a) address the pharmacological features; (b) outline the clinical scenario underlying the increased interest in D-penicillamine by overviewing the evolution of its main therapeutic goals in humans and dogs; and finally, (c) provide a discussion on its use and prescription in veterinary medicine from a regulatory perspective.
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Affiliation(s)
- Michela Pugliese
- Department of Veterinary Science, University of Messina, 98166 Messina, Italy; (M.P.); (V.B.); (E.G.); (P.L.); (A.P.)
| | - Vito Biondi
- Department of Veterinary Science, University of Messina, 98166 Messina, Italy; (M.P.); (V.B.); (E.G.); (P.L.); (A.P.)
| | - Enrico Gugliandolo
- Department of Veterinary Science, University of Messina, 98166 Messina, Italy; (M.P.); (V.B.); (E.G.); (P.L.); (A.P.)
| | - Patrizia Licata
- Department of Veterinary Science, University of Messina, 98166 Messina, Italy; (M.P.); (V.B.); (E.G.); (P.L.); (A.P.)
| | - Alessio Filippo Peritore
- Department of Chemical, Biological, Pharmaceutical, and Environmental Science, University of Messina, 98168 Messina, Italy;
| | - Rosalia Crupi
- Department of Veterinary Science, University of Messina, 98166 Messina, Italy; (M.P.); (V.B.); (E.G.); (P.L.); (A.P.)
- Correspondence:
| | - Annamaria Passantino
- Department of Veterinary Science, University of Messina, 98166 Messina, Italy; (M.P.); (V.B.); (E.G.); (P.L.); (A.P.)
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29
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Moini M, To U, Schilsky ML. Recent advances in Wilson disease. Transl Gastroenterol Hepatol 2021; 6:21. [PMID: 33824925 DOI: 10.21037/tgh-2020-02] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Accepted: 03/19/2020] [Indexed: 12/17/2022] Open
Abstract
Wilson disease (WD) is rare genetic disorder that presents with varied phenotype that can at times make the diagnosis challenging. Medical treatments are available, but there are still unmet needs for patients. Since life-long therapy is necessary, adherence to medical therapy and best practices for monitoring and individualizing therapy continue to evolve. Studies are ongoing that address some of these issues. In the current review we focused our attention to recent advances in the diagnosis of WD, current medical treatments, future potential therapies and treatment monitoring. We include discussion of new methodology for detection and quantitation of ophthalmologic signs of WD, new brain imaging modalities for early detection of neurologic involvement in patients and potential new diagnostic methodology using blood samples that may be applicable to newborn screening and adult disease diagnosis. In addition, there are new strategies aimed at improving adherence and outcomes with currently available therapies, including once daily chelation dosing and discussion of the efficacy of different zinc salt compounds. With respect to new therapies with different mechanisms of action, we discuss studies on Bis-choline tetrathiomolybdate (TTM) in patients, pre-clinical studies of a novel chelator methanobactin and other animal studies exploring cures for WD with gene therapy using adeno-associated vectors (AAVs) that introduce ATP7B into liver cells. There are also promising advances in the more accurate measurement of non-ceruloplasmin bound copper and exchangeable copper in the circulation which would potentially help with monitoring and individualization of treatment and possibly play a role in future disease diagnosis.
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Affiliation(s)
- Maryam Moini
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Division of Gastroenterology, University of Toronto, Toronto, Canada
| | - Uyen To
- Department of Medicine and Surgery, Division of Digestive Diseases and Transplantation and Immunology, Yale University, New Haven CT, USA
| | - Michael L Schilsky
- Department of Medicine and Surgery, Division of Digestive Diseases and Transplantation and Immunology, Yale University, New Haven CT, USA
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30
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Yuan XZ, Yang RM, Wang XP. Management Perspective of Wilson's Disease: Early Diagnosis and Individualized Therapy. Curr Neuropharmacol 2021; 19:465-485. [PMID: 32351182 PMCID: PMC8206458 DOI: 10.2174/1570159x18666200429233517] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 04/13/2020] [Accepted: 04/24/2020] [Indexed: 02/05/2023] Open
Abstract
Wilson's disease (WD) is an inherited disease caused by mutations in ATP7B and is characterized by the pathological accumulation of copper in the liver and brain. Common clinical manifestations of WD include a wide range of liver disease and neurological symptoms. In some patients, psychiatric symptoms may be the only manifestation at the time of diagnosis. The clinical features of WD are highly variable and can mimic any disease of internal medicine. Therefore, for unexplained medical diseases, the possibility of WD should not be ignored. Early diagnosis and treatment can improve the prognosis of WD patients and reduce disability and early death. Gene sequencing is becoming a valuable method to diagnose WD, and if possible, all WD patients and their siblings should be genetically sequenced. Copper chelators including D-penicillamine, trientine, and dimercaptosuccinic acid can significantly improve the liver injury and symptoms of WD patients but may have a limited effect on neurological symptoms. Zinc salts may be more appropriate for the treatment of asymptomatic patients or for the maintenance treatment of symptomatic patients. High-quality clinical trials for the drug treatment of WD are still lacking, therefore, individualized treatment options for patients are recommended. Individualized treatment can be determined based on the clinical features of the WD patients, efficacy and adverse effects of the drugs, and the experience of the physician. Liver transplantation is the only effective method to save patients with acute liver failure or with severe liver disease who fail drug treatment.
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Affiliation(s)
| | | | - Xiao-Ping Wang
- Address correspondence to this author at the Department of Neurology, TongRen Hospital, Shanghai Jiao Tong University School of Medicine, No.1111 Xianxia Road, 200336, Shanghai, China; Tel: +86-021-52039999-72223; Fax: +86-021-52039999-72223; E-mail:
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31
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Gromadzka G, Tarnacka B, Flaga A, Adamczyk A. Copper Dyshomeostasis in Neurodegenerative Diseases-Therapeutic Implications. Int J Mol Sci 2020; 21:E9259. [PMID: 33291628 PMCID: PMC7730516 DOI: 10.3390/ijms21239259] [Citation(s) in RCA: 179] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 11/27/2020] [Accepted: 11/28/2020] [Indexed: 12/12/2022] Open
Abstract
Copper is one of the most abundant basic transition metals in the human body. It takes part in oxygen metabolism, collagen synthesis, and skin pigmentation, maintaining the integrity of blood vessels, as well as in iron homeostasis, antioxidant defense, and neurotransmitter synthesis. It may also be involved in cell signaling and may participate in modulation of membrane receptor-ligand interactions, control of kinase and related phosphatase functions, as well as many cellular pathways. Its role is also important in controlling gene expression in the nucleus. In the nervous system in particular, copper is involved in myelination, and by modulating synaptic activity as well as excitotoxic cell death and signaling cascades induced by neurotrophic factors, copper is important for various neuronal functions. Current data suggest that both excess copper levels and copper deficiency can be harmful, and careful homeostatic control is important. This knowledge opens up an important new area for potential therapeutic interventions based on copper supplementation or removal in neurodegenerative diseases including Wilson's disease (WD), Menkes disease (MD), Alzheimer's disease (AD), Parkinson's disease (PD), and others. However, much remains to be discovered, in particular, how to regulate copper homeostasis to prevent neurodegeneration, when to chelate copper, and when to supplement it.
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Affiliation(s)
- Grażyna Gromadzka
- Collegium Medicum, Faculty of Medicine, Cardinal Stefan Wyszynski University, Wóycickiego 1/3 Street, 01-938 Warsaw, Poland;
| | - Beata Tarnacka
- Department of Rehabilitation, Eleonora Reicher National Institute of Geriatrics, Rheumatology and Rehabilitation, Rehabilitation Clinic, Medical University of Warsaw, Spartańska 1 Street, 02-637 Warsaw, Poland;
| | - Anna Flaga
- Collegium Medicum, Faculty of Medicine, Cardinal Stefan Wyszynski University, Wóycickiego 1/3 Street, 01-938 Warsaw, Poland;
| | - Agata Adamczyk
- Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawińskiego Street, 02-106 Warsaw, Poland;
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32
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Efe SC, Gurbuz AS, Ozturk S, Demir K. Strain and strain rate echocardiography variables in adult Wilson's disease patients: A speckle tracking echocardiography study. JOURNAL OF CLINICAL ULTRASOUND : JCU 2020; 48:324-329. [PMID: 32374439 DOI: 10.1002/jcu.22849] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 04/01/2020] [Accepted: 04/03/2020] [Indexed: 06/11/2023]
Abstract
PURPOSE Although the hepatic and neurological consequences of Wilson's disease (WD) have been investigated in detail, its cardiac involvement remains little studied. Our aim was to investigate potential cardiac differences in strain (ST) and strain rate (STR) echocardiography in adult WD patients compared with controls. METHODS We included 30 patients with WD and a control group of 26 sex and age matched healthy adults. None of the subjects in either group had cardiac complaint. WD patients were clinically evaluated by a neurologist and undergone cranial magnetic resonance imaging. They were then divided into two groups according to the presence (NW) or absence (non-NW) of neurological involvement. Standard and advanced speckle tracking echocardiographic evaluations were performed in each group according to guidelines. RESULTS Left ventricular (LV) systolic and diastolic diameters and wall thickness measurements were within normal limits and did not differ significantly between the groups (P > .05). Neither atrial peak longitudinal and circumferential ST variables nor LV global and longitudinal ST and STR variables showed significant differences between the NW, the non-NW, and the control group (P > .05). CONCLUSION Our echocardiographic study showed no detectable difference between adult WD patients with or without neurological involvement and healthy subjects.
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Affiliation(s)
- Süleyman Cagan Efe
- Department of Cardiology, Istanbul Education and Research Hospital, Istanbul, Turkey
| | | | - Semi Ozturk
- Department of Cardiology, Haseki Training and Education Hospital, Istanbul, Turkey
| | - Kadir Demir
- Department of Gastroenterology, Istanbul University, Istanbul, Turkey
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De Fabregues O, Viñas J, Palasí A, Quintana M, Cardona I, Auger C, Vargas V. Ammonium tetrathiomolybdate in the decoppering phase treatment of Wilson's disease with neurological symptoms: A case series. Brain Behav 2020; 10:e01596. [PMID: 32202078 PMCID: PMC7218247 DOI: 10.1002/brb3.1596] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 02/04/2020] [Accepted: 02/13/2020] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVES To present our experience with ammonium tetrathiomolybdate (ATTM) in the decoppering phase treatment of Wilson's disease (WD) with neurological symptoms. METHODS An uncontrolled longitudinal study was carried out to describe a case series of five patients diagnosed of WD with neurological symptoms in our hospital over the last 5 years and receiving ATTM for 8 (or 16) weeks. Unified Wilson's Disease Rating Scale (UWDRS), Global Assessment Scale (GAS) for WD and the Brewer-adapted Unified Huntington's Disease Rating Scale (UHDRS) for WD, magnetic resonance imaging, and monitoring for potential adverse effects were carried out in all patients before starting ATTM and 3 months later when ATTM was stopped and zinc treatment was initiated. RESULTS All five patients presented neurological clinical improvement in UWDRS, GAS, and Brewer-adapted UHDRS for WD. Neuroimaging improvement was present in 2/5 patients with brain edema reduction. Mild anemia, leukopenia, and elevation of transaminases were detected in 1 patient, with complete remission after stopping ATTM for 1 week and then restarting at a half dose. CONCLUSION ATTM could be a good treatment for the initial treatment of WD with neurological symptoms due to its high efficacy, with a lower rate of neurological deterioration than the drugs currently available, despite the potential adverse effects.
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Affiliation(s)
- Oriol De Fabregues
- Movement Disorders Unit, Neurology Department, Vall d'Hebron University Hospital, Neurodegenerative Diseases Research Group-Vall d'Hebron Research Institute, Autonomous University of Barcelona, Barcelona, Spain
| | - Jaume Viñas
- Movement Disorders Unit, Neurology Department, Vall d'Hebron University Hospital, Neurodegenerative Diseases Research Group-Vall d'Hebron Research Institute, Autonomous University of Barcelona, Barcelona, Spain
| | - Antoni Palasí
- Movement Disorders Unit, Neurology Department, Vall d'Hebron University Hospital, Neurodegenerative Diseases Research Group-Vall d'Hebron Research Institute, Autonomous University of Barcelona, Barcelona, Spain
| | - Manuel Quintana
- Movement Disorders Unit, Neurology Department, Vall d'Hebron University Hospital, Neurodegenerative Diseases Research Group-Vall d'Hebron Research Institute, Autonomous University of Barcelona, Barcelona, Spain
| | - Ignasi Cardona
- Pharmacy Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Cristina Auger
- Magnetic Resonance Unit, Department of Radiology (IDI), Vall d'Hebron University Hospital, Vall d'Hebron Research Institute, Autonomous University of Barcelona, Barcelona, Spain
| | - Víctor Vargas
- Liver Unit, Vall d'Hebron University Hospital, CIBERehd, Vall d'Hebron Research Institute, Autonomous University of Barcelona, Barcelona, Spain
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Han Y, Dong J, Xu C, Rao R, Shu S, Li G, Cheng N, Wu Y, Yang H, Han Y, Zhong K. Application of 9.4T MRI in Wilson Disease Model TX Mice With Quantitative Susceptibility Mapping to Assess Copper Distribution. Front Behav Neurosci 2020; 14:59. [PMID: 32390811 PMCID: PMC7189732 DOI: 10.3389/fnbeh.2020.00059] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 03/26/2020] [Indexed: 01/14/2023] Open
Abstract
In the current study, we used 9.4-tesla magnetic resonance imaging (9.4T MRI) and inductively coupled plasma mass spectrometry (ICP-MS) to investigate the distribution of copper in the brain samples of a murine model of Wilson's disease (WD) following penicillamine (PCA) treatment. We also evaluated if the distribution of copper in the brain samples of mice was correlated with behavioral symptoms. Results from the behavioral experiments showed that 7 days of PCA treatment decreased the total distance traveled in the open field and the number of rearing and climbing instances among the toxic milk (TX) mice as compared with model group. We also observed that the open arm ratio in the elevated plus-maze (EPM) was reduced, escape latency in the Barnes maze test was increased, and avoidance in the open field was enhanced in TX mice following 14 days of PCA treatment as compared with those in untreated TX mice. We found that PCA treatment for 21-28 days improved the cognitive abilities, exploratory behavior, and movement behavior of TX mice. The PCA-treated mice also exhibited varying degrees of magnetic susceptibilities in the cortex, corpus striatum, hippocampus, and amygdaloid nucleus across the treatment period. Low copper concentrations were found in all of the analyzed brain regions of PCA-treated mice after 21-28 days as compared with the model group (P < 0.05). However, copper concentrations were increased in the primary motor cortex and cerebellum at 7 days post-PCA treatment as compared with those in the model group (P < 0.05). After 14 days of PCA treatment, the copper concentrations in the sensorimotor cortex, corpus striatum, hippocampus, and amygdaloid nucleus were higher than those detected without treatment. The results from a Pearson's correlation analysis revealed that there was a significant (P < 0.05) correlation between copper concentrations and magnetic susceptibility in all of the brain regions that were analyzed. Therefore, our results indicate that copper concentration and magnetic susceptibility are associated with alterations in mood-related behavior, recognition memory, and movement behaviors in TX mice that are treated with PCA. The redistribution of copper in the TX mouse brain during PCA treatment may aggravate changes in behavioral performance.
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Affiliation(s)
- Yongsheng Han
- Hospital Affiliated to the Institute of Neurology Anhui University of TCM, Hefei, China
| | - Jianjian Dong
- Hospital Affiliated to the Institute of Neurology Anhui University of TCM, Hefei, China.,High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences (CAS), Hefei, China
| | - Chenchen Xu
- Hospital Affiliated to the Institute of Neurology Anhui University of TCM, Hefei, China
| | - Rao Rao
- Hospital Affiliated to the Institute of Neurology Anhui University of TCM, Hefei, China
| | - Shan Shu
- Hospital Affiliated to the Institute of Neurology Anhui University of TCM, Hefei, China
| | - Guangda Li
- Hospital Affiliated to the Institute of Neurology Anhui University of TCM, Hefei, China
| | - Nan Cheng
- Hospital Affiliated to the Institute of Neurology Anhui University of TCM, Hefei, China
| | - Yun Wu
- High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences (CAS), Hefei, China
| | - Hongyi Yang
- High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences (CAS), Hefei, China
| | - Yongzhu Han
- Hospital Affiliated to the Institute of Neurology Anhui University of TCM, Hefei, China
| | - Kai Zhong
- High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences (CAS), Hefei, China
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Baldari S, Di Rocco G, Toietta G. Current Biomedical Use of Copper Chelation Therapy. Int J Mol Sci 2020; 21:1069. [PMID: 32041110 PMCID: PMC7037088 DOI: 10.3390/ijms21031069] [Citation(s) in RCA: 113] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 02/03/2020] [Accepted: 02/04/2020] [Indexed: 12/14/2022] Open
Abstract
Copper is an essential microelement that plays an important role in a wide variety of biological processes. Copper concentration has to be finely regulated, as any imbalance in its homeostasis can induce abnormalities. In particular, excess copper plays an important role in the etiopathogenesis of the genetic disease Wilson's syndrome, in neurological and neurodegenerative pathologies such as Alzheimer's and Parkinson's diseases, in idiopathic pulmonary fibrosis, in diabetes, and in several forms of cancer. Copper chelating agents are among the most promising tools to keep copper concentration at physiological levels. In this review, we focus on the most relevant compounds experimentally and clinically evaluated for their ability to counteract copper homeostasis deregulation. In particular, we provide a general overview of the main disorders characterized by a pathological increase in copper levels, summarizing the principal copper chelating therapies adopted in clinical trials.
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Affiliation(s)
- Silvia Baldari
- Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, via E. Chianesi 53, 00144 Rome, Italy; (S.B.); (G.D.R.)
- Department of Medical Surgical Sciences and Biotechnologies, University of Rome “La Sapienza”, C.so della Repubblica 79, 04100 Latina, Italy
| | - Giuliana Di Rocco
- Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, via E. Chianesi 53, 00144 Rome, Italy; (S.B.); (G.D.R.)
| | - Gabriele Toietta
- Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, via E. Chianesi 53, 00144 Rome, Italy; (S.B.); (G.D.R.)
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Leung M, Wu Lanzafame J, Medici V. Switching Pharmacological Treatment in Wilson Disease: Case Report and Recommendations. J Investig Med High Impact Case Rep 2020; 8:2324709619896876. [PMID: 31920114 PMCID: PMC6956597 DOI: 10.1177/2324709619896876] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background. Available treatments for Wilson disease (WD) prevent longterm complications of copper accumulation. Current anti-copper agents include zinc salts, penicillamine, and trientine. Patients with WD may switch between the agents for a number of reasons. Due to the different mechanisms of action between the copper chelators and zinc salts, transitioning could require a period of overlap and increased monitoring. There are no large studies that investigate the best transition strategies between agents. In this article, we review the treatments for WD and how to monitor for treatment efficacy. Case Summary. The patient had been diagnosed with WD for over 20 years prior to establishing care in our Hepatology Clinic. During his initial course, he was transitioned from penicillamine to zinc due to evidence suggesting penicillamine had greater adverse effects in the long term. Later, he was switched to trientine. His liver enzymes and 24-hour urine copper were monitored. During these years, he intermittently had some financial hardship, requiring him to be on penicillamine rather than trientine. He also had developed acute kidney injury. Overall, his liver disease remained under control and he never had signs of decompensated cirrhosis, but had fluctuations of liver enzymes over the years. Conclusion. Anti-copper treatment for WD has to be tailored to medication side effects profile, patient's chronic and emerging comorbidities, as well as costs. Transitioning regimens is often challenging, and it requires closer monitoring, with no predictors of response.
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Affiliation(s)
- Marcia Leung
- University of California Davis, Sacramento, CA, USA
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Masełbas W, Członkowska A, Litwin T, Niewada M. Persistence with treatment for Wilson disease: a retrospective study. BMC Neurol 2019; 19:278. [PMID: 31718567 PMCID: PMC6849180 DOI: 10.1186/s12883-019-1502-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 10/17/2019] [Indexed: 12/29/2022] Open
Abstract
Background Wilson disease (WD) is genetically induced failure of copper metabolism which can be successfully treated with pharmacological agents. The prognosis for survival in most WD patients is favorable if diagnosis and anti-copper treatment are provided early. Many observations imply that persistence with drug treatment is generally low in patients with chronic diseases, which impact the treatment effectiveness, but such results are very limited in WD. The aim of our study was to assess persistence with treatment among WD patients, to analyze its effect on patient outcome and to identify factors that might be related to persistence. Methods 170 newly diagnosed, symptomatic patients with WD who started treatment between 1995 and 2005 were analyzed retrospectively to assess treatment non-persistence, which was defined as at least one reported break of more than 3 months or minimum two breaks lasting longer than 2 months. Results were further analyzed according to selected clinical variables. Results Only 74.1% of patients were persistent with treatment during the mean 11.7 years of follow up. Treatment persistence closely impacted positive clinical outcomes. In patients classified as persistent, improvement and lack of WD progression were observed more often compared to those classified as non-persistent (29.4 and 68.3% vs. 2.3 and 45.5%; p < 0.001, respectively). In contrast, non-persistent patients presented more often with worsening WD than persistent patients (52.3% vs. 2.4%). Type of WD treatment, gender, phenotypic presentation, adverse events and duration of treatment were not related to treatment persistence. Higher or upper/post-secondary education and a supportive family attitude towards treatment were the most important factors related to persistence. Conclusions One quarter of WD patients were not taking anti-copper treatment regularly and this had an important negative effect on clinical outcome. Family support played an important role in treatment persistence.
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Affiliation(s)
- Wojciech Masełbas
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland
| | - Anna Członkowska
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland. .,2nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland.
| | - Tomasz Litwin
- 2nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Maciej Niewada
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland
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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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Abstract
Wilson disease is an autosomal recessive disorder based on inborn error of copper metabolism. The copper accumulates in the liver, brain, cornea, kidney, and other organs. This disease should be considered any individual with liver abnormality except infant, any patient older than teenage with neurological (especially for extra pyramidal signs) or neuropsychiatric disorder with or without liver disease and sibling of Wilson disease patient. Typically, a combination of low serum ceruloplasmine levels and high levels of urinary copper contents is sufficient to establish a diagnosis. As other diagnostic tests, measurement of hepatic copper content and ATP7B gene analysis are available. The key strategy of treatment is to reduce the amount of copper in the liver and other tissues by administering both copper-chelating agents, such as D-penicillamine or Trientine, and/or zinc acetate. The author recommend zinc acetate monotherapy for mild to moderate hepatic disorder, Trientine mono therapy for mild to moderate neurologic disorder and combination therapy of Trientine and zinc acetate for sever hepatic or neurologic disorder.
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Affiliation(s)
- Norikazu Shimizu
- Department of Pediatrics, Toho University School of Medicine, Ohashi Medical Center
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40
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Cleymaet S, Nagayoshi K, Gettings E, Faden J. A review and update on the diagnosis and treatment of neuropsychiatric Wilson disease. Expert Rev Neurother 2019; 19:1117-1126. [DOI: 10.1080/14737175.2019.1645009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Sean Cleymaet
- Department of Neurology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Katsuko Nagayoshi
- Department of Psychiatry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Edward Gettings
- Department of Neurology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Justin Faden
- Department of Psychiatry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
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Litwin T, Dusek P, Skowrońska M, Członkowska A. Treatment of Wilson’s disease – an update. Expert Opin Orphan Drugs 2019. [DOI: 10.1080/21678707.2019.1638248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Affiliation(s)
- Tomasz Litwin
- 2nd Department of Neurology, Institute Psychiatry and Neurology, Warsaw, Poland
| | - Petr Dusek
- Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine and General University Hospital, Prague, Czech Republic
| | - Marta Skowrońska
- 2nd Department of Neurology, Institute Psychiatry and Neurology, Warsaw, Poland
| | - Anna Członkowska
- 2nd Department of Neurology, Institute Psychiatry and Neurology, Warsaw, Poland
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An urgent need to assess safe levels of inorganic copper in nutritional supplements/parenteral nutrition for subset of Alzheimer’s disease patients. Neurotoxicology 2019; 73:168-174. [DOI: 10.1016/j.neuro.2019.04.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 04/01/2019] [Accepted: 04/01/2019] [Indexed: 02/07/2023]
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Abstract
The availability of effective therapies distinguishes Wilson disease (WD) from other inherited neurometabolic diseases. The cause of hepatic, neurologic or psychiatric symptoms is copper overload and subsequent copper toxicity. Diagnosed WD patients require life-long pharmacologic therapy that is focused on reversal of copper overload with maintenance of a long-term negative copper balance. This is associated with the rapid control of free or non-ceruloplasmin bound copper that is mostly responsible for acute cytotoxic effects. Currently available therapies can be divided into chelators and zinc salts. They have different mechanisms of action and the onset of efficacy that influences their selection in acute and chronic stages of therapy. We review the use of D-penicillamine and trientine for chelation therapies, including the required monitoring of therapy for its efficacy and possible overtreatment with iatrogenic copper deficiency. Additionally, the use of zinc salts is also discussed, including a possibility of its use for the initial therapy in an acute stage of the disease. Supportive and symptomatic therapies for liver failure and neuropsychiatric symptoms are also reviewed.
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Affiliation(s)
- Peter Hedera
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
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Litwin T, Dzieżyc K, Członkowska A. Wilson disease-treatment perspectives. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:S68. [PMID: 31179305 DOI: 10.21037/atm.2018.12.09] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Wilson disease (WD) is a genetic disorder caused by pathological tissue copper accumulation with secondary damage of affected organs (mainly, but not limited to, the liver and brain). The main clinical symptoms of WD are, in concordance with the pathogenesis, hepatic and/or neuropsychiatric. Current treatment options for WD, based on drugs leading to negative copper body balance like chelators or zinc salts, were introduced more than 40 years ago and are generally effective in the majority of WD cases if used lifelong. However, especially in neurological patients, treatment may lead to neurological deterioration, which is often irreversible. Further, almost 50% of neurologically affected WD patients present with persistent neurological deficits despite the use of anti-copper treatment. In addition, up to 30% of patients treated with the widely used drug, d-penicillamine, present with adverse events related to treatment, which often leads to treatment discontinuation. Finally, almost 25% of WD patients do not adhere with anti-copper treatment, partially due to drug-related adverse events and complex treatment regimens (3 times daily, before meals, etc.). These limitations with current treatments have led to the search for other WD treatment possibilities. Currently, research is mainly focused on: (I) new agents with better safety profiles and less neurological deterioration properties compared with traditional chelators, e.g., tetrathiomolybdate salts or central nervous system-penetrable trientine, with the aim to provide more effective copper removal from brain tissue; (II) other non-chelating drugs that lead to removal of copper from cells [e.g., methanobactin (currently in preclinical studies)]; (III) cell and gene therapy. In this article, current research on future treatments for WD is reviewed.
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Affiliation(s)
- Tomasz Litwin
- Second Department of Neurology, Institute Psychiatry and Neurology, Warsaw, Poland
| | - Karolina Dzieżyc
- Second Department of Neurology, Institute Psychiatry and Neurology, Warsaw, Poland
| | - Anna Członkowska
- Second Department of Neurology, Institute Psychiatry and Neurology, Warsaw, Poland
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Mohr I, Weiss KH. Current anti-copper therapies in management of Wilson disease. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:S69. [PMID: 31179306 DOI: 10.21037/atm.2019.02.48] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In Wilson disease (WD) severity of disease can vary widely, depending on time of diagnosis. Early treatment can prevent the development of symptoms in patients. In all patients, lifelong medical treatment is indicated. Currently available medical regimens include the copper chelators for example D-penicillamine (DPA) or trientine (TETA), acting to increase copper excretion and zinc salts (ZS), which reduce copper uptake. In this chapter, we discuss considerations regarding choice of drug and safety limitations.
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Affiliation(s)
- Isabelle Mohr
- Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
| | - Karl Heinz Weiss
- Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
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Chalana A, Karri R, Das R, Kumar B, Rai RK, Saxena H, Gupta A, Banerjee M, Jha KK, Roy G. Copper-Driven Deselenization: A Strategy for Selective Conversion of Copper Ion to Nanozyme and Its Implication for Copper-Related Disorders. ACS APPLIED MATERIALS & INTERFACES 2019; 11:4766-4776. [PMID: 30644707 DOI: 10.1021/acsami.8b16786] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Synthetic organic molecules, which can selectively convert excess intracellular copper (Cu) ions to nanozymes with an ability to protect cells from oxidative stress, are highly significant in developing therapeutic agents against Cu-related disorder like Wilson's disease. Here, we report 1,3-bis(2-hydroxyethyl)-1 H-benzoimidazole-2-selenone (1), which shows a remarkable ability to remove Cu ion from glutathione, a major cytosolic Cu-binding ligand, and thereafter converts it into copper selenide (CuSe) nanozyme that exhibits remarkable glutathione peroxidase-like activity, at cellular level of H2O2 concentration, with excellent cytoprotective effect against oxidative stress in hepatocyte. Cu-driven deselenization of 1, under physiologically relevant conditions, occurred in two steps. The activation of C═Se bond by metal ion is the crucial first step, followed by cleavage of the metal-activated C═Se bond, initiated by the OH group of N-(CH2)2OH substituent through neighboring group participation (deselenization step), resulted in the controlled synthesis of various types of Cu2-xSe nanocrystals (NCs) (nanodisks, nanocubes, and nanosheets) and tetragonal Cu3Se2 NCs, depending upon the oxidation state of the Cu ion used to activate the C═Se bond. Deselenization of 1 is highly metal-selective. Except Cu, other essential metal ions, including Mn2+, Fe2+, Co2+, Ni2+, or Zn2+, failed to produce metal selenide under identical reaction conditions. Moreover, no significant change in the expression level of Cu-metabolism-related genes, including metallothioneines MT1A, is observed in liver cells co-treated with Cu and 1, as opposed to the large increase in the concentrations of these genes observed in cells treated with Cu alone, suggesting the participation of 1 in Cu homeostasis in hepatocyte.
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Wilson's disease: A master of disguise. Parkinsonism Relat Disord 2019; 59:140-145. [DOI: 10.1016/j.parkreldis.2019.02.016] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 02/11/2019] [Accepted: 02/13/2019] [Indexed: 01/12/2023]
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Abstract
Wilson disease (WD) is an autosomal recessively-inherited disorder of copper metabolism and characterised by a pathological accumulation of copper. The ATP7B gene encodes for a transmembrane copper transporter essential for biliary copper excretion. Depending on time of diagnosis, severity of disease can vary widely. Almost all patients show evidence of progressive liver disease. Neurological impairments or psychiatric symptoms are common in WD patients not diagnosed during adolescence. WD is a treatable disorder, and early treatment can prevent the development of symptoms in patients diagnosed while still asymptomatic. This is why the early diagnosis of WD is crucial. The diagnosis is based on clinical symptoms, abnormal measures of copper metabolism and DNA analysis. Available treatment includes chelators and zinc salts which increase copper excretion and reduce copper uptake. In severe cases, liver transplantation is indicated and accomplishes a phenotypic correction of the hepatic gene defect. Recently, clinical development of the new copper modulating agent tetrathiomolybdate has started and direct genetic therapies are being tested in animal models. The following review focuses especially on biochemical markers and how they can be utilised in diagnosis and drug monitoring.
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Nagral A, Sarma MS, Matthai J, Kukkle PL, Devarbhavi H, Sinha S, Alam S, Bavdekar A, Dhiman RK, Eapen CE, Goyal V, Mohan N, Kandadai RM, Sathiyasekaran M, Poddar U, Sibal A, Sankaranarayanan S, Srivastava A, Thapa BR, Wadia PM, Yachha SK, Dhawan A. Wilson's Disease: Clinical Practice Guidelines of the Indian National Association for Study of the Liver, the Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition, and the Movement Disorders Society of India. J Clin Exp Hepatol 2019; 9:74-98. [PMID: 30765941 PMCID: PMC6363961 DOI: 10.1016/j.jceh.2018.08.009] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Accepted: 08/25/2018] [Indexed: 12/12/2022] Open
Abstract
Clinical practice guidelines for Wilson's disease (WD) have been published by the American Association for the Study of Liver Diseases and European Association for the Study of the Liver in 2008 and 2012, respectively. Their focus was on the hepatic aspects of the disease. Recently, a position paper on pediatric WD was published by the European Society of Pediatric Gastroenterology Hepatology and Nutrition. A need was felt to harmonize guidelines for the hepatic, pediatric, and neurological aspects of the disease and contextualize them to the resource-constrained settings. Therefore, experts from national societies from India representing 3 disciplines, hepatology (Indian National Association for Study of the Liver), pediatric hepatology (Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition), and neurology (Movement Disorders Society of India) got together to evolve fresh guidelines. A literature search on retrospective and prospective studies of WD using MEDLINE (PubMed) was performed. Members voted on each recommendation, using the nominal voting technique. The Grades of Recommendation, Assessment, Development and Evaluation system was used to determine the quality of evidence. Questions related to diagnostic tests, scoring system, and its modification to a version suitable for resource-constrained settings were posed. While ceruloplasmin and 24-h urine copper continue to be important, there is little role of serum copper and penicillamine challenge test in the diagnostic algorithm. A new scoring system - Modified Leipzig score has been suggested with extra points being added for family history and serum ceruloplasmin lower than 5 mg/dl. Liver dry copper estimation and penicillamine challenge test have been removed from the scoring system. Differences in pharmacological approach to neurological and hepatic disease and global monitoring scales have been included. Rising bilirubin and worsening encephalopathy are suggested as indicators predicting need for liver transplant but need to be validated. The clinical practice guidelines provide recommendations for a comprehensive management of WD which will be of value to all specialties.
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Key Words
- AASLD, American Association for the Study of Liver Diseases
- ACLF, Acute on Chronic Liver Failure
- ALF, Acute Liver Failure
- ALT, Alanine Transaminase
- AST, Aspartate Transaminase
- Cu, Copper
- DP, D-Penicillamine
- EASL, European Association for the Study of the Liver
- GAS for WD, Global Assessment Scale for Wilson's Disease
- HCC, Hepatocellular Carcinoma
- INR, International Normalized Ratio
- KF, Kayser-Fleischer
- LT, Liver Transplantation
- MARS, Molecular Absorption Recirculating System
- MELD, Model for End-Stage Liver Disease
- MRI, Magnetic Resonance Imaging
- NGS, Next-Generation Sequencing
- NWI, New Wilson's Index
- PELD, Pediatric end stage liver disease
- TPE, Total Plasma Exchange
- TTM, Tetrathiomolybdate
- WD, Wilson's Disease
- Wilson's disease scoring
- genetic disorder
- modified Leipzig scoring
- rare disease
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Affiliation(s)
- Aabha Nagral
- Department of Gastroenterology, Jaslok Hospital and Research Centre, Mumbai, India
- Department of Gastroenterology, Apollo Hospitals, Navi Mumbai, India
| | - Moinak S. Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - John Matthai
- Department of Paediatric Gastroenterology, Masonic Medical Centre for Children, Coimbatore, India
| | | | - Harshad Devarbhavi
- Department of Gastroenterology and Hepatology, St. John's Medical College Hospital, Bangalore, India
| | - Sanjib Sinha
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Seema Alam
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | | | - Radha K. Dhiman
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | | | - Vinay Goyal
- Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
| | - Neelam Mohan
- Department of Pediatric Gastroenterology, Hepatology & Liver Transplantation, Medanta – The Medicity Hospital, Gurgaon, India
| | - Rukmini M. Kandadai
- Department of Neurology, Nizam's Institute of Medical Sciences, Hyderabad, India
| | - Malathi Sathiyasekaran
- Department of Pediatric Gastroenterology, Kanchi Kamakoti Childs Trust Hospital Chennai, India
| | - Ujjal Poddar
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Anupam Sibal
- Department of Pediatric Gastroenterology and Hepatology, Indraprastha Apollo Hospitals, New Delhi, India
| | | | - Anshu Srivastava
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Baburam R. Thapa
- Department of Gastroenterology & Pediatric Gastroenterology, MM Medical Institute of Medical Sciences and Research, Mullana, Ambala, India
| | - Pettarusp M. Wadia
- Department of Neurology, Jaslok Hospital and Research Centre, Mumbai, India
| | - Surendra K. Yachha
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Anil Dhawan
- Department of Pediatrics and Pediatric Liver GI and Nutrition Center and Mowat Labs, King's College Hospital, London, UK
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Predictors of seizure in Wilson disease: A clinico-radiological and biomarkers study. Neurotoxicology 2018; 71:87-92. [PMID: 30583001 DOI: 10.1016/j.neuro.2018.12.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 10/12/2018] [Accepted: 12/20/2018] [Indexed: 12/24/2022]
Abstract
BACKGROUND There is paucity of studies on predictors of seizures in Wilson disease with neurological manifestation (WDNM), and none has evaluated the role of copper (Cu) induced oxidative stress, proinflammatory and excitotoxicity in the genesis of seizure. OBJECTIVES To report frequency, refractoriness, and outcome of seizure in WDNM. We also evaluate role of Cu induced oxidative stress, excitotoxicity and cytokines in predicting seizures. METHODS The diagnosis of WDNM was based on clinical, MRI, KF ring and 24 h urinary Cu. Detailed clinical examination including severity of WD, occurrence of seizure, seizure semiology, antiepileptic drug (AED) and breakthrough seizures were noted. Cranial MRI and electroencephalography findings were noted. Serum free-Cu, oxidative stress markers (glutathione, total antioxidant capacity, malondialdehyde), glutamate and cytokines (interleukin 6, 8 and 10 and tumour necrosis factor α) were measured by atomic absorption spectrophotometer, spectrophotometer, fluorometer and flow cytometer respectively, and correlated with seizures. Patients were treated with zinc with or without penicillamine, and those with epilepsy received second-generation antiepileptic drugs (AEDs). RESULTS Out of 110 patients with WDNM, 16(14.5%) had seizures; focal in 11(68.7%) and generalized in 5(31.3%). Patients with seizure had higher serum free-Cu (35.87 ± 1.34 vs 31.72 ± 0.68; P = 0.02), severe dystonia (P = 0.04), and more frequent cortical (100% vs 6.4%; P < 0.01) and subcortical (81.3% vs 20.2%; P < 0.01) lesions on MRI compared to those without seizure. Oxidative stress markers (glutathione, total antioxidant capacity, malondialdehyde), cytokines and glutamate were elevated in WDNM compared to controls. On multivariate logistic regression analysis, cortical involvement (OR = 105.49; 95%CI = 8.74-1272.39; P < 0.01) and number of MRI lesions (OR = 1.99; 95% CI = 1.11-3.57; P = 0.02) were independent predictors of seizure. The seizures were controlled with single and dual AEDs in seven patients each, and two patients needed three AEDs. All the patients had seizure remission for a median follow up of 66(24-180) months. CONCLUSION About one-sixth WDNM patients have seizures especially in those with cortical and extensive MRI lesions. Seizures are easily controlled by AEDs.
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