Advances in Wilson's Disease and Other Neurodegenerations with Brain Metal Accumulations

A special issue of Diagnostics (ISSN 2075-4418). This special issue belongs to the section "Pathology and Molecular Diagnostics".

Deadline for manuscript submissions: 31 March 2024 | Viewed by 10393

Special Issue Editor

Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
Interests: Wilson’s disease; neurodegeneration with brain iron accumulation; stroke, multiple sclerosis; clinical trials

Special Issue Information

Dear Colleagues, 

Wilson’s disease (WD) is an inherited disorders of copper metabolism with pathological copper accumulation in different tissues with secondary damage to affected organs (mainly liver and brain). The disease is potentially treatable if early diagnosis and correct treatment are given. The current WD diagnosis is based mainly on clinical symptoms, copper metabolism, and genetical analysis. The WD treatment is based on drugs leading to negative copper body balance (chelators or zinc salts), which were discovered in the 50s and 70s of XX century. In recent years, the progress in WD diagnosis and treatment has been observed. Next-generation sequencing improved the genetic analyses, and direct measurement of ATP7B peptides was proposed as a method to identify patients with WD. Studies with PET with copper-64 visualized disturbances copper metabolism in WD patients compared to healthy controls. The new biomarkers as well as clinical and neuroradiological scales for WD were established. Finally, the new treatment modalities including gene therapy were proposed. Furthermore, WD, particularly the neurological form, often needs to be distinguished from other disorders characterized by brain metals accumulation, such as neurodegenerations with brain iron accumulation (NBIA); manganese transporter deficiency (or manganism due to manganeses overexposure) as well as primary familial brain calcifications (or secondary brain calcifications). Also, in these group of disorders, progress in diagnosis as well as in treatment perspectives is observed. The purpose of this Special Issue is to present the new techniques in WD and other disorders with brain metal accumulation diagnosis, treatment, and monitoring possibilities including original studies, case reports (difficult cases) and more current reviews for physicians involved in WD as well as in other brain metal accumulation disorders’ treatment.

Dr. Tomasz Litwin
Guest Editor

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Keywords

  • Wilson’s disease
  • NBIA
  • iron
  • copper
  • manganese
  • extrapyramidal disorders
  • genetics
  • symptomatic neurological treatment
  • liver transplantation
  • clinical trials

Published Papers (6 papers)

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Research

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14 pages, 875 KiB  
Article
Prevalence and Significance of Autoantibody Seropositivity in Children with Wilson’s Disease
by Wojciech Jańczyk, Joanna B. Bierła, Ilona Trojanowska, Aldona Wierzbicka-Rucińska, Bożena Cukrowska and Piotr Socha
Diagnostics 2023, 13(4), 768; https://doi.org/10.3390/diagnostics13040768 - 17 Feb 2023
Cited by 2 | Viewed by 1419
Abstract
Autoantibodies occur in healthy subjects as well as in children with Wilson’s disease (WD), but their prevalence and significance are unknown. Thus, we aimed to assess the prevalence of autoantibodies and autoimmune markers, and their relationship to liver injury in WD children. The [...] Read more.
Autoantibodies occur in healthy subjects as well as in children with Wilson’s disease (WD), but their prevalence and significance are unknown. Thus, we aimed to assess the prevalence of autoantibodies and autoimmune markers, and their relationship to liver injury in WD children. The study included 74 WD and 75 healthy children as a control group. Patients with WD underwent transient elastography (TE) examinations, as well as determination of liver function tests, copper metabolism markers, and serum immunoglobulins (Ig). In the sera of the WD patients and controls, anti-nuclear (ANA), anti-smooth muscle, anti-mitochondrial, anti-parietal cell, anti-liver/kidney microsomal, anti-neutrophil cytoplasmic autoantibodies, and specific celiac antibodies were determined. Among the autoantibodies, only the prevalence of ANA in children with WD was higher than in the controls. There was no significant relationship between the presence of autoantibodies and liver steatosis or stiffness after TE. However, advanced liver stiffness (E > 8.2 kPa) was related to IgA, IgG, and gamma globulin production. The type of treatment did not influence the prevalence of autoantibodies. Our results suggest that autoimmune disturbances in WD might not be directly related to liver damage as expressed by steatosis and/or liver stiffness after TE. Full article
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Review

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10 pages, 273 KiB  
Review
Elastography of the Liver in Wilson’s Disease
by Piotr Nehring, Jowita Szeligowska and Adam Przybyłkowski
Diagnostics 2023, 13(11), 1898; https://doi.org/10.3390/diagnostics13111898 - 29 May 2023
Viewed by 946
Abstract
Staging of liver fibrosis is of special significance in Wilson’s disease as it determines the patient’s prognosis and treatment. Histopathological examination is a standard method for fibrosis assessment; however, non-invasive methods like transient elastography and share wave elastography are believed to be reliable [...] Read more.
Staging of liver fibrosis is of special significance in Wilson’s disease as it determines the patient’s prognosis and treatment. Histopathological examination is a standard method for fibrosis assessment; however, non-invasive methods like transient elastography and share wave elastography are believed to be reliable and repetitive and are expected to replace liver biopsy in Wilson’s disease. This article presents a short description of available elastography techniques and the results of the most recent studies on elastography of the liver in patients with Wilson’s disease. Full article
18 pages, 353 KiB  
Review
Monitoring of Copper in Wilson Disease
by Grażyna Gromadzka, Marta Grycan and Adam M. Przybyłkowski
Diagnostics 2023, 13(11), 1830; https://doi.org/10.3390/diagnostics13111830 - 23 May 2023
Cited by 4 | Viewed by 1767
Abstract
(1) Introduction: Wilson’s disease (WND) is an autosomal recessive disorder of copper (Cu) metabolism. Many tools are available to diagnose and monitor the clinical course of WND. Laboratory tests to determine disorders of Cu metabolism are of significant diagnostic importance. (2) Methods: A [...] Read more.
(1) Introduction: Wilson’s disease (WND) is an autosomal recessive disorder of copper (Cu) metabolism. Many tools are available to diagnose and monitor the clinical course of WND. Laboratory tests to determine disorders of Cu metabolism are of significant diagnostic importance. (2) Methods: A systematic review of the literature in the PubMed, Science Direct, and Wiley Online Library databases was conducted. (Results): For many years, Cu metabolism in WND was assessed with serum ceruloplasmin (CP) concentration, radioactive Cu test, total serum Cu concentration, urinary copper excretion, and Cu content in the liver. The results of these studies are not always unambiguous and easy to interpret. New methods have been developed to calculate non-CP Cu (NCC) directly. New parameters, such as relative Cu exchange (REC), reflecting the ratio of CuEXC to total serum Cu, as well as relative Cu exchange (REC), reflecting the ratio of CuEXC to total serum Cu, have been shown to be an accurate tool for the diagnosis of WND. Recently, a direct and fast LC-ICP-MS method for the study of CuEXC was presented. A new method to assess Cu metabolism during treatment with ALXN1840 (bis-choline tetrathiomolybdate [TTM]) has been developed. The assay enables the bioanalysis of CP and different types of Cu, including CP-Cu, direct NCC (dNCC), and labile bound copper (LBC) in human plasma. Conclusions: A few diagnostic and monitoring tools are available for patients with WND. While many patients are diagnosed and adequately assessed with currently available methods, diagnosis and monitoring is a real challenge in a group of patients who are stuck with borderline results, ambiguous genetic findings, and unclear clinical phenotypes. Technological progress and the characterization of new diagnostic parameters, including those related to Cu metabolism, may provide confidence in the more accurate diagnosis of WND in the future. Full article
9 pages, 278 KiB  
Review
Blood Based Biomarkers of Central Nervous System Involvement in Wilson’s Disease
by Agnieszka Antos, Anna Członkowska, Jan Bembenek, Marta Skowronska, Iwona Kurkowska-Jastrzębska and Tomasz Litwin
Diagnostics 2023, 13(9), 1554; https://doi.org/10.3390/diagnostics13091554 - 26 Apr 2023
Cited by 6 | Viewed by 1142
Abstract
Wilson’s disease (WD) is an inherited disorder of copper metabolism with clinical symptoms related to pathological copper accumulation, which are mainly hepatic and/or neuropsychiatric. The disease is potentially treatable with pharmacological agents (chelators or zinc salts). As such, key factors for a favorable [...] Read more.
Wilson’s disease (WD) is an inherited disorder of copper metabolism with clinical symptoms related to pathological copper accumulation, which are mainly hepatic and/or neuropsychiatric. The disease is potentially treatable with pharmacological agents (chelators or zinc salts). As such, key factors for a favorable treatment outcome are early diagnosis and anti-copper treatment initiation as well as appropriate treatment monitoring for safety and efficacy. Despite the generally favorable outcome in most treated patients, almost 10% of the general population of WD patients and about 25% of patients in the group with initial neurological phenotype of disease experience early neurological deterioration. In almost 50% of patients with neurological symptoms, the symptoms persist. A search for new treatment modalities (e.g., gene therapy, molybdenum salts) aims to prevent early neurological deterioration as well as improve treatment outcomes. In addition to evaluating the clinical signs and symptoms of the disease, serum biomarkers for diagnosis and treatment monitoring are very important for WD management. Sensitive serum biomarkers of copper metabolism and liver injury are well described. However, there is a need to establish blood-based biomarkers of central nervous system (CNS) injury to help identify patients at risk of early neurological deterioration and aid in their monitoring. Based on the available literature and studies of WD patients, the authors reviewed serum biomarkers of CNS involvement in WD, as well as their potential clinical significance. Full article
15 pages, 312 KiB  
Review
Wilson’s Disease—Genetic Puzzles with Diagnostic Implications
by Grażyna Gromadzka, Maria Bendykowska and Adam Przybyłkowski
Diagnostics 2023, 13(7), 1287; https://doi.org/10.3390/diagnostics13071287 - 29 Mar 2023
Cited by 3 | Viewed by 1755
Abstract
(1) Introduction: Wilson’s disease (WND) is an autosomal recessive disorder of copper metabolism. The WND gene is ATP7B, located on chromosome 13. WND is characterized by high clinical variability, which causes diagnostic difficulties. (2) Methods: The PubMed, Science Direct, and Wiley Online [...] Read more.
(1) Introduction: Wilson’s disease (WND) is an autosomal recessive disorder of copper metabolism. The WND gene is ATP7B, located on chromosome 13. WND is characterized by high clinical variability, which causes diagnostic difficulties. (2) Methods: The PubMed, Science Direct, and Wiley Online Library medical databases were reviewed using the following phrases: “Wilson’s disease”, “ATP7B genotype”, “genotype-phenotype”, “epigenetics”, “genetic modifiers”, and their combinations. Publications presenting the results of experimental and clinical studies, as well as review papers, were selected, which concerned: (i) the diversity of genetic strategies and tests used in WND diagnosis; (ii) the difficulties of genetic diagnosis, including uncertainty as to the pathogenicity of variants; (iii) genetic counseling; (iv) phenotypic effects of ATP7B variants in patients with WND and in heterozygous carriers (HzcWND); (v) genetic and epigenetics factors modifying the clinical picture of the disease. (3) Results and conclusions: The genetic diagnosis of WND is carried out using a variety of strategies and tests. Due to the large number of known variants in the ATP7B gene (>900), the usefulness of genetic tests in routine diagnostics is still relatively small and even analyses performed using the most advanced technologies, including next-generation sequencing, require additional tests, including biochemical evidence of abnormal copper metabolism, to confirm the diagnosis of WND. Pseudodominant inheritance, the presence of three various pathogenic variants in the same patient, genotypes indicating the possibility of segmental uniparental disomy, have been reported. Genotype–phenotype relationships in WND are complex. The ATP7B genotype, to some extent, determines the clinical picture of the disease, but other genetic and epigenetic modifiers are also relevant. Full article
14 pages, 301 KiB  
Review
Neurological Wilson’s Disease Signs—Hepatic Encephalopathy or Copper Toxicosis?
by Anna Jopowicz and Beata Tarnacka
Diagnostics 2023, 13(5), 893; https://doi.org/10.3390/diagnostics13050893 - 27 Feb 2023
Cited by 2 | Viewed by 2508
Abstract
Wilson’s disease (WD) is a rare autosomal recessive (AR) disorder resulting from mutations in the ATP7B gene, which is responsible for the encryption of transmembrane copper transporting ATPase. The symptomatic presentation of the disease is estimated to be about 1 in 30,000. The [...] Read more.
Wilson’s disease (WD) is a rare autosomal recessive (AR) disorder resulting from mutations in the ATP7B gene, which is responsible for the encryption of transmembrane copper transporting ATPase. The symptomatic presentation of the disease is estimated to be about 1 in 30,000. The impairment of ATP7B function results in a copper overload in hepatocytes, which further leads to liver pathology. This copper overload also occurs in other organs, most particularly in the brain. This could then cause the occurrence of neurological and psychiatric disorders. Symptoms differ substantially and most often occur between the ages of 5 and 35 years. Early symptoms are commonly hepatic, neurological, or psychiatric. While disease presentation is most often asymptomatic, it could also range as far as to include fulminant hepatic failure, ataxia, and cognitive disorders. Various treatments are available for Wilson’s disease, including chelation therapy and zinc salts, which can reverse copper overload through different mechanisms. In select cases, liver transplantation is recommended. New medications, such as tetrathiomolybdate salts, are currently being investigated in clinical trials. With prompt diagnosis and treatment, prognosis is favorable; however, diagnosing patients before the onset of severe symptoms is a significant concern. Early screening for WD could help in diagnosing patients earlier and improving treatment outcomes. Full article
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