Materiały źródłowe

• #1 Pathogenesis of Wilson disease – PubMed

  https://pubmed.ncbi.nlm.nih.gov/28433109/

  Wilson disease is an autosomal-recessive disorder originating from a genetic defect in the copper-transporting ATPase ATP7B that is required for biliary copper secretion and loading of ceruloplasmin with copper. Impaired ATP7B function in Wilson disease results in excessive accumulation of copper in liver, brain, and other tissues. Toxic copper deposits may induce oxidative stress, modify expression of genes, directly inhibit proteins, and impair mitochondrial function, leading to hepatic, neuropsychiatric, renal, musculoskeletal, and other symptoms. […] In the brain, copper accumulates in astrocytes, leading to impairment of the blood-brain barrier and consequent damage to neurons and oligodendrocytes. Basal ganglia and brainstem are the brain regions with highest susceptibility to copper toxicity and their lesions lead to various combinations of movement and psychiatric disorders. […] We will specify the physiologic functions of ATP7B and the consequences of its dysfunction and summarize the current knowledge on the pathogenesis of liver and neuropsychiatric disease. Finally, we will describe the consequences of copper overload in Wilson disease in other tissues.

• #2 Wilson Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK441990/

  Wilson disease, also known as hepatolenticular degeneration, is a rare autosomal recessive disorder caused by gene mutations, leading to abnormal copper accumulation in the liver, brain, cornea, and other organs. […] Wilson disease is an autosomal recessive condition caused by 1 of several mutations in ATP7B gene which encodes the ATP7B protein transporter on the long arm of chromosome 13 (13q) responsible for excreting excess copper into bile and out of the body. […] Through faulty copper excretory mechanisms, excess copper accumulates in the liver and spills into the blood, accumulating in other organs and tissues, particularly in the brain, kidney, and eyes. Excess copper then leads to the formation of a toxic hydroxyl group, increasing oxidative stress in the cells and damaging tissue, which can result in organ dysfunction and clinical symptoms, including liver failure, neuropsychiatric symptoms, movement disorders, and Kayser-Fleischer (KF) rings in the cornea.

• #3 Wilson disease: Epidemiology and pathogenesis – UpToDate

  https://www.uptodate.com/contents/wilson-disease-epidemiology-and-pathogenesis

  Wilson disease (hepatolenticular degeneration) results from a defect in hepatocellular copper transport, leading to the accumulation of copper in the liver and other tissues, including the brain. Over time, the damage from the accumulation of copper results in the hepatic, neurologic, and psychiatric manifestations of Wilson disease. […] This topic will review the epidemiology and pathogenesis of Wilson disease. […] PATHOGENESIS […] Impaired incorporation of copper […] Hepatocyte injury from copper […] Extrahepatic copper deposition.

• #4 Wilson’s disease: Revisiting an old friend

  https://www.wjgnet.com/1948-5182/full/v13/i6/634.htm

  Wilson’s disease (WD) is a rare condition caused by copper accumulation primarily in the liver and secondly in other organs, such as the central nervous system. It is a hereditary autosomal recessive disease caused by a deficiency in the ATP7B transporter. This protein facilitates the incorporation of copper into ceruloplasmin. More than 800 mutations associated with WD have been described. […] The ATP7B gene is located on chromosome 13q14.3 and comprises 20 introns and 21 exons, encoding a protein of 165 amino acids, whose function is the incorporation of copper into ceruloplasmin. Currently, more than 800 mutations have been discovered in the gene, of which 380 have confirmed involvement in the pathogenesis of the disease. […] The potential role that epigenetics could have in the gene expression of the disease should be highlighted. Some experimental models have shown changes in DNA methylation through breast milk enriched with methyl groups that could be related to the clinical manifestation of WD.

• #5 Pulsenotes | Wilson’s disease

  https://app.pulsenotes.com/medicine/hepatology/notes/wilson-s-disease

  Wilson’s disease is an inherited, multi-system, progressive disorder of copper metabolism. […] It is caused by mutations to the ATP7B gene on chromosome 13. About 500 different mutations causing Wilson’s disease have been identified in this gene. ATP7B encodes a copper-transporting P-type ATPase that is found in hepatocytes (in the trans-Golgi network). The majority of these mutations are missense (single base pair change) that lead to loss-of-function. This means complete disruption of the normal copper-transporting protein function and the accumulation of copper in affected tissues. […] Treatment aims to reduce levels of copper and prevent further end-organ damage. […] Wilson’s is a progressive disease, early recognition and treatment is essential.

• #6 Diagnosis and Treatment of Wilson Disease | AASLD

  https://www.aasld.org/practice-guidelines/diagnosis-and-treatment-wilson-disease

  Wilson disease (WD; also known as hepatolenticular degeneration) was first described in 1912 by Kinnear Wilson as progressive lenticular degeneration, a familial, lethal neurological disease accompanied by chronic liver disease leading to cirrhosis. […] Over the next several decades, the role of copper in the pathogenesis of WD was established, and the pattern of inheritance was determined to be autosomal recessive. […] In 1993, the abnormal gene in WD was identified. This gene, ATP7B, encodes a metal-transporting P-type adenosine triphosphatase (ATPase), which is expressed mainly in hepatocytes and functions in the transmembrane transport of copper within hepatocytes. Absent or reduced function of ATP7B protein leads to decreased hepatocellular excretion of copper into bile. This results in hepatic copper accumulation and injury. Eventually, copper is released into the bloodstream and deposited in other organs, notably the brain, kidneys, and cornea.

• #7 Diagnosis and Treatment of Wilson Disease | AASLD

  https://www.aasld.org/practice-guidelines/diagnosis-and-treatment-wilson-disease

  Failure to incorporate copper into ceruloplasmin is an additional consequence of the loss of functional ATP7B protein. The hepatic production and secretion of the ceruloplasmin protein without copper, apoceruloplasmin, result in the decreased blood level of ceruloplasmin found in most patients with WD due to the reduced half-life of apoceruloplasmin.

• #8 Wilson’s disease – Wikipedia

  https://en.wikipedia.org/wiki/Wilson%27s_disease

  Wilson’s disease is caused by a mutation in the Wilson disease protein (ATP7B) gene. This protein transports excess copper into bile, where it is excreted in waste products. […] Copper enters the body through the digestive tract. A transporter protein on the cells of the small bowel, copper membrane transporter 1 (Ctr1; SLC31A1), carries copper inside the cells, where some is bound to metallothionein and part is carried by ATOX1 to an organelle known as the trans-Golgi network. Here, in response to rising concentrations of copper, an enzyme called ATP7A (Menkes’ protein) releases copper into the portal vein to the liver. Liver cells also carry the CMT1 protein, and metallothionein and ATOX1 bind it inside the cell, but here, ATP7B links copper to ceruloplasmin and releases it into the bloodstream, as well as removing excess copper by secreting it into bile. Both functions of ATP7B are impaired in Wilson’s disease. Copper accumulates in the liver tissue; ceruloplasmin is still secreted, but in a form that lacks copper (termed apo-ceruloplasmin) and is rapidly degraded in the bloodstream.

• #9 Histopathology of Wilson Disease | IntechOpen

  https://www.intechopen.com/chapters/74467

  Wilson Disease (WD) is a genetic metabolic disease of copper metabolism. The implicated gene is ATP7B, encodes a P-type ATPase which transports copper. The resultant defective metabolism of copper results in copper accumulation in multiple tissues especially liver, eye and central nervous system. […] WD is caused by mutations in the ATP7B gene encoding a copper transporting P-type ATPase required for copper excretion into the bile. […] The hepatic protein ATP7B encodes a copper-transporting P-type ATPase, transporting copper into the secretory pathway for incorporation into apoceruloplasmin, forming ceruloplasmin. ATP7B moves copper into the trans-Golgi network, where ceruloplasmin peptide acquires its complement of copper, assumes its folded state and is then released into the circulation. Excess is excreted eventually into the bile. Without the normal complement of copper, the peptide folds differently and has a decreased circulating half-life, leading to a low level of serum ceruloplasmin. Biliary excretion of copper is necessary for its homeostasis. When ATPB7 is defective, excess copper accumulates in the hepatocytes. Eventually the excess copper exceeds the storage capacity causing hepatocellular injury and release of copper into the circulation. Most WD patients have a low level of circulating ceruloplasmin which is a direct result of defective copper handling in hepatocytes as a result of mutation of the ATP7B gene. Free copper is extremely toxic and can produce irreversible cellular damage. The functional consequences of pathogenic ATP7B mutation are increased intracellular copper levels. This produces oxidative stress and free radical formation as well as mitochondrial dysfunction, which results in cell death in the liver, brain, kidneys, heart, eyes, and joints.

• #10 Wilson Disease – Nutritional Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/nutritional-disorders/mineral-deficiency-and-toxicity/wilson-disease

  Wilson disease is a disorder of copper metabolism that affects men and women; about 1 person in 30,000 has the disorder. Affected people are homozygous for the mutant recessive gene, located on chromosome 13. […] The genetic defect in Wilson disease impairs copper transport. The impaired transport decreases copper secretion into the bile, thus causing the copper overload and resultant accumulation in the liver, which begins at birth. The impaired transport also interferes with incorporation of copper into the copper protein ceruloplasmin, thus decreasing serum levels of ceruloplasmin. […] Hepatic fibrosis develops, ultimately causing cirrhosis. Copper diffuses out of the liver into the blood, then into other tissues. It is most destructive to the brain but also damages the kidneys and reproductive organs and causes hemolytic anemia. Some copper is deposited around the rim of the cornea and edge of the iris, causing Kayser-Fleischer rings. The rings appear to encircle the iris.

• #11 Wilson disease: Epidemiology and pathogenesis – UpToDate

  https://www.uptodate.com/contents/wilson-disease-epidemiology-and-pathogenesis/print

  Wilson disease (hepatolenticular degeneration) results from a defect in hepatocellular copper transport, leading to the accumulation of copper in the liver and other tissues, including the brain. Over time, the damage from the accumulation of copper results in the hepatic, neurologic, and psychiatric manifestations of Wilson disease. […] This topic will review the epidemiology and pathogenesis of Wilson disease. […] Copper is absorbed in the stomach and duodenum, binds mainly to circulating albumin, and is taken up by various tissues. The daily requirement for copper is approximately 0.75 mg. Excess copper is predominantly excreted into the bile, where it ends up as fecal copper. Renal losses account for only 5 to 15 percent of the daily excretion of copper.

• #12 Wilson Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK441990/

  Copper enters the body through the digestive tract via transporter proteins in the small intestine, specifically copper transporter 1 (CTR1; SLC31A1). This transporter facilitates the uptake of copper into cells, where copper is bound to metallothionein. […] In Wilson disease, dysfunctional ATP7B leads to copper accumulation in the liver, and ceruloplasmin is secreted in a form that lacks copper and is rapidly degraded in the bloodstream. […] When the copper level in the liver exceeds the naturally bound proteins, it leads to oxidative damage by forming reactive oxygen species. […] The liver releases copper into the bloodstream that is not bound by ceruloplasmin. This free copper is deposited in several organs, including the brain, the kidneys, and the eyes. […] In the brain, copper deposits in the basal ganglia, putamen, and globus pallidus are involved in the coordination of movement and neurocognitive processes, eg, mood regulation.

• #13 Wilson disease: more complex than just simply a copper overload condition?—a narrative review – Stremmel – AME Medical Journal

  https://amj.amegroups.org/article/view/7172/html

  Copper overload leads to release in blood for excretion in urine and distribution to other organs, preferentially to the basal ganglia of the brain. […] It is the free copper which induces the organ manifestation in Wilson disease and represents the target of therapy. […] Cu overload is most impressively seen in Wilson disease where mutations only of the ATP7B gene are causative (about 1,400 reported mutations). […] The other pathophysiologically more relevant consequence of ATP7B malfunction is impairment of Cu excretion in bile resulting in hepatocellular accumulation, although bile flow is maintained. […] When the metallothionein storage capacity is exhausted, the hepatocyte has the option to stop further influx and to export Cu+ through CTR1 back to the systemic circulation. […] Later in the course of the disease excessive hepatic copper is distributed to intracellular Cu storing organelles, which could be lysosomes.

• #14 Wilson disease: more complex than just simply a copper overload condition?—a narrative review – Stremmel – AME Medical Journal

  https://amj.amegroups.org/article/view/7172/html

  The free Cu is distributed via the histidine-albumin shuttle throughout the organism. […] The presentation of Wilson disease reveals a predominant hepatic, predominant neurologic, a mixed or asymptomatic phenotype. […] If failure of biliary excretion is essential for pathogenesis, the question arises whether there are ATP7B independent routes of biliary copper excretion. […] The switch of just Cu overload, where Cu+ is bound to metallothionein, to Cu-induced hepatocellular injury is not well defined. […] It is established that malfunctional ATP7B is the trigger of liver injury. […] Nevertheless, the narrative review presented here shows that all this knowledge is not suitable to prevent the onset of serious symptoms in many cases or to explain the variability in the type and severity of disease-associated symptoms. […] In particular, key questions that need to be elucidated are: Is it indeed the intracellular free fraction of Cu+ which causes membrane destruction?

• #15 Wilson Disease: Practice Essentials, Background, Etiology

  https://emedicine.medscape.com/article/183456-overview

  Wilson disease is a rare autosomal recessive inherited disorder of copper metabolism that is characterized by excessive deposition of copper in the liver, brain, and other tissues. […] The major physiologic aberration is excessive absorption of copper from the small intestine and decreased excretion of copper by the liver. […] The transport of copper by the copper-transporting P-type ATPase is defective in Wilson disease secondary to one of several mutations in the ATP7B gene. […] The excess copper resulting from Wilson disease promotes free radical formation that results in oxidation of lipids and proteins. […] Ultrastructural abnormalities in the earliest stages of hepatocellular injury, involving the endoplasmic reticulum, mitochondria, peroxisomes, and nuclei, have been identified. […] Initially, the excess copper accumulates in the liver, leading to damage to hepatocytes. Eventually, as liver copper levels increase, it increases in the circulation and is deposited in other organs.

• #16 Wilson’s Disease—Crossroads of Genetics, Inflammation and Immunity/Autoimmunity: Clinical and Molecular Issues

  https://www.mdpi.com/1422-0067/25/16/9034

  Copper and iron are redox-active and participate in the Fenton and Haber–Weiss reactions, which lead to the formation of free oxygen radicals. In these reactions, divalent Cu2+ is reduced to monovalent Cu+, which is converted back to Cu2+, while Fe3+ is reduced to Fe2+, which is converted back to Fe3+. […] The results of our studies on the role of oxidative stress and natural antioxidant mechanisms in WD indicate that the effectiveness of antioxidant mechanisms is greatly reduced due to copper overload; treatment that reduces the burden of copper improves the antioxidant status of patients but does not resolve it; the effectiveness of antioxidant protection increases after treatment; interindividual variability within genes encoding proteins involved in the antioxidant defense system may modulate phenotypic expressions of WD.

• #17 Wilson’s disease – Wikipedia

  https://en.wikipedia.org/wiki/Wilson%27s_disease

  When the amount of copper in the liver overwhelms the proteins that normally bind it, it causes oxidative damage to the liver through a process known as Fenton chemistry; this damage eventually leads to chronic active hepatitis, fibrosis (deposition of connective tissue), and cirrhosis. The liver also releases copper into the bloodstream that is not bound to ceruloplasmin. This free copper precipitates throughout the body, but particularly in the kidneys, eyes, and brain. In the brain, most copper is deposited in the basal ganglia, particularly in the putamen and globus pallidus (together called the lenticular nucleus); these areas normally participate in the coordination of movement and play a significant role in neurocognitive processes such as the processing of stimuli and mood regulation. Damage to these areas, again by Fenton chemistry, produces the neuropsychiatric symptoms seen in Wilson’s disease.

• #18 Wilson’s Disease—Crossroads of Genetics, Inflammation and Immunity/Autoimmunity: Clinical and Molecular Issues

  https://www.mdpi.com/1422-0067/25/16/9034

  Copper and iron are redox-active and participate in the Fenton and Haber–Weiss reactions, which lead to the formation of free oxygen radicals. In these reactions, divalent Cu2+ is reduced to monovalent Cu+, which is converted back to Cu2+, while Fe3+ is reduced to Fe2+, which is converted back to Fe3+. […] The results of our studies on the role of oxidative stress and natural antioxidant mechanisms in WD indicate that the effectiveness of antioxidant mechanisms is greatly reduced due to copper overload; treatment that reduces the burden of copper improves the antioxidant status of patients but does not resolve it; the effectiveness of antioxidant protection increases after treatment; interindividual variability within genes encoding proteins involved in the antioxidant defense system may modulate phenotypic expressions of WD.

• #19 Wilson’s Disease—Crossroads of Genetics, Inflammation and Immunity/Autoimmunity: Clinical and Molecular Issues

  https://www.mdpi.com/1422-0067/25/16/9034

  In addition to participating in free radical reactions, copper and iron can contribute to cell death in the cuproptosis and ferroptosis processes. […] Cuproptosis is a relatively recently described form of cell death caused by copper accumulation in mitochondria, which impairs mitochondrial respiration and protein lipidation, leading to membrane permeability, cell damage, and the initiation of apoptosis pathways under various conditions. […] The cuproptosis ability of cells has been shown to be related to glutaminase (GLS) and metal regulatory transcription factor 1 (MTF1). […] Another important mechanism in the pathogenesis of cell death in WD is ferroptosis. Ferroptosis is an iron-dependent phospholipid peroxidation process that represents a spontaneous form of cell death that results from imbalances in cellular iron homeostasis, cellular metabolism, redox states, and the accumulation of lipid peroxides in the cell membrane, which leads to cell death.

• #20 Wilson Disease: Practice Essentials, Background, Etiology

  https://emedicine.medscape.com/article/183456-overview

  Wilson disease is a rare autosomal recessive inherited disorder of copper metabolism that is characterized by excessive deposition of copper in the liver, brain, and other tissues. […] The major physiologic aberration is excessive absorption of copper from the small intestine and decreased excretion of copper by the liver. […] The transport of copper by the copper-transporting P-type ATPase is defective in Wilson disease secondary to one of several mutations in the ATP7B gene. […] The excess copper resulting from Wilson disease promotes free radical formation that results in oxidation of lipids and proteins. […] Ultrastructural abnormalities in the earliest stages of hepatocellular injury, involving the endoplasmic reticulum, mitochondria, peroxisomes, and nuclei, have been identified. […] Initially, the excess copper accumulates in the liver, leading to damage to hepatocytes. Eventually, as liver copper levels increase, it increases in the circulation and is deposited in other organs.

• #21 Wilson’s Disease—Crossroads of Genetics, Inflammation and Immunity/Autoimmunity: Clinical and Molecular Issues

  https://www.mdpi.com/1422-0067/25/16/9034

  In both types of cell death, ferroptosis and cuproptosis, mitochondria play an important role. Ferroptosis and cuproptosis are closely related to mitochondrial metabolism, highlighting the importance of studying mitochondria to understand mechanisms, regulatory processes, and disease implications. […] The inflammatory process is part of the protective response to various tissue injuries and is usually a beneficial process. Unfortunately, uncontrolled chronic inflammation may contribute to a variety of chronic inflammatory diseases. […] Copper not only increases the concentration of free radicals in the cells, but also weakens the ability to eliminate them by reducing the amount of the antioxidant GSH. […] It has been shown that copper can activate transcription factors sensitive to oxidative factors, which can promote the production of inflammatory mediators in endothelial cells.

• #22 Wilson’s Disease—Crossroads of Genetics, Inflammation and Immunity/Autoimmunity: Clinical and Molecular Issues

  https://www.mdpi.com/1422-0067/25/16/9034

  Tissue damage in WD may result from various molecular mechanisms. Oxidative stress, mitochondrial damage, and apoptosis play a particular role, but inflammatory/ immune/ autoimmune responses may also be important. […] Several hypotheses have been proposed as to the exact mechanism by which copper ions cause cell death. These include the initiation of apoptosis, caspase-independent cell death, generation of reactive oxygen species (ROS), and disruption of the ubiquitin–proteasome system. However, there is still no universally accepted theory. Therefore, further studies are needed to uncover the exact mechanisms controlling copper-induced cell death. […] Interestingly, in WD not only copper, but also iron metabolism is affected. This is because the metabolic pathways of these two elements are related at several stages.

• #23 Wilson’s Disease—Crossroads of Genetics, Inflammation and Immunity/Autoimmunity: Clinical and Molecular Issues

  https://www.mdpi.com/1422-0067/25/16/9034

  In addition to participating in free radical reactions, copper and iron can contribute to cell death in the cuproptosis and ferroptosis processes. […] Cuproptosis is a relatively recently described form of cell death caused by copper accumulation in mitochondria, which impairs mitochondrial respiration and protein lipidation, leading to membrane permeability, cell damage, and the initiation of apoptosis pathways under various conditions. […] The cuproptosis ability of cells has been shown to be related to glutaminase (GLS) and metal regulatory transcription factor 1 (MTF1). […] Another important mechanism in the pathogenesis of cell death in WD is ferroptosis. Ferroptosis is an iron-dependent phospholipid peroxidation process that represents a spontaneous form of cell death that results from imbalances in cellular iron homeostasis, cellular metabolism, redox states, and the accumulation of lipid peroxides in the cell membrane, which leads to cell death.

• #24 Wilson’s Disease: Facing the Challenge of Diagnosing a Rare Disease

  https://www.mdpi.com/2227-9059/9/9/1100

  In the cell, accumulation of copper produces an increase of ROS, which triggers oxidative stress and mitochondrial dysfunction. […] The abnormal deposits of iron contribute to the worsening of the clinical picture, since metabolism of iron and copper are closely related. […] Copper release from hepatocytes to circulation and its accumulation in tissues induce oxidative stress and triggers an inflammatory response, which contributes to WD pathogenesis.

• #25 Wilson’s disease: A review of what we have learned

  https://www.wjgnet.com/1948-5182/full/v7/i29/2859.htm

  Wilsons disease (WD), which results from the defective ATP7B protein product, is characterized by impaired copper metabolism and its clinical consequences vary from an asymptomatic state to fulminant hepatic failure, chronic liver disease with or without cirrhosis, neurological, and psychiatric manifestations. […] Copper overload, and actually free copper as the main acting element, exerts its toxicity through two main mechanisms: Direct oxidative stress, with lipid peroxidation of membranes, DNA, and mitochondria, as well as due to unregulated apoptosis leading to cell death from copper-induced changes in the anti-apoptotic protein, X-linked inhibitor of apoptosis, and its loss of inhibitory control of caspase-3. […] It is now known that it is not the accumulation of copper itself what is deleterious to the organism, but rather free copper in the blood, which determines copper intoxication, as opposed to ceruloplasmin-bound copper. Thus, the old paradigm of eliminating copper stores as the therapeutic objective has given way to the concept of normalizing free copper concentrations in the bloodstream.

• #26 Wilson’s Disease | Calgary Guide

  https://calgaryguide.ucalgary.ca/wilson-disease/wilsons-disease/

  Wilson Disease: Pathogenesis and clinical findings […] Autosomal Recessive mutation in ATP7B gene, defect in hepatic Cu transport protein […] Impaired Cu transport from liver into bile, Cu incorporation into apoceruloplasmin (protein responsible for carrying Cu in the blood) […] Hepatic Cu accumulation, deposition in hepatocyte lysosomes […] Hepatocyte injury (speculated mechanism: free radicals) […] Cu leak from damaged hepatocytes […] Early asymptomatic liver dysfunction […] Cu movement into bloodstream […] Cu deposition in vulnerable tissues […] Continued hepatocyte injury progressive liver damage.

• #27 Wilson’s disease – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/wilsons-disease/symptoms-causes/syc-20353251

  Wilson’s disease is caused by a changed gene inherited from each parent. Inheriting a changed gene from just one parent rarely affects a person’s health. But that person has one changed gene and one typical gene. Two carriers of changed genes have a 25% chance of having a child with two typical genes, a 50% chance of having a child who is a carrier, and a 25% chance of having a child who is affected by Wilson’s disease. […] Wilson’s disease is caused by a changed gene passed down from each parent. If you get only one affected gene, you won’t get the disease yourself, but you’ll be a carrier. This means you could pass the affected gene to your children. […] If Wilson’s disease isn’t treated, sometimes it can lead to death. Serious complications include: […] Scarring of the liver, also known as cirrhosis. As liver cells try to repair damage due to high copper levels, scar tissue forms in the liver. This makes it harder for the liver to work.

• #28 Wilson’s Disease—Crossroads of Genetics, Inflammation and Immunity/Autoimmunity: Clinical and Molecular Issues

  https://www.mdpi.com/1422-0067/25/16/9034

  The pathogenesis of liver cell damage from copper overload is not fully understood. A common feature of WD is the presence of liver inflammation, ranging from chronic hepatitis to fulminant hepatitis. Liver inflammation in WD is closely related to copper accumulation. […] The regulatory role of increased copper in downregulating SAHH activity, and the consequent upregulation of its substrate SAH and its potential secondary epigenetic effects on gene expression, suggest that Met metabolism may be the missing link between copper accumulation, inflammation, and hepatocyte damage in WD.

• #29 Wilson’s disease: Revisiting an old friend

  https://www.wjgnet.com/1948-5182/full/v13/i6/634.htm

  Wilson’s disease (WD) is a rare condition caused by copper accumulation primarily in the liver and secondly in other organs, such as the central nervous system. It is a hereditary autosomal recessive disease caused by a deficiency in the ATP7B transporter. This protein facilitates the incorporation of copper into ceruloplasmin. More than 800 mutations associated with WD have been described. […] The ATP7B gene is located on chromosome 13q14.3 and comprises 20 introns and 21 exons, encoding a protein of 165 amino acids, whose function is the incorporation of copper into ceruloplasmin. Currently, more than 800 mutations have been discovered in the gene, of which 380 have confirmed involvement in the pathogenesis of the disease. […] The potential role that epigenetics could have in the gene expression of the disease should be highlighted. Some experimental models have shown changes in DNA methylation through breast milk enriched with methyl groups that could be related to the clinical manifestation of WD.

• #30 Epigenomic signatures in liver and blood of Wilson disease patients include hypermethylation of liver-specific enhancers | Epigenetics & Chromatin | Full Text

  https://epigeneticsandchromatin.biomedcentral.com/articles/10.1186/s13072-019-0255-z

  There is strong evidence supporting the involvement of alterations in methionine metabolism in the pathogenesis of WD in animal models and indirect evidence supporting a role for the same mechanisms in the onset and progression of this condition in humans. […] This epigenomic signature reveals methylation changes occurring over liver-specific enhancers and transcription factor binding sites, demonstrating that WD is a genetic disease whose progression and, potentially, pathogenesis is associated with epigenetic changes. […] Hypermethylated DMRs identified in WD were specifically enriched in liver-specific enhancers and transcription factor binding sites, which is a novel finding for the WD field. […] Our results demonstrating hypermethylation over HNF4A and other transcription factor binding sites within liver-specific enhancers and promoters provides a new potential explanation for these prior molecular findings in WD pathogenesis. […] These DMRs likely represent an epigenomic signature of WD that includes direct alterations from increased copper levels, responses to disease progression, and inputs from the environment such as diet.

• #31 Pathogenesis of Wilson disease – PubMed

  https://pubmed.ncbi.nlm.nih.gov/28433109/

  Wilson disease is an autosomal-recessive disorder originating from a genetic defect in the copper-transporting ATPase ATP7B that is required for biliary copper secretion and loading of ceruloplasmin with copper. Impaired ATP7B function in Wilson disease results in excessive accumulation of copper in liver, brain, and other tissues. Toxic copper deposits may induce oxidative stress, modify expression of genes, directly inhibit proteins, and impair mitochondrial function, leading to hepatic, neuropsychiatric, renal, musculoskeletal, and other symptoms. […] In the brain, copper accumulates in astrocytes, leading to impairment of the blood-brain barrier and consequent damage to neurons and oligodendrocytes. Basal ganglia and brainstem are the brain regions with highest susceptibility to copper toxicity and their lesions lead to various combinations of movement and psychiatric disorders. […] We will specify the physiologic functions of ATP7B and the consequences of its dysfunction and summarize the current knowledge on the pathogenesis of liver and neuropsychiatric disease. Finally, we will describe the consequences of copper overload in Wilson disease in other tissues.

• #32 Wilson’s disease – Wikipedia

  https://en.wikipedia.org/wiki/Wilson%27s_disease

  When the amount of copper in the liver overwhelms the proteins that normally bind it, it causes oxidative damage to the liver through a process known as Fenton chemistry; this damage eventually leads to chronic active hepatitis, fibrosis (deposition of connective tissue), and cirrhosis. The liver also releases copper into the bloodstream that is not bound to ceruloplasmin. This free copper precipitates throughout the body, but particularly in the kidneys, eyes, and brain. In the brain, most copper is deposited in the basal ganglia, particularly in the putamen and globus pallidus (together called the lenticular nucleus); these areas normally participate in the coordination of movement and play a significant role in neurocognitive processes such as the processing of stimuli and mood regulation. Damage to these areas, again by Fenton chemistry, produces the neuropsychiatric symptoms seen in Wilson’s disease.

• #33 Wilson’s disease: update on pathogenesis, biomarkers and treatments | Journal of Neurology, Neurosurgery & Psychiatry

  https://jnnp.bmj.com/content/92/10/1053.abstract

  Wilsons disease is an autosomalrecessive disorder of copper metabolism caused by mutations in ATP7B and associated with neurological, psychiatric, ophthalmological and hepatic manifestations. […] The genetic and molecular mechanisms associated with ATP7B dysfunction have been well characterised, but despite extensive efforts to identify genotypephenotype correlations, the reason why only some patients develop neurological or psychiatric features remains unclear. […] We discuss pathological processes through which copper accumulation leads to neurodegeneration, such as mitochondrial dysfunction, the role of brain iron metabolism and the broader concept of selective neuronal vulnerability in Wilsons disease. […] We describe recent progress in developing imaging and wet (fluid) biomarkers for neurological involvement, including findings from quantitative MRI and other neuroimaging studies, and the development of a semiquantitative scoring system for assessing radiological severity. […] Finally, we cover the use of established and novel chelating agents, paradoxical neurological worsening, and progress developing targeted molecular and gene therapy for Wilsons disease, before discussing future directions for translational research.

• #34 Wilson’s disease: update on pathogenesis, biomarkers and treatments | Journal of Neurology, Neurosurgery & Psychiatry

  https://jnnp.bmj.com/content/92/10/1053

  Wilsons disease is an autosomal recessive disorder of copper metabolism caused by mutations in ATP7B and associated with neurological, psychiatric, ophthalmological and hepatic manifestations. […] The genetic and molecular mechanisms associated with ATP7B dysfunction have been well characterised, but despite extensive efforts to identify genotype-phenotype correlations, the reason why only some patients develop neurological or psychiatric features remains unclear. […] We discuss pathological processes through which copper accumulation leads to neurodegeneration, such as mitochondrial dysfunction, the role of brain iron metabolism and the broader concept of selective neuronal vulnerability in Wilsons disease. […] We describe recent progress in developing imaging and wet (fluid) biomarkers for neurological involvement, including findings from quantitative MRI and other neuroimaging studies, and the development of a semiquantitative scoring system for assessing radiological severity. […] Finally, we cover the use of established and novel chelating agents, paradoxical neurological worsening, and progress developing targeted molecular and gene therapy for Wilsons disease, before discussing future directions for translational research.

• #35 Wilson’s disease – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/wilsons-disease/symptoms-causes/syc-20353251

  Liver failure. This can occur suddenly what’s known as acute liver failure or decompensated Wilson’s disease. It also can come about slowly over years. A liver transplant might be a treatment option. […] Lasting nervous system issues. Tremors, involuntary muscle movements, clumsy walking and having a hard time speaking usually improve with treatment for Wilson’s disease. But some people have lasting nervous system problems, even with treatment. […] Kidney problems. Wilson’s disease can damage the kidneys, leading to issues such as kidney stones and an unusual number of amino acids removed in the urine. […] Mental health issues. These might include personality changes, depression, irritability, bipolar disorder or psychosis. […] Blood problems. These might include the destruction of red blood cells what’s known as hemolysis. This leads to anemia and jaundice.

• #36 Wilson Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK441990/

  The accumulation of free copper in the bloodstream leads to oxidative damage to erythrocytes, resulting in intravascular hemolysis, which in turn causes the notable indirect hyperbilirubinemia and overt jaundice characteristic of this condition. […] In the kidney, there is direct copper toxicity to renal tubular cells, as well as the potential bile cast nephropathy due to acute hemolysis.

• #37 Wilson’s disease – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/wilsons-disease/symptoms-causes/syc-20353251

  Liver failure. This can occur suddenly what’s known as acute liver failure or decompensated Wilson’s disease. It also can come about slowly over years. A liver transplant might be a treatment option. […] Lasting nervous system issues. Tremors, involuntary muscle movements, clumsy walking and having a hard time speaking usually improve with treatment for Wilson’s disease. But some people have lasting nervous system problems, even with treatment. […] Kidney problems. Wilson’s disease can damage the kidneys, leading to issues such as kidney stones and an unusual number of amino acids removed in the urine. […] Mental health issues. These might include personality changes, depression, irritability, bipolar disorder or psychosis. […] Blood problems. These might include the destruction of red blood cells what’s known as hemolysis. This leads to anemia and jaundice.

• #38 Wilson Disease – Nutritional Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/nutritional-disorders/mineral-deficiency-and-toxicity/wilson-disease

  Wilson disease is a disorder of copper metabolism that affects men and women; about 1 person in 30,000 has the disorder. Affected people are homozygous for the mutant recessive gene, located on chromosome 13. […] The genetic defect in Wilson disease impairs copper transport. The impaired transport decreases copper secretion into the bile, thus causing the copper overload and resultant accumulation in the liver, which begins at birth. The impaired transport also interferes with incorporation of copper into the copper protein ceruloplasmin, thus decreasing serum levels of ceruloplasmin. […] Hepatic fibrosis develops, ultimately causing cirrhosis. Copper diffuses out of the liver into the blood, then into other tissues. It is most destructive to the brain but also damages the kidneys and reproductive organs and causes hemolytic anemia. Some copper is deposited around the rim of the cornea and edge of the iris, causing Kayser-Fleischer rings. The rings appear to encircle the iris.

• #39 Wilson’s disease – Wikipedia

  https://en.wikipedia.org/wiki/Wilson%27s_disease

  Why Wilson’s disease causes hemolysis is unclear, but various lines of evidence suggest that a high level of free (nonceruloplasmin-bound) copper may be directly affecting the oxidation of hemoglobin, or inhibiting the energy-supplying enzymes in red blood cells, or causing direct damage to cell membranes.

• #40 Wilson’s disease – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/wilsons-disease/symptoms-causes/syc-20353251

  Liver failure. This can occur suddenly what’s known as acute liver failure or decompensated Wilson’s disease. It also can come about slowly over years. A liver transplant might be a treatment option. […] Lasting nervous system issues. Tremors, involuntary muscle movements, clumsy walking and having a hard time speaking usually improve with treatment for Wilson’s disease. But some people have lasting nervous system problems, even with treatment. […] Kidney problems. Wilson’s disease can damage the kidneys, leading to issues such as kidney stones and an unusual number of amino acids removed in the urine. […] Mental health issues. These might include personality changes, depression, irritability, bipolar disorder or psychosis. […] Blood problems. These might include the destruction of red blood cells what’s known as hemolysis. This leads to anemia and jaundice.

• #41 Cardiac and autonomic function in patients with Wilson’s disease | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1007-7

  The clinical effect of copper accumulation on the heart of patients suffering from Wilsons disease (WD) is not completely understood. […] Our data demonstrate that cardiac involvement and autonomic dysfunction in WD is possible, however the underlying cause is still not known. […] The generally cited mechanism of pathology development in WD involves oxidative damage due to copper overload and intramitochondrial membrane crosslinking that culminates in mitochondrial destruction and liver failure. […] There is still no clear evidence of how and to what extent excessive copper accumulations leads to cardiac dysfunction. […] The presence of fibrotic tissue is considered to be the basis for ventricular arrhythmias, which can be also detected in WD patients. […] Therefore, we conclude that premature ventricular contractions are a sign of copper toxicity to the heart.

• #42 Cardiac and autonomic function in patients with Wilson’s disease | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1007-7

  One possible explanation might be a decreased HRV, which was observed in our WD patients. […] The underlying mechanism between decreased HRV in the cited studies and WD patients might be different. […] A recently published longitudinal cohort study revealed that patients suffering from WD exhibited a statistically significant 55% increased risk of heart failure. […] It remains unclear how WD patients develop heart failure, as recently shown by Grandis et al. […] However, patients with an exacerbation in medical history had higher troponin than those without, which might point to a copper related toxicity and inflammation to the myocardium. […] This hypothesis is supported by the fact, that in one patient suffering from acute exacerbation adequate medical therapy and successful de-coppering was able to decrease elevated troponin levels and thus reduce the effect of copper-overload inflammation.

• #43 Clinical and genetic characterization of patients with late onset Wilson’s disease | npj Genomic Medicine

  https://www.nature.com/articles/s41525-024-00459-z

  Wilsons disease (WD; OMIM #277900) is a rare autosomal recessive disorder of copper metabolism caused by variants in ATP7B, which encodes a copper-transporting P1B-type ATPase located in the trans-Golgi network. ATP7B is mainly expressed in the liver, and functional defects in the protein lead to failure of ceruloplasmin biosynthesis and biliary copper excretion, with copper accumulating first in the liver and then in the brain, cornea, and other tissues. As a result, patients with WD may present with hepatic and/or neurological symptoms, corneal Kayser-Fleischer (KF) rings, and low ceruloplasmin levels. […] Hundreds of variants have been identified in patients with WD, and their various effects on ATP7B stability, catalytic and transport activities, and intracellular localization have been reported. Variants with partially affected ATP7B function may be accompanied by a slower accumulation of copper in the liver and other organs, and patients may develop symptoms at a later age or even never become symptomatic throughout their life, exhibiting low penetrance characteristics that affect the genetic and clinical prevalence of WD.

• #44

  https://link.springer.com/article/10.1007/s11894-005-0062-5

  Wilson disease is caused by disease-specific mutations of the copper transporting ATPase, ATP7B. […] Both environmental and extragenic effects contribute to the varied phenotypic presentations of this disease. […] The failure of some disease-specific mutants to localize properly to the trans-Golgi was demonstrated by transfection of liver cell lines. These data show the importance of proper cellular localization for ATP7B function. […] These studies suggest that alterations in other proteins in the copper metabolic pathway may affect the phenotypic expression of Wilson disease. This concept is similar to that now being developed for iron overload disorders, where there are several different gene products that may act in concert to influence phenotypic expression of disease.

• #45 Wilson’s Disease: Facing the Challenge of Diagnosing a Rare Disease

  https://www.mdpi.com/2227-9059/9/9/1100

  Wilson disease (WD) is a rare disorder caused by mutations in ATP7B, which leads to the defective biliary excretion of copper. The subsequent gradual accumulation of copper in different organs produces an extremely variable clinical picture, which comprises hepatic, neurological psychiatric, ophthalmological, and other disturbances. […] WD is caused by mutations in the ATP7B gene, which encodes for a copper transporter that is responsible for biliary excretion of copper and its incorporation into ceruloplasmin. […] The main underlying problem lies in suboptimal diagnostic tests and elusive biomarkers to diagnose a rare genetic disease characterized by incomplete penetrance and highly variable expression. […] Copper deposits lead to mitochondrial dysfunction and cause hepatic steatosis, so that genes involved in lipid metabolism may be good candidates to act as genetic modifiers, such as PNPLA3 and APOE.

• #46 Wilson disease: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/wilson-disease/

  Wilson disease is caused by variants (also known as mutations) in the ATP7B gene. This gene provides instructions for making a protein called copper-transporting ATPase 2, which plays a role in the transport of copper from the liver to other parts of the body. Copper is necessary for many cellular functions, but it is toxic when present in excessive amounts. The copper-transporting ATPase 2 protein is particularly important for the elimination of excess copper from the body. Variants in the ATP7B gene prevent the transport protein from functioning properly. With a shortage of functional protein, excess copper is not removed from the body. As a result, copper accumulates to toxic levels that can damage tissues and organs, particularly the liver and brain. […] Research indicates that a normal variation in the PRNP gene may modify the course of Wilson disease. The PRNP gene provides instructions for making prion protein, which is active in the brain and other tissues and appears to be involved in transporting copper. Studies have focused on the effects of a PRNP gene variation that affects position 129 of the prion protein. At this position, people can have either the protein building block (amino acid) methionine or the amino acid valine. Among people who have variants in the ATP7B gene, it appears that having methionine instead of valine at position 129 of the prion protein is associated with delayed onset of symptoms and an increased occurrence of neurological symptoms, particularly tremors. Larger studies are needed, however, before the effects of this PRNP gene variation on Wilson disease can be established.

• #47 Clinical and genetic characterization of patients with late onset Wilson’s disease | npj Genomic Medicine

  https://www.nature.com/articles/s41525-024-00459-z

  The current data suggest a relationship between the variants A874V, V1106I, T935M, and R919G and the late onset of WD, as well as a correlation between R778L, P992L, and PTV and the early onset of WD, among which A874V, R778L, P992L, and PTV were confirmed in our previous study. Our data strongly suggest that A874V, V1106I, and T935M are associated with late-onset WD, with V1106I and T935M exhibiting low penetrance. […] The absence of these variant combinations in patients with WD implies that they may be nonpathogenic or that patients with these genotypes may be overlooked due to atypical clinical features. However, this conclusion was established based on several premises. One concern is that the genetic background of the East Asian subgroup in gnomAD may not represent the Chinese population, as there are differences in hotspot variants among different regions of China. Other issues include a lack of Hardy-Weinberg equilibrium, the relatively small number of patients with late-onset WD included in the current study, and the limited number of patients with WD with acquired genetic information; therefore, these results should be confirmed in more patients with WD. […] Our research revealed distinct clinical and genetic characteristics of patients with late-onset WD, which may provide valuable insights into the genetic basis and diagnosis of this disease.

• #48 Epigenomic signatures in liver and blood of Wilson disease patients include hypermethylation of liver-specific enhancers | Epigenetics & Chromatin | Full Text

  https://epigeneticsandchromatin.biomedcentral.com/articles/10.1186/s13072-019-0255-z

  Wilson disease (WD) is an autosomal recessive disease caused by mutations in ATP7B encoding a copper transporter. […] The goal of this study was to analyze alterations in DNA methylation at the whole-genome level in liver and blood from patients with WD to investigate epigenomic alterations associated with WD diagnosis and phenotype. […] WD-specific liver DMRs were associated with genes enriched for functions in folate and lipid metabolism and acute inflammatory response and could differentiate early from advanced fibrosis in WD patients. […] Functional annotation revealed that WD-hypermethylated liver DMRs were enriched in liver-specific enhancers, flanking active liver promoters, and binding sites of liver developmental transcription factors, including Hepatocyte Nuclear Factor 4 alpha (HNF4A), Retinoid X Receptor alpha (RXRA), Forkhead Box A1 (FOXA1), and FOXA2.

• #49 Epigenomic signatures in liver and blood of Wilson disease patients include hypermethylation of liver-specific enhancers | Epigenetics & Chromatin | Full Text

  https://epigeneticsandchromatin.biomedcentral.com/articles/10.1186/s13072-019-0255-z

  There is strong evidence supporting the involvement of alterations in methionine metabolism in the pathogenesis of WD in animal models and indirect evidence supporting a role for the same mechanisms in the onset and progression of this condition in humans. […] This epigenomic signature reveals methylation changes occurring over liver-specific enhancers and transcription factor binding sites, demonstrating that WD is a genetic disease whose progression and, potentially, pathogenesis is associated with epigenetic changes. […] Hypermethylated DMRs identified in WD were specifically enriched in liver-specific enhancers and transcription factor binding sites, which is a novel finding for the WD field. […] Our results demonstrating hypermethylation over HNF4A and other transcription factor binding sites within liver-specific enhancers and promoters provides a new potential explanation for these prior molecular findings in WD pathogenesis. […] These DMRs likely represent an epigenomic signature of WD that includes direct alterations from increased copper levels, responses to disease progression, and inputs from the environment such as diet.

• #50 Wilson’s disease: Revisiting an old friend

  https://www.wjgnet.com/1948-5182/full/v13/i6/634.htm

  Wilson’s disease (WD) is a rare condition caused by copper accumulation primarily in the liver and secondly in other organs, such as the central nervous system. It is a hereditary autosomal recessive disease caused by a deficiency in the ATP7B transporter. This protein facilitates the incorporation of copper into ceruloplasmin. More than 800 mutations associated with WD have been described. […] The ATP7B gene is located on chromosome 13q14.3 and comprises 20 introns and 21 exons, encoding a protein of 165 amino acids, whose function is the incorporation of copper into ceruloplasmin. Currently, more than 800 mutations have been discovered in the gene, of which 380 have confirmed involvement in the pathogenesis of the disease. […] The potential role that epigenetics could have in the gene expression of the disease should be highlighted. Some experimental models have shown changes in DNA methylation through breast milk enriched with methyl groups that could be related to the clinical manifestation of WD.

• #51 Histopathology of Wilson Disease | IntechOpen

  https://www.intechopen.com/chapters/74467

  The most common ones are single-nucleotide missense and nonsense mutations, chased by insertions/deletions, and, rarely, splice site mutations. H1069Q is the most common mutation around the world, seen in most of the WD carriers in Europe and USA, with some absence for this mutation in some countries. […] The wide range of disease patterns cannot be explained just by different mutations. Environmental, epigenetic, and other genetic factors are also contribute pathogenesis of WD. […] The main therapeutic strategy is using chelating agents, particularly D-penicillamine. Liver transplantation (LT) is reserved for patients unresponsive to medical therapy or with fulminant hepatic failure. LT for neurological complications is highly controversial and generally cannot be recommended.

• #52 Histopathology of Wilson Disease | IntechOpen

  https://mts.intechopen.com/redirector/articles/histopathology-of-wilson-disease

  The most common ones are single-nucleotide missense and nonsense mutations, chased by insertions/deletions, and, rarely, splice site mutations. H1069Q is the most common mutation around the world, seen in most of the WD carriers in Europe and USA, with some absence for this mutation in some countries. […] The wide range of disease patterns cannot be explained just by different mutations. Environmental, epigenetic, and other genetic factors are also contribute pathogenesis of WD. […] The main therapeutic strategy is using chelating agents, particularly D-penicillamine. Liver transplantation (LT) is reserved for patients unresponsive to medical therapy or with fulminant hepatic failure.

• #53 Wilson’s Disease—Crossroads of Genetics, Inflammation and Immunity/Autoimmunity: Clinical and Molecular Issues

  https://www.mdpi.com/1422-0067/25/16/9034

  Tissue damage in WD may result from various molecular mechanisms. Oxidative stress, mitochondrial damage, and apoptosis play a particular role, but inflammatory/ immune/ autoimmune responses may also be important. […] Several hypotheses have been proposed as to the exact mechanism by which copper ions cause cell death. These include the initiation of apoptosis, caspase-independent cell death, generation of reactive oxygen species (ROS), and disruption of the ubiquitin–proteasome system. However, there is still no universally accepted theory. Therefore, further studies are needed to uncover the exact mechanisms controlling copper-induced cell death. […] Interestingly, in WD not only copper, but also iron metabolism is affected. This is because the metabolic pathways of these two elements are related at several stages.

• #54 Wilson’s Disease—Crossroads of Genetics, Inflammation and Immunity/Autoimmunity: Clinical and Molecular Issues

  https://www.mdpi.com/1422-0067/25/16/9034

  In both types of cell death, ferroptosis and cuproptosis, mitochondria play an important role. Ferroptosis and cuproptosis are closely related to mitochondrial metabolism, highlighting the importance of studying mitochondria to understand mechanisms, regulatory processes, and disease implications. […] The inflammatory process is part of the protective response to various tissue injuries and is usually a beneficial process. Unfortunately, uncontrolled chronic inflammation may contribute to a variety of chronic inflammatory diseases. […] Copper not only increases the concentration of free radicals in the cells, but also weakens the ability to eliminate them by reducing the amount of the antioxidant GSH. […] It has been shown that copper can activate transcription factors sensitive to oxidative factors, which can promote the production of inflammatory mediators in endothelial cells.

• #55 Wilson’s Disease—Crossroads of Genetics, Inflammation and Immunity/Autoimmunity: Clinical and Molecular Issues

  https://www.mdpi.com/1422-0067/25/16/9034

  The pathogenesis of liver cell damage from copper overload is not fully understood. A common feature of WD is the presence of liver inflammation, ranging from chronic hepatitis to fulminant hepatitis. Liver inflammation in WD is closely related to copper accumulation. […] The regulatory role of increased copper in downregulating SAHH activity, and the consequent upregulation of its substrate SAH and its potential secondary epigenetic effects on gene expression, suggest that Met metabolism may be the missing link between copper accumulation, inflammation, and hepatocyte damage in WD.

• #56 Wilson’s disease: A review of what we have learned

  https://www.wjgnet.com/1948-5182/full/v7/i29/2859.htm

  Treatment principles in WD include the establishment of a certain diagnosis, since the treatment is lifelong, as well as the monitoring of compliance, early detection of complications, and integral management including early neuropsychiatric screening/evaluation and physiotherapy, as required. […] Treatment is based on the removal of copper excess by chelating agents such as penicillamine, trientine, or tetrathiomolybdate or by blocking the intestinal copper absorption with zinc salts, with the ultimate goal of normalizing free plasmatic copper. […] Neurological damage, in some cases irreversible, may be induced by massive and sudden free copper elevation following therapy with D-penicillamine and other potent chelators; neurological worsening has in fact been linked with spikes in free copper, induced by chelators including D-penicillamine.

• #57 Wilson’s disease: A review of what we have learned

  https://www.wjgnet.com/1948-5182/full/v7/i29/2859.htm

  The mechanism behind neurological worsening is the mobilization of important amounts of free copper, which together with an increase in malanodialdehyde and a reduction in glutathione, lead to cellular damage. […] Although not standardized, combined therapy, with the administration of either D-penicillamine and zinc, or trientine and zinc, at widely spaced intervals during the day, is a valid strategy that has yielded good results.

• #58 Wilson’s disease: Revisiting an old friend

  https://www.wjgnet.com/1948-5182/full/v13/i6/634.htm

  The diagnosis is established with a combination of clinical signs and tests, including the measurement of ceruloplasmin, urinary copper excretion, copper quantification in liver biopsy, or genetic assessment. […] DPA is the first-line drug for WD, and its mechanism involves chelation of circulating copper which will subsequently be excreted in the urine. DPA reduces copper’s affinity for proteins by facilitating the removal of copper from tissues, and it induces the synthesis of metallothionein in the liver, a cysteine-rich protein with a high affinity for metal ions. […] Although neurological worsening typically occurs with DPA treatment, it has also been demonstrated with trientine and to a lesser extent with zinc salts. Free copper induces oxidative stress which damages brain tissue. […] The development of new and effective treatments, including gene therapy, is promising for the future treatment of this disease.

• #59 Wilson’s disease: A review of what we have learned

  https://www.wjgnet.com/1948-5182/full/v7/i29/2859.htm

  Treatment principles in WD include the establishment of a certain diagnosis, since the treatment is lifelong, as well as the monitoring of compliance, early detection of complications, and integral management including early neuropsychiatric screening/evaluation and physiotherapy, as required. […] Treatment is based on the removal of copper excess by chelating agents such as penicillamine, trientine, or tetrathiomolybdate or by blocking the intestinal copper absorption with zinc salts, with the ultimate goal of normalizing free plasmatic copper. […] Neurological damage, in some cases irreversible, may be induced by massive and sudden free copper elevation following therapy with D-penicillamine and other potent chelators; neurological worsening has in fact been linked with spikes in free copper, induced by chelators including D-penicillamine.

• #60 Wilson’s disease: A review of what we have learned

  https://www.wjgnet.com/1948-5182/full/v7/i29/2859.htm

  Treatment principles in WD include the establishment of a certain diagnosis, since the treatment is lifelong, as well as the monitoring of compliance, early detection of complications, and integral management including early neuropsychiatric screening/evaluation and physiotherapy, as required. […] Treatment is based on the removal of copper excess by chelating agents such as penicillamine, trientine, or tetrathiomolybdate or by blocking the intestinal copper absorption with zinc salts, with the ultimate goal of normalizing free plasmatic copper. […] Neurological damage, in some cases irreversible, may be induced by massive and sudden free copper elevation following therapy with D-penicillamine and other potent chelators; neurological worsening has in fact been linked with spikes in free copper, induced by chelators including D-penicillamine.

• #61 Wilson’s disease: A review of what we have learned

  https://www.wjgnet.com/1948-5182/full/v7/i29/2859.htm

  Wilsons disease (WD), which results from the defective ATP7B protein product, is characterized by impaired copper metabolism and its clinical consequences vary from an asymptomatic state to fulminant hepatic failure, chronic liver disease with or without cirrhosis, neurological, and psychiatric manifestations. […] Copper overload, and actually free copper as the main acting element, exerts its toxicity through two main mechanisms: Direct oxidative stress, with lipid peroxidation of membranes, DNA, and mitochondria, as well as due to unregulated apoptosis leading to cell death from copper-induced changes in the anti-apoptotic protein, X-linked inhibitor of apoptosis, and its loss of inhibitory control of caspase-3. […] It is now known that it is not the accumulation of copper itself what is deleterious to the organism, but rather free copper in the blood, which determines copper intoxication, as opposed to ceruloplasmin-bound copper. Thus, the old paradigm of eliminating copper stores as the therapeutic objective has given way to the concept of normalizing free copper concentrations in the bloodstream.

• #62 Wilson’s disease: A review of what we have learned

  https://www.wjgnet.com/1948-5182/full/v7/i29/2859.htm

  The mechanism behind neurological worsening is the mobilization of important amounts of free copper, which together with an increase in malanodialdehyde and a reduction in glutathione, lead to cellular damage. […] Although not standardized, combined therapy, with the administration of either D-penicillamine and zinc, or trientine and zinc, at widely spaced intervals during the day, is a valid strategy that has yielded good results.

• #63 Wilson Disease: Pathogenesis, Diagnosis, and Treatment – Page 2

  https://www.medscape.com/viewarticle/756588_2

  The genetic basis for Wilson disease (WD), the ATP7B mutation, was identified and cloned in 1993.[10,11] […] The first treatment developed was British anti-lewisite (BAL), a compound developed for countering the toxic effects of mustard gas that was found to be a chelator of copper. This parenterally administered medication resulted in increased copper excretion and reversed neurologic symptoms in many patients.[14] […] A very important historic milestone with respect to treatment of WD was the recognition that preemptive treatment could prevent the development of disease progression, something that seems almost incontrovertible at this time, but which was not initially accepted.[20] […] Liver transplantation is curative and represents a gross form of genetic therapy for WD.

• #64 Wilson’s disease: update on pathogenesis, biomarkers and treatments | Journal of Neurology, Neurosurgery & Psychiatry

  https://jnnp.bmj.com/content/92/10/1053.abstract

  Wilsons disease is an autosomalrecessive disorder of copper metabolism caused by mutations in ATP7B and associated with neurological, psychiatric, ophthalmological and hepatic manifestations. […] The genetic and molecular mechanisms associated with ATP7B dysfunction have been well characterised, but despite extensive efforts to identify genotypephenotype correlations, the reason why only some patients develop neurological or psychiatric features remains unclear. […] We discuss pathological processes through which copper accumulation leads to neurodegeneration, such as mitochondrial dysfunction, the role of brain iron metabolism and the broader concept of selective neuronal vulnerability in Wilsons disease. […] We describe recent progress in developing imaging and wet (fluid) biomarkers for neurological involvement, including findings from quantitative MRI and other neuroimaging studies, and the development of a semiquantitative scoring system for assessing radiological severity. […] Finally, we cover the use of established and novel chelating agents, paradoxical neurological worsening, and progress developing targeted molecular and gene therapy for Wilsons disease, before discussing future directions for translational research.

• #65 Prime Medicine Reports First Quarter 2025 Financial Results

  https://www.globenewswire.com/news-release/2025/05/08/3077199/0/en/Prime-Medicine-Reports-First-Quarter-2025-Financial-Results-and-Provides-Business-Updates.html

  — IND and/or CTA for PM577 for Wilsons Disease on-track for 1H 2026 — […] Both our Wilsons Disease and AATD programs are advancing through preclinical development, and we look forward to initiating clinical trials in both indications in 2026. […] Advance PM577 through investigational new drug (IND)-enabling studies for the treatment of Wilsons Disease patients with the most prevalent Wilsons Disease mutation in the United States. […] File investigational new drug (IND) and/or clinical trial application (CTA) for PM577 in the first half of 2026. […] the potential of Prime Editing to correct the causative mutations of diseases, including of AATD, Wilsons Disease, CF and p47phox CGD;

• #66 Pulsenotes | Wilson’s disease

  https://app.pulsenotes.com/medicine/hepatology/notes/wilson-s-disease

  Wilson’s disease is an inherited, multi-system, progressive disorder of copper metabolism. […] It is caused by mutations to the ATP7B gene on chromosome 13. About 500 different mutations causing Wilson’s disease have been identified in this gene. ATP7B encodes a copper-transporting P-type ATPase that is found in hepatocytes (in the trans-Golgi network). The majority of these mutations are missense (single base pair change) that lead to loss-of-function. This means complete disruption of the normal copper-transporting protein function and the accumulation of copper in affected tissues. […] Treatment aims to reduce levels of copper and prevent further end-organ damage. […] Wilson’s is a progressive disease, early recognition and treatment is essential.

• #67 A Neglected Case of Wilson Disease

  https://brieflands.com/articles/jcp-19753

  There is no single diagnostic test for WD and diagnosis is usually made by lab tests following clinical suspicions. […] Diagnosis is based on low serum copper and ceruloplasmin levels, high copper concentrations in the liver, high copper excretion in the 24-hour urine, and conducting a penicillamine challenge test if doubt remains. […] Therefore, it is essential that the first physician diagnoses WD properly to avoid unwanted injuries to the liver.

• #68

  https://discovery.ucl.ac.uk/id/eprint/10136191/

  Wilsons disease is an autosomalrecessive disorder of copper metabolism caused by mutations in ATP7B and associated with neurological, psychiatric, ophthalmological and hepatic manifestations. […] The genetic and molecular mechanisms associated with ATP7B dysfunction have been well characterised, but despite extensive efforts to identify genotypephenotype correlations, the reason why only some patients develop neurological or psychiatric features remains unclear. […] We discuss pathological processes through which copper accumulation leads to neurodegeneration, such as mitochondrial dysfunction, the role of brain iron metabolism and the broader concept of selective neuronal vulnerability in Wilsons disease. […] We highlight limitations in our current approach to making a diagnosis and novel diagnostic biomarkers, including the potential for newborn screening programmes. […] Finally, we cover the use of established and novel chelating agents, paradoxical neurological worsening, and progress developing targeted molecular and gene therapy for Wilsons disease, before discussing future directions for translational research.

• #69 Pathogenesis of Wilson disease – PubMed

  https://pubmed.ncbi.nlm.nih.gov/28433109/

  Wilson disease is an autosomal-recessive disorder originating from a genetic defect in the copper-transporting ATPase ATP7B that is required for biliary copper secretion and loading of ceruloplasmin with copper. Impaired ATP7B function in Wilson disease results in excessive accumulation of copper in liver, brain, and other tissues. Toxic copper deposits may induce oxidative stress, modify expression of genes, directly inhibit proteins, and impair mitochondrial function, leading to hepatic, neuropsychiatric, renal, musculoskeletal, and other symptoms. […] In the brain, copper accumulates in astrocytes, leading to impairment of the blood-brain barrier and consequent damage to neurons and oligodendrocytes. Basal ganglia and brainstem are the brain regions with highest susceptibility to copper toxicity and their lesions lead to various combinations of movement and psychiatric disorders. […] We will specify the physiologic functions of ATP7B and the consequences of its dysfunction and summarize the current knowledge on the pathogenesis of liver and neuropsychiatric disease. Finally, we will describe the consequences of copper overload in Wilson disease in other tissues.

• #70 Clinical and genetic characterization of patients with late onset Wilson’s disease | npj Genomic Medicine

  https://www.nature.com/articles/s41525-024-00459-z

  Wilsons disease (WD; OMIM #277900) is a rare autosomal recessive disorder of copper metabolism caused by variants in ATP7B, which encodes a copper-transporting P1B-type ATPase located in the trans-Golgi network. ATP7B is mainly expressed in the liver, and functional defects in the protein lead to failure of ceruloplasmin biosynthesis and biliary copper excretion, with copper accumulating first in the liver and then in the brain, cornea, and other tissues. As a result, patients with WD may present with hepatic and/or neurological symptoms, corneal Kayser-Fleischer (KF) rings, and low ceruloplasmin levels. […] Hundreds of variants have been identified in patients with WD, and their various effects on ATP7B stability, catalytic and transport activities, and intracellular localization have been reported. Variants with partially affected ATP7B function may be accompanied by a slower accumulation of copper in the liver and other organs, and patients may develop symptoms at a later age or even never become symptomatic throughout their life, exhibiting low penetrance characteristics that affect the genetic and clinical prevalence of WD.

• #71 WilsonGen a comprehensive clinically annotated genomic variant resource for Wilson’s Disease | Scientific Reports

  https://www.nature.com/articles/s41598-020-66099-2

  To the best of our knowledge, this is the most comprehensive database of genetic variants in WD and the only resource with systematic classification of variants according to the ACMG and AMP guidelines. […] The variants were re-classified as pathogenic, likely pathogenic, benign, likely benign and variants of uncertain significance (VUS) according to the ACMG guidelines. […] The pieces of evidence collected for the particular variant submitted to the Genetic Variant Interpretation Tool developed by the University of Maryland and interpretation of variant arranged in our database. […] The most pathogenic and likely pathogenic variants were observed in the important functional domain of protein which might significantly affect the functionality of ATP7B protein. […] The availability of a well classified and annotated resource of genetic variants could also enable understanding of population specificity of genetic variants associated with WD. […] The resource would also be a central point to enable evidence-based genetic counselling of patients.

• #72 Wilson disease: more complex than just simply a copper overload condition?—a narrative review – Stremmel – AME Medical Journal

  https://amj.amegroups.org/article/view/7172/html

  The free Cu is distributed via the histidine-albumin shuttle throughout the organism. […] The presentation of Wilson disease reveals a predominant hepatic, predominant neurologic, a mixed or asymptomatic phenotype. […] If failure of biliary excretion is essential for pathogenesis, the question arises whether there are ATP7B independent routes of biliary copper excretion. […] The switch of just Cu overload, where Cu+ is bound to metallothionein, to Cu-induced hepatocellular injury is not well defined. […] It is established that malfunctional ATP7B is the trigger of liver injury. […] Nevertheless, the narrative review presented here shows that all this knowledge is not suitable to prevent the onset of serious symptoms in many cases or to explain the variability in the type and severity of disease-associated symptoms. […] In particular, key questions that need to be elucidated are: Is it indeed the intracellular free fraction of Cu+ which causes membrane destruction?

• #73 Wilson’s Disease—Crossroads of Genetics, Inflammation and Immunity/Autoimmunity: Clinical and Molecular Issues

  https://www.mdpi.com/1422-0067/25/16/9034

  Tissue damage in WD may result from various molecular mechanisms. Oxidative stress, mitochondrial damage, and apoptosis play a particular role, but inflammatory/ immune/ autoimmune responses may also be important. […] Several hypotheses have been proposed as to the exact mechanism by which copper ions cause cell death. These include the initiation of apoptosis, caspase-independent cell death, generation of reactive oxygen species (ROS), and disruption of the ubiquitin–proteasome system. However, there is still no universally accepted theory. Therefore, further studies are needed to uncover the exact mechanisms controlling copper-induced cell death. […] Interestingly, in WD not only copper, but also iron metabolism is affected. This is because the metabolic pathways of these two elements are related at several stages.

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