Wilson’s+Disease

WILSON'S DISEASE

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=**1. Introduction** =

Wilson’s disease is an inherited disorder presenting itself when two mutant alleles are acquired, one from each parent. Generally, 1 in 90 individual is a carrier of the mutated allele, having the potential to affect a large amount of the population. The underlying cause of Wilson’s disease is mutations in the //ATP7B// gene which codes for a copper transporting ATPase. Normally translated ATPase protein is responsible for excreting copper by transporting it out through bile. When there is a mutation, the protein becomes non-functional leading to copper buildup primarily in the brain and liver causing organ failure.

==**__1.1 Major Symptoms: Neurological__ ** ==  Copper accumulation in the brain causes neurological symptoms, with 35% of all patients exhibiting some form of neurological manifestation, such as dystonia, bradykinesia, and rigidity. Copper in the brain accumulates mainly in the lenticular** † ** nucleus of the basal ganglia, and comprises of the putamen and the globus pallidus. Other affected structures in the brain include the cerebellum, caudate, midbrain, pons, and thalamus. Moreover, changes in the white matter and cortical atrophy were also observed in structural brain MRIs. Damage to the basal ganglia explains the resulting movement disorders seen in Wilson’s disease, along with the accompanying cognitive impairments seen in some patients. Many of these resemble symptoms seen in Parkinson’s disease which is also characterized by motor dysfunctions and originates in the basal ganglia. Parkinsonian like symptoms include rigidity, characterized by impaired joint movementsdue to increased muscle tone) and akinesia which is trouble initiating movements. Tremors, dystonia (repetition of movements and twitching) and ataxia (poor coordination and unsteadiness) can also occur. Psychiatric symptoms, exhibited by 12% 3 of patients, can include behavioural changes, psychosis, depression and anxiety. Some patients may also have insomnia, migraines, and seizures.

==**__1.2 Other Symptoms__ ** ==  Other symptoms present themselves primarily in the liver and often the eyes. Liver cirrhosis culminating in liver failure occurs in about 43% of patients 3. Chronic hepatitis, fulminant hepatic failure (with our without hemolytic anaemia), fibrosis, portal hypertension leading to encephalopathy can also occur. Renal failure ophthalmic symptoms are also known to occur. A very apparent diagnostic criterion is the appearance of Kayser-Fleischer rings in the boundary of the cornea due to copper deposits in Descemet’s membrane. The golden brown rings characteristic of Kayser-Fleischer can be seen with the naked eye but confirmation requires slit lamp examination. Other ophthalmic signs, only observable by slit-lamp examination, are sunflower cataracts 6. Underlying pathophysiology for these symptoms and signs is the disruption in copper metabolism leading to copper deposition in various organs.

**__1.3 Pathophysiology__ **
  Copper is essential for important enzymes to function but can also be toxic if present in high amounts. Normally, copper is required by enzymes such as ceruloplasmin, tyrosinase, and dopamine β-hydroxylase, to name a few. These enzymes are involved in carrying copper in the blood, melanin production, and conversion of dopamine to norepinephrine, respectively. Copper is also used as a prosthetic group for enzymes required in <span style="font-family: 'Times New Roman',Times,serif; font-size: 18px;"> antioxidant defence (superoxide dismutase), cellular respiration (cytochrome c oxidase) and connective tissue biosynthesis (lysyl oxidase).

<span style="font-family: 'Times New Roman',Times,serif; font-size: 18px;"> <span style="font-family: 'Times New Roman',Times,serif; font-size: 18px;"> Dietary copper is absorbed by enterocytes (cells in the small intestinevia CTR1 (copper transporter 1) and transported to the liver by the portal vein. Once in the hepatocytes, a small protportion of the absorbed copper transferred to metallothionein, which is found in the cytoplasm of hepatocytes and protects them from copper toxicity. The rest of the copper is delivered to ATP7B (copper transporter) by the copper chaperone protein Atox1. ATP7B transports into the Trans Golgi Network and mediates copper attachment to ceruloplasmin. Under high copper load, it exports copper to vesicles to be targeted for secretion via bile. Biliary excretion further requires the interaction of the COMMD1 protein with ATP7B<span style="font-family: 'Times New Roman',Times,serif; font-size: 18px; vertical-align: super;">6 . Majority of the copper in the bloodstream is carried by ceruloplasmin and the bound copper is exchanged at the cell surface. In the liver, however, there is a two-step delivery mechanism which involves the modification of ceruloplasmin followed by its absorption into the hepatocytes where it undergoes proteolysis to release the copper 7.

<span style="font-family: 'Times New Roman',Times,serif; font-size: 18px;"> When the //ATP7B// gene is mutated, the resulting ATP7B copper transporter is non-functional and efficient export and excretion of copper is impaired. Copper then builds up in various organs to the extent that it becomes toxic for the cells. Copper in high amounts can enable production of reactive oxygen species which damage cells by oxidative stress. Oxidative damage (occurring via Fenton chemistry) eventually leads to cirrhosis in the liver. Excess copper can also deposit in the brain and cornea causing various other pathologies 7.

=<span style="color: #000080; display: block; font-family: Georgia,serif; font-size: 30px; text-align: center;">**2. Genetics** =

<span style="font-family: 'Times New Roman',Times,serif; font-size: 18px;"><span style="font-family: 'Times New Roman',Times,serif; font-size: 18px;"> Wilson’s disease is a genetic disorder caused entirely due to a gene mutation. It is autosomal recessive, requiring two mutant alleles of the //ATP7B// gene for symptoms and consequent pathology to develop. <span style="font-family: 'Times New Roman',Times,serif; font-size: 16px;">

<span style="font-family: 'Times New Roman',Times,serif; font-size: 18px;">**<span style="color: #0088ff; font-family: 'Times New Roman',Times,serif; font-size: 20px;">__2.1 ATP7B gene__ **
<span style="font-family: 'Times New Roman',Times,serif; font-size: 16px;"> T<span style="font-family: 'Times New Roman',Times,serif; font-size: 18px;">he copper transporter is a P-Type ATPase encoded by the ATP7B gene which found on chromosome 13 (13q14.3 * ). It is more than 10 000 base pairs long and constitutes of 21 exons. P-Type ATPases normally use the energy they get from hydrolyzing ATP for the trafficking of metals. The //ATP7B// gene when translated correctly leads to the production of the copper transport which supplies copper to various enzymes that require it as a co factor to carry out normal functions. It also transports copper out the body through bile to ensure that copper levels remain acceptable and non-toxic. Mutations in the ATP7B gene causes the copper transport protein to dysfunction leading to copper not being delivered to the necessary enzymes and it’s accumulation in toxic amounts in the body; the specific alterations depend on the nature of the mutations

==<span style="font-family: 'Times New Roman',Times,serif; font-size: 18px;">**<span style="color: #0088ff; font-family: 'Times New Roman',Times,serif; font-size: 20px;">__2.2 Mutations__ **<span style="font-family: 'Times New Roman',Times,serif; font-size: 18px;"> == <span style="font-family: 'Times New Roman',Times,serif; font-size: 18px;"> The //ATP7B// gene can be altered by 1 of the 520 mutations that have been found so far. The majority of these mutations are missense or point mutations, in which a single nucleotide is changed or substituted by another nucleotide resulting in a codon change. The codon change usually translates to a different amino acid in the protein, causing a structural and therefore functional change. Point mutations can also include deletions, with 80 out of the 520 characterized mutations being nucleotide deletions. Generally the deletions result in the loss of a few nucleotides but large deletions have also been discovered. The ‘c.51þ384_1708-953del’ deletion is the loss of exons 2, 3 and 4 resulting in a total of 8798 nucleotides being deleted. The most common of these missense mutations, found in more than 50% of patients who have European ancestry, is the H1069Q mutation. This mutation causes the amino acid histadine (H) at position 1069 to be substituted by the amino acid glutamine (Q). The resultant protein is less stable than wild type and more prone to unfolding. The wild type protein, by contrast, has doubled the affinity for ATP than the mutant, making it more resistant to denaturation 8.

==<span style="font-family: 'Times New Roman',Times,serif; font-size: 18px;">**<span style="color: #0088ff; font-family: 'Times New Roman',Times,serif; font-size: 20px;">__2.3 Other genes involved in Wilson’s disease__ ** == <span style="font-family: 'Times New Roman',Times,serif; font-size: 18px;"> Multiple other genes are thought to have a role in clinical presentation of Wilson’s disease and are under investigation. One of these is the //PRNP// gene that normally makes the prion protein (Prp), which when mutated causes prion’s disease. It has been shown that having a polymorphism at codon 129 (V129M polymorphism) increases the severity of the neurological symptoms, mostly tremors. Codon 129 can be either a methionine or a valine. For a severe phenotype to present itself, the patient has to be homozygous for methionine in both PRNP alleles. Severity of symptoms is also specific for Wilson’s disease patients who are elderly. Alternatively, being heterozygous (one methionine and one valine) may be related to later onset of Wilson’s disease. Being homozygous for methionine makes a patient more vulnerable to developing severe neurological symptoms.

<span style="font-family: 'Times New Roman',Times,serif; font-size: 18px;"> Another gene, //ApoE//, codes for apolipoprotein E which is normally involved in lipoprotein formation. This gene has multiple alleles, combinations of which produce different isoforms of the protein. The while type genotype comprises of two ε3 alleles (ε3/ε3), whereas the genotype hypothesized to have implication in Wilson’s disease must have at least one ε4 allele (ε4/-). According to a few studies, having a ε4 allele decreases the age of onset of Wilson’s disease symptoms, especially in women who were simultaneously homozygous for the H1069Q ATP7B mutation. Another study, however, done in children of Chinese Han ethnicity did not find any correlation between earlier onset of symptoms and allele variation. Another study implicated that having a ε3/ε3 genotype as opposed to any other genotype (ε2- or ε4-positive) significantly delayed the age of onset of symptoms by 5 to 11 years. They also proposed a variety of mechanisms by which isoform ε3 of the apolipoprotein could be protective against onset of neurological symptoms. Further and meticulous research is required on the role of ApoE and its various isoforms to make any firm conclusions about its role in Wilson’s disease.

<span style="font-family: 'Times New Roman',Times,serif; font-size: 18px;"> The //HFE// or hemochromatosis gene produces a protein important in iron metabolism. Some studies reported that the rate of HFE gene polymorphisms were greater in Wilson’s disease. However, these results were not reproduced by other studies. In contrast, one study proposed another correlation: Wilson’s disease patients had different iron metabolism depending on the levels of ceruloplasmin in serum and their gender. These findings were subsequently determined to have no major clinical implication. The role of iron metabolism needs to be investigated because it is known that copper and iron metabolism pathways interact and inappropriate concentrations of either produce ROS (reactive oxygen species) leading to neurodegenerative disease but more rigorous studies are needed to implicate its involvement.

<span style="font-family: 'Times New Roman',Times,serif; font-size: 18px;"> The //MTHFR// gene encodes for the protein 5,10-methylenetetrahydrofolate reductase, important in amino acid processing. Depending on the nature of the polymorphisms of the MTHFR gene in patients with Wilson’s disease, symptoms had either an earlier age of onset or a lesser frequency of neurological symptoms. Those with the A1289C polymorphism developed symptoms at an earlier age and those with the C677T polymorphism had hepatic symptoms appear in a higher frequency. The research implicates the role of MTHFR gene polymorphisms in altering Wilson’s disease phenotypes. More studies must be conducted for 100% correlations.

=<span style="color: #000080; display: block; font-family: Georgia,serif; font-size: 30px; text-align: center;">**3. Treatment** =

<span style="color: #0088ff; font-family: 'Times New Roman',Times,serif; font-size: 20px;">__3.1 Pharmacological__
<span style="font-family: 'Times New Roman',Times,serif; font-size: 18px;"> There are multiple drugs available for treatment, all of which have their pros and cons. One commonly used drug is penicillamine, which is a copper chelator, which facilitates copper excretion via urine. However, 50% of patients, who were initially experiencing neurological symptoms, developed more severe symptoms when treated with penicillamine. Another copper chelator, trientine, has the same side effect in 26% of patients. This happens because by binding copper, trientine transports it out of the liver but invariably end up transporting some of it to the brain. Zinc therapy has been shown to be effective and also lacks the toxic side effects. The only caveat with zinc therapy is that it cannot be used on patients with acute symptoms because it works slowly over time. Zinc works by increasing the levels of metallothionein in the intestinal cells, which reduces dietary copper uptake. Furthermore, it also reduces the reabsorption of endogenous copper, this facilitating its excretion and preventing copper from accumulating in the body. ==<span style="font-family: 'Times New Roman',Times,serif; font-size: 18px;"> == <span style="font-family: 'Times New Roman',Times,serif; font-size: 18px;"> The development of a new drug, Ammonium Tetrathiomolybdate, has shown to be more effective than trientine for treating neurological symptoms an is still in the trial phase. Extensive studies with Tetrathiomolybdate have shown its role in producing anti-inflammatory, antif<span style="font-family: 'Times New Roman',Times,serif; font-size: 18px;">ibrotic and antiautoimmune effects. These effects may be produced due to the copper sequestering effects of Tetrathiomolybdate, indirectly leading to inhibition of cytokines that require copper to function normally. It is a promising drug treatment not only against Wilson’s disease but multiple other pathologies. It works by forming a stable complex with copper and one other protein; the other protein it can bind is variable so it has multiple options. The bound copper is then unavailable for absorption in the intestine or uptake by cells when travelling in the blood. There is slow degradation of this complex in hepatocytes followed by biliary excretion of the waste components 19.

<span style="font-family: 'Times New Roman',Times,serif; font-size: 18px;">**<span style="color: #0088ff; font-family: 'Times New Roman',Times,serif; font-size: 20px;">__3.2 Alternatives__ **
<span style="font-family: 'Times New Roman',Times,serif; font-size: 18px;"> Alternative treatments or suggestions in addition to drug therapy include limiting the intake of copper in the diet. Avoiding foods high in copper, such has mushrooms and chocolate, is beneficial. Liver transplant may be necessary if other treatments fail to work and there is risk of liver failure (i.e patients with fulminant hepatic failure) 6. Physiotherapy is also recommended for patients with neurological symptoms to maintain motor functions during and after drug therapy. Wilson’s disease presents itself with various symptoms, which requires a multimodal treatment approach. Treatment needs to be tailored to individual patients, as some patients might respond to one drug better than others. The future direction in treatments may include gene therapy and transplant of hepatocytes. Gene therapy looks to be promising as shown by studies examining ongoing gene therapy trials 6.

<span style="font-family: 'Times New Roman',Times,serif; font-size: 18px;"> **†** Wilson’s disease most commonly affects the liver (hepatic symptoms) and the neurological symptoms are mostly localized to the lenticular nucleus of the basal ganglia. Hence, Wilson’s disease is also known as hepatolenticular degeneration

<span style="font-family: 'Times New Roman',Times,serif; font-size: 18px;"> * A gene’s location on the chromosome in written in a standardized manner. The rules of describing the location of the gene are as follows: First indicate the chromosome on which the gene is found (i.e. chromosome 13). Then indicate the arm of the chromosome on which the gene resides. The letter ‘p’ defines the short arm whereas the long arm is designated ‘q’ (long arm or short arm is based on the position of the centromere). Finally indicate position of the gene on that arm (i.e. position 14.3; specifically means that it’s found from base pairs 52,506,804 to 52,585,629)

<span style="font-family: 'Times New Roman',Times,serif; font-size: 18px;">References: <span style="display: block; font-family: 'Times New Roman',serif; font-size: 16px; height: 1px; left: -40px; overflow: hidden; position: absolute; top: 3018px; width: 1px;">