Wilson's disease

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Wilson's disease
Other namesWilson disease, hepatolenticular degeneration
Wilson's Disease 4.jpg
Boy with Wilson's disease
Specialty Gastroenterology
Symptoms Swelling of the legs, yellowish skin, personality changes [1]
Usual onsetAge 5 to 35 [1]
CausesGenetic
Differential diagnosis Chronic liver disease, Parkinson's disease, multiple sclerosis, others [2] [3]
TreatmentDietary changes, chelating agents, zinc supplements, liver transplant [1]
Frequency~1 per 30,000 [1]

Wilson's disease (also called Hepatolenticular degeneration) is a genetic disorder characterized by the excess build-up of copper in the body. Symptoms are typically related to the brain and liver. Liver-related symptoms include vomiting, weakness, fluid build-up in the abdomen, swelling of the legs, yellowish skin, and itchiness. Brain-related symptoms include tremors, muscle stiffness, trouble in speaking, personality changes, anxiety, and psychosis. [1]

Contents

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. The condition is autosomal recessive; for people to be affected, they must inherit a mutated copy of the gene from both parents. Diagnosis may be difficult and often involves a combination of blood tests, urine tests, and a liver biopsy. Genetic testing may be used to screen family members of those affected. [1]

Wilson's disease is typically treated with dietary changes and medication. Dietary changes involve eating a low-copper diet and not using copper cookware. Medications used include chelating agents, such as trientine and D-penicillamine, and zinc supplements. Complications of Wilson's disease can include liver failure and kidney problems. A liver transplant may be helpful to those for whom other treatments are not effective or if liver failure occurs. [1]

Wilson's disease occurs in about one in 30,000 people. [1] Symptoms usually begin between the ages of 5 and 35 years. [1] It was first described in 1854 by German pathologist Friedrich Theodor von Frerichs and is named after British neurologist Samuel Wilson. [4]

Signs and symptoms

The main sites of copper accumulation are the liver and brain. Consequently, liver disease and neuropsychiatric symptoms are the main features that lead to diagnosis. [5] People with liver problems tend to come for medical attention earlier (generally as children or teenagers) than those with neurological and psychiatric symptoms, who tend to be in their 20s or older. Some are identified only because relatives have been diagnosed with Wilson's disease; many of these, when tested, turn out to have been experiencing symptoms of the condition but have not received a diagnosis. [6]

Liver disease

Liver disease may present itself as tiredness, jaundice, increased bleeding tendency or confusion (due to hepatic encephalopathy), and portal hypertension. [7] The last, a condition in which the pressure in the portal vein is markedly increased, leads to esophageal varices (distended veins in the esophagus that may bleed in a life-threatening fashion) as well as enlargement of the spleen (splenomegaly) and accumulation of fluid in the abdominal cavity (ascites). On examination, signs of chronic liver disease such as spider angiomata (small distended blood vessels, usually on the chest) may be observed. Chronic active hepatitis has already caused cirrhosis of the liver in most patients by the time they develop symptoms. While most people with cirrhosis have an increased risk of hepatocellular carcinoma (liver cancer), this risk is relatively low in Wilson's disease. [5]

About 5% of all people are diagnosed only when they develop fulminant acute liver failure, often in the context of hemolytic anemia (anemia due to the destruction of red blood cells). This leads to abnormalities in protein production (identified by deranged coagulation) and metabolism by the liver. The deranged protein metabolism leads to the accumulation of waste products, such as ammonia, in the bloodstream. When these irritate the brain, patients develop hepatic encephalopathy – a serious condition that causes confusion, coma, seizures and, finally, life-threatening swelling of the brain). [5]

Neuropsychiatric symptoms

Girl with Wilson's disease showing neurological symptoms Wilson's Disease 5.jpg
Girl with Wilson's disease showing neurological symptoms

About half of the people with Wilson's disease have neurological or psychiatric symptoms. Most initially have mild cognitive deterioration and clumsiness, as well as changes in behavior. Specific neurological symptoms usually then follow, often in the form of parkinsonism (cogwheel rigidity, bradykinesia, or slowed movements and a lack of balance are the most common parkinsonian features [8] ) with or without a typical hand tremor, masked facial expressions, slurred speech, ataxia (lack of coordination), or dystonia (twisting and repetitive movements of part of the body). Seizures and migraine appear to be more common in Wilson's disease. [5] A characteristic tremor described as "wing-beating tremor" is encountered in many people with Wilson's; this is absent at rest but can be provoked by abducting the arms and flexing the elbows toward the midline. [9]

Cognition can also be affected in Wilson's disease, in two non-mutually exclusive categories: frontal lobe disorder (may present as impulsivity, impaired judgement, promiscuity, apathy, and executive dysfunction with poor planning and decision-making) and subcortical dementia (may present as slow thinking, memory loss, and executive dysfunction, without signs of aphasia, apraxia, or agnosia). These cognitive involvements are thought to be related and closely linked to psychiatric manifestations of the disease. [8]

Psychiatric problems due to Wilson's disease may include behavioral changes, depression, anxiety disorders, and psychosis. [5] Psychiatric symptoms are commonly seen in conjunction with neurological symptoms and are rarely manifested on their own. These symptoms are often poorly defined and can sometimes be attributed to other causes. Because of this, diagnosis of Wilson's disease is rarely made when only psychiatric symptoms are present. [8]

Other organ systems

A brown ring on the edge of the iris (Kayser-Fleischer ring) is common in Wilson's disease, especially when neurological symptoms are present. Kayser-Fleischer ringArrow.jpg
A brown ring on the edge of the iris (Kayser–Fleischer ring) is common in Wilson's disease, especially when neurological symptoms are present.

Medical conditions have been linked with copper accumulation in Wilson's disease:

Genetics

Wilson's disease has an autosomal recessive pattern of inheritance. Autorecessive.svg
Wilson's disease has an autosomal recessive pattern of inheritance.

The Wilson's disease gene (ATP7B) is on chromosome 13 (13q14.3) and is expressed primarily in the liver, kidney, and placenta. The gene codes for a P-type (cation transport enzyme) ATPase that transports copper into bile and incorporates it into ceruloplasmin. [5] Most people who have Wilson's disease – 60% – are homozygous for ATP7B mutations (two abnormal copies), and 30% of them have only one abnormal copy. In about 10% of cases, people with Wilson's disease have no detectable mutations. [6]

Although 300 possible mutations of ATP7B have been described, a very small number of those cause most cases of Wilson's disease; which mutation an individual will have tends to be specific to the population they are part of. For instance, in Western populations, the H1069Q mutation (replacement of a histidine by a glutamine at position 1069 in the protein) is present in 37%–63% of cases, while in China this mutation is very uncommon; R778L (arginine to leucine at 778) is found more often there. Relatively little is known about the relative impact of the various mutations, although the H1069Q mutation seems to predict later onset and predominantly neurological problems, according to some studies. [5] [15] A comprehensive clinically annotated resource, WilsonGen, provides a clinical classification for the variants as per the recent ACMG & AMP guidelines. [16]

A normal variation in the PRNP gene can modify the course of the disease by delaying the age of onset and affecting the type of symptoms that develop. This gene produces prion protein, which is active in the brain and other tissues and also appears to be involved in transporting copper. [17] A role for the ApoE gene was initially suspected, but could not be confirmed. [15]

The condition is inherited in an autosomal recessive pattern. To inherit it, both of the parents of an individual must carry an affected gene. Most people with Wilson's disease have no family history of the condition. [15] People with only one abnormal gene are called carriers (heterozygotes) and may have mild, but medically insignificant, abnormalities of copper metabolism. [14]

There are several hereditary diseases that cause copper overload in the liver; Wilson's disease is the most common of them. All can cause cirrhosis at a young age. The other copper overload diseases are Indian childhood cirrhosis (ICC), endemic Tyrolean infantile cirrhosis, and idiopathic copper toxicosis. These three, unlike Wilson's disease, are not related to ATP7B mutations; for example, ICC has been linked to mutations in the KRT8 and the KRT18 genes. [15]

Pathophysiology

Normal absorption and distribution of copper: Cu = copper, CP = ceruloplasmin, green = ATP7B carrying copper Copper metabolism.png
Normal absorption and distribution of copper: Cu = copper, CP = ceruloplasmin, green = ATP7B carrying copper

Copper is needed by the body for a number of functions, predominantly as a cofactor for a number of enzymes such as ceruloplasmin, cytochrome c oxidase, dopamine β-hydroxylase, superoxide dismutase, and tyrosinase. [15]

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. [15]

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. [15]

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. [18]

Diagnosis

Location of the basal ganglia, the part of the brain affected by Wilson's disease Basal ganglia and related structures (2).svg
Location of the basal ganglia, the part of the brain affected by Wilson's disease

Wilson's disease may be suspected on the basis of any of the symptoms mentioned above, or when a close relative has been found to have Wilson's. Most have slightly abnormal liver function tests such as raised aspartate transaminase, alanine transaminase, and bilirubin levels. If the liver damage is significant, albumin may be decreased due to an inability of damaged liver cells to produce this protein; likewise, the prothrombin time (a test of coagulation) may be prolonged as the liver is unable to produce proteins known as clotting factors. [5] Alkaline phosphatase levels are relatively low in those with Wilson's-related acute liver failure. [19] If neurological symptoms are seen, magnetic resonance imaging of the brain is usually performed; this shows hyperintensities in the part of the brain called the basal ganglia in the T2 setting. [14] MRI may also demonstrate the characteristic "face of the giant panda" pattern. [20]

No totally reliable test for Wilson's disease is known, but levels of ceruloplasmin and copper in the blood, as well of the amount of copper excreted in urine during a 24-hour period, are together used to form an impression of the amount of copper in the body. The most accurate test is a liver biopsy. [5]

Ceruloplasmin

Ceruloplasmin PBB Protein CP image.jpg
Ceruloplasmin

Levels of ceruloplasmin are abnormally low (<0.2 g/L) in 80–95% of cases. [5] It can be present at normal levels, though, in people with ongoing inflammation, as it is an acute phase protein. Low ceruloplasmin is also found in Menkes disease and aceruloplasminemia, which are related to, but much rarer than Wilson's disease. [5] [14] The combination of neurological symptoms, eye signs, and a low ceruloplasmin level is considered sufficient for the diagnosis of Wilson's disease. In many cases, however, further tests are needed. [14]

Serum and urine copper

Serum copper is low, which may seem paradoxical given that Wilson's disease is a disease of copper excess. However, 95% of plasma copper is carried by ceruloplasmin, which is often low in Wilson's disease. Urine copper is elevated in Wilson's disease and is collected for 24 hours in a bottle with a copper-free liner. Levels above 100 μg/24h (1.6 μmol/24h) confirm Wilson's disease, and levels above 40 μg/24h (0.6 μmol/24h) are strongly indicative. [5] High urine copper levels are not unique to Wilson's disease; they are sometimes observed in autoimmune hepatitis and in cholestasis (any disease obstructing the flow of bile from the liver to the small bowel). [14]

In children, the following penicillamine test may be used: a 500 mg oral dose of penicillamine is administered, and all urine collected for 24 hours. If the entire day's urine contains more than 1600 μg (25 μmol) of copper, it is a reliable indicator of Wilson's disease. This test has not been validated in adults. [14]

Slit-lamp examination

The eyes of the patient are examined using a slit lamp to look for Kayser–Fleischer rings, which are strongly associated with Wilson's disease and are caused by copper deposition on the inner cornea in Descemet's membrane. [10]

Liver biopsy

Once other investigations have indicated Wilson's disease, the ideal test is the removal of a small amount of liver tissue through a liver biopsy. This is assessed microscopically for the degree of steatosis and cirrhosis, and histochemistry and quantification of copper are used to measure the severity of the copper accumulation. A level of 250  μg of copper per gram of dried liver tissue confirms Wilson's disease. Occasionally, lower levels of copper are found; in that case, the combination of the biopsy findings with all other tests could still lead to a formal diagnosis of Wilson's. [5]

In the earlier stages of the disease, the biopsy typically shows steatosis (deposition of fatty material), increased glycogen in the nucleus, and areas of necrosis (cell death). In more advanced disease, the changes observed are quite similar to those seen in autoimmune hepatitis, such as infiltration by inflammatory cells, piecemeal necrosis, and fibrosis (scar tissue). In advanced disease, finally, cirrhosis is the main finding. In acute liver failure, degeneration of the liver cells and collapse of the liver tissue architecture is seen, typically on a background of cirrhotic changes. Histochemical methods for detecting copper are inconsistent and unreliable, and taken alone are regarded as insufficient to establish a diagnosis. [14]

Genetic testing

Mutation analysis of the ATP7B gene, as well as other genes linked to copper accumulation in the liver, may be performed. Once a mutation is confirmed, family members can be screened for the disease as part of clinical genetics family counseling. [5] Regional distributions of genes associated with Wilson's disease are important to follow, as this can help clinicians design appropriate screening strategies. Since mutations of the ATP7B gene vary between populations, research and genetic testing done in countries such as the USA or United Kingdom can pose problems, as they tend to have more mixed populations. [21]

Treatment

Diet

In general, a diet low in copper-containing foods is recommended. High-copper foods avoided in Wilson's disease include mushrooms, nuts, chocolate, dried fruit, liver, sesame seeds, sesame oil, and shellfish. [5]

Medication

Medical treatments are available for Wilson's disease. Some increase the removal of copper from the body, while others prevent the absorption of copper from the diet.

Generally, penicillamine is the first treatment used. This binds to copper (by chelation) and leads to excretion of copper in the urine. Hence, monitoring of the amount of copper in the urine can be done to ensure a sufficiently high dose is taken. Penicillamine is not without problems; about 20% experience a side effect or complication of penicillamine treatment, such as drug-induced lupus (causing joint pains and a skin rash) or myasthenia (a nerve condition leading to muscle weakness). In those who presented with neurological symptoms, almost half experience a paradoxical worsening in their symptoms. While this phenomenon is observed in other treatments for Wilson's, it is usually taken as an indication for discontinuing penicillamine and commencing second-line treatment. [5] [14] Those intolerant to penicillamine may instead be commenced on trientine hydrochloride, which also has chelating properties. Some recommend trientine as first-line treatment, but experience with penicillamine is more extensive. [14] A further agent with known activity in Wilson's disease, under clinical investigation by Wilson Therapeutics, is tetrathiomolybdate. It is regarded as experimental, [14] though some studies have shown a beneficial effect. [5]

Once all results have returned to normal, zinc (usually in the form of a zinc acetate prescription called Galzin) may be used instead of chelators to maintain stable copper levels in the body. Zinc stimulates metallothionein, a protein in gut cells that binds copper and prevents its absorption and transport to the liver. Zinc therapy is continued unless symptoms recur or if the urinary excretion of copper increases. [14]

In rare cases where none of the oral treatments is effective, especially with severe neurological disease, dimercaprol (British anti-Lewisite) is occasionally necessary. This treatment is injected intramuscularly (into a muscle) every few weeks and has unpleasant side effects such as pain. [22]

People who are asymptomatic (for instance, those diagnosed through family screening or only as a result of abnormal test results) are generally treated, as the copper accumulation may cause long-term damage in the future. Whether these people are best treated with penicillamine or zinc acetate is unclear. [14]

Physical and occupational therapies

Physiotherapy and occupational therapy are beneficial for patients with the neurological form of the disease. The copper-chelating treatment may take up to six months to start working, and these therapies can assist in coping with ataxia, dystonia, and tremors, as well as preventing the development of contractures that can result from dystonia. [23]

Transplantation

Liver transplantation is an effective cure for Wilson's disease, but is used only in particular scenarios because of the risks and complications associated with the procedure. It is used mainly in people with fulminant liver failure who fail to respond to medical treatment or in those with advanced chronic liver disease. Liver transplantation is avoided in severe neuropsychiatric illnesses, in which its benefit has not been demonstrated. [5] [14]

Prognosis

Left untreated, Wilson's disease tends to become progressively worse and is eventually fatal. Serious complications include liver cirrhosis, acute kidney failure, and psychosis. Liver cancer and cholangiocarcinoma may occur, but at a lower incidence than other chronic liver diseases, and the risk is greatly reduced with treatment. [13] With early detection and treatment, most of those affected can live relatively normal lives and have a life expectancy close to that of the general population. [13] Liver and neurological damage that occurs prior to treatment may improve, but it is often permanent. [24] Fertility is usually normal and pregnancy complications are not increased in those with Wilson's disease that is treated. [13]

History

The disease bears the name of British physician Samuel Alexander Kinnier Wilson (1878–1937), a neurologist who described the condition, including the pathological changes in the brain and liver, in 1912. [25] Wilson's work had been predated by, and drew on, reports from German neurologist Karl Westphal (in 1883), who termed it "pseudo-sclerosis"; by the British neurologist William Gowers (in 1888); [26] by the Finnish neuropathologist Ernst Alexander Homén (in 1889–1892), who noted the hereditary nature of the disease; [27] and by Adolph Strümpell (in 1898), who noted hepatic cirrhosis. [26] Neuropathologist John Nathaniel Cumings made the link with copper accumulation in both the liver and the brain in 1948. [28] The occurrence of hemolysis was noted in 1967. [29]

In 1951, Cumings (in England), and New Zealand neurologist Derek Denny-Brown (working in the United States), simultaneously reported the first effective treatment, using the metal chelator British anti-Lewisite. [30] [31] This treatment had to be injected, but was one of the first therapies available in the field of neurology, a field that classically was able to observe and diagnose, but had few treatments to offer. [26] [32] The first oral chelation agent effective in Wilson's disease, penicillamine, was discovered in 1956 by British neurologist John Walshe. [33] In 1982, Walshe also introduced trientine, [34] and was the first to develop tetra-thiomolybdate for clinical use. [35] Zinc acetate therapy initially made its appearance in the Netherlands, where physicians Schouwink and Hoogenraad used it in 1961 and in the 1970s, respectively, and was further developed later by Brewer and colleagues at the University of Michigan. [22] [36]

The genetic basis of Wilson's disease, and its link to ATP7B mutations, was elucidated by several research groups in the 1980s and 1990s. [37] [38]

In other animals

Hereditary copper accumulation has been described in Bedlington Terriers, [39] where it generally only affects the liver. In Bedlington Terriers it is due to mutations in the COMMD1 (or MURR1) gene. [40] The discovery of these mutations in the dogs led researchers to examine the corresponding human genes, but COMMD1 mutations could not be detected in humans with non-Wilsonian copper accumulation states (such as Indian childhood cirrhosis). [41]

See also

Related Research Articles

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<span class="mw-page-title-main">Alpha-1 antitrypsin deficiency</span> Medical condition

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<span class="mw-page-title-main">Leigh syndrome</span> Metabolic disease

Leigh syndrome is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who first described the condition in 1951. Normal levels of thiamine, thiamine monophosphate, and thiamine diphosphate are commonly found, but there is a reduced or absent level of thiamine triphosphate. This is thought to be caused by a blockage in the enzyme thiamine-diphosphate kinase, and therefore treatment in some patients would be to take thiamine triphosphate daily. While the majority of patients typically exhibit symptoms between the ages of 3 and 12 months, instances of adult onset have also been documented.

<span class="mw-page-title-main">Gaucher's disease</span> Medical condition

Gaucher's disease or Gaucher disease (GD) is a genetic disorder in which glucocerebroside accumulates in cells and certain organs. The disorder is characterized by bruising, fatigue, anemia, low blood platelet count and enlargement of the liver and spleen, and is caused by a hereditary deficiency of the enzyme glucocerebrosidase, which acts on glucocerebroside. When the enzyme is defective, glucocerebroside accumulates, particularly in white blood cells and especially in macrophages. Glucocerebroside can collect in the spleen, liver, kidneys, lungs, brain, and bone marrow.

<span class="mw-page-title-main">Kayser–Fleischer ring</span> Medical condition

Kayser–Fleischer rings are dark rings that appear to encircle the cornea of the eye. They are due to copper deposition in the Descemet's membrane as a result of particular liver diseases. They are named after German ophthalmologists Bernhard Kayser and Bruno Fleischer who first described them in 1902 and 1903. Initially thought to be due to the accumulation of silver, they were first demonstrated to contain copper in 1934.

<span class="mw-page-title-main">Ceruloplasmin</span> Mammalian protein found in Homo sapiens

Ceruloplasmin is a ferroxidase enzyme that in humans is encoded by the CP gene.

<span class="mw-page-title-main">Hepatic encephalopathy</span> Brain disease resulting from liver failure

Hepatic encephalopathy (HE) is an altered level of consciousness as a result of liver failure. Its onset may be gradual or sudden. Other symptoms may include movement problems, changes in mood, or changes in personality. In the advanced stages it can result in a coma.

<span class="mw-page-title-main">Menkes disease</span> X-linked recessive copper-transport disorder

Menkes disease (MNK), also known as Menkes syndrome, is an X-linked recessive disorder caused by mutations in genes coding for the copper-transport protein ATP7A, leading to copper deficiency. Characteristic findings include kinky hair, growth failure, and nervous system deterioration. Like all X-linked recessive conditions, Menkes disease is more common in males than in females. The disorder was first described by John Hans Menkes in 1962.

<span class="mw-page-title-main">Maple syrup urine disease</span> Autosomal recessive metabolic disorder

Maple syrup urine disease (MSUD) is a rare, inherited metabolic disorder that affects the body's ability to metabolize amino acids due to a deficiency in the activity of the branched-chain alpha-ketoacid dehydrogenase (BCKAD) complex. It particularly affects the metabolism of amino acids—leucine, isoleucine, and valine. With MSUD, the body is not able to properly break down these amino acids, therefore leading to the amino acids to build up in urine and become toxic. The condition gets its name from the distinctive sweet odor of affected infants' urine and earwax due to the buildup of these amino acids.

<span class="mw-page-title-main">Aceruloplasminemia</span> Medical condition

Aceruloplasminemia is a rare autosomal recessive disorder in which the liver can not synthesize the protein ceruloplasmin properly, which is needed to transport copper around the blood. Copper deficiency in the brain results in neurological problems that generally appear in adulthood and worsen over time.

<span class="mw-page-title-main">Mitochondrial neurogastrointestinal encephalopathy syndrome</span> Medical condition

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<span class="mw-page-title-main">Copper deficiency</span> Insufficient level of copper in the body, leading to anaemia and nervous symptoms

Copper deficiency, or hypocupremia, is defined either as insufficient copper to meet the needs of the body, or as a serum copper level below the normal range. Symptoms may include fatigue, decreased red blood cells, early greying of the hair, and neurological problems presenting as numbness, tingling, muscle weakness, and ataxia. The neurodegenerative syndrome of copper deficiency has been recognized for some time in ruminant animals, in which it is commonly known as "swayback". Copper deficiency can manifest in parallel with vitamin B12 and other nutritional deficiencies.

<span class="mw-page-title-main">Jansky–Bielschowsky disease</span> Medical condition

Jansky–Bielschowsky disease is an extremely rare autosomal recessive genetic disorder that is part of the neuronal ceroid lipofuscinosis (NCL) family of neurodegenerative disorders. It is caused by the accumulation of lipopigments in the body due to a deficiency in tripeptidyl peptidase I as a result of a mutation in the TPP1 gene. Symptoms appear between ages 2 and 4 and consist of typical neurodegenerative complications: loss of muscle function (ataxia), drug resistant seizures (epilepsy), apraxia, development of muscle twitches (myoclonus), and vision impairment. This late-infantile form of the disease progresses rapidly once symptoms are onset and ends in death between age 8 and teens. The prevalence of Jansky–Bielschowsky disease is unknown; however, NCL collectively affects an estimated 1 in 100,000 individuals worldwide. Jansky–Bielschowsky disease is related to late-infantile Batten disease and LINCL, and is under the umbrella of neuronal ceroid lipofuscinosis.

<span class="mw-page-title-main">Neuroferritinopathy</span> Medical condition

Neuroferritinopathy is a genetic neurodegenerative disorder characterized by the accumulation of iron in the basal ganglia, cerebellum, and motor cortex of the human brain. Symptoms, which are extrapyramidal in nature, progress slowly and generally do not become apparent until adulthood. These symptoms include chorea, dystonia, and cognitive deficits which worsen with age.

<span class="mw-page-title-main">Copper in biology</span>

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<span class="mw-page-title-main">Wilson disease protein</span>

Wilson disease protein (WND), also known as ATP7B protein, is a copper-transporting P-type ATPase which is encoded by the ATP7B gene. The ATP7B protein is located in the trans-Golgi network of the liver and brain and balances the copper level in the body by excreting excess copper into bile and plasma. Genetic disorder of the ATP7B gene may cause Wilson's disease, a disease in which copper accumulates in tissues, leading to neurological or psychiatric issues and liver diseases.

<span class="mw-page-title-main">Adult polyglucosan body disease</span> Medical condition

Adult polyglucosan body disease (APBD) is a rare monogenic glycogen storage disorder caused by an inborn error of metabolism. Symptoms can emerge any time after the age of 30. Early symptoms include trouble controlling urination, trouble walking, and lack of sensation in the legs. People eventually develop dementia.

<span class="mw-page-title-main">Tiomolibdic acid</span> Chemical compound

Tiomolibdic acid is a chelating agent under investigation for the treatment of cancer and of Wilson's disease, a rare and potentially fatal disease in which the body cannot regulate copper. It is developed by Wilson Therapeutics and used in form of the salt bis-choline tetrathiomolybdate.

<span class="mw-page-title-main">Tyrosinemia type I</span> Medical condition

Tyrosinemia type I is a genetic disorder that disrupts the metabolism of the amino acid tyrosine, resulting in damage primarily to the liver along with the kidneys and peripheral nerves. The inability of cells to process tyrosine can lead to chronic liver damage ending in liver failure, as well as renal disease and rickets. Symptoms such as poor growth and enlarged liver are associated with the clinical presentation of the disease. If not detected via newborn screening and management not begun before symptoms appear, clinical manifestation of disease occurs typically within the first two years of life. The severity of the disease is correlated with the timing of onset of symptoms, earlier being more severe. If diagnosed through newborn screening prior to clinical manifestation, and well managed with diet and medication, normal growth and development is possible.

<span class="mw-page-title-main">SRD5A3-CDG</span> Medical condition

SRD5A3-CDG is a rare, non X-linked congenital disorder of glycosylation (CDG) due to a mutation in the steroid 5 alpha reductase type 3 gene. It is one of over 150 documented types of Congenital disorders of Glycosylation. Like many other CDGs, SRD5A3 is ultra-rare, with around 38 documented cases in the world.

References

  1. 1 2 3 4 5 6 7 8 9 "Wilson Disease". NIDDK. July 2014. Archived from the original on 2016-10-04. Retrieved 2016-11-06.
  2. ↑ Lynn DJ, Newton HB, Rae-Grant A (2004). The 5-minute Neurology Consult. Lippincott Williams & Wilkins. p. 442. ISBN   9780683307238. Archived from the original on 2016-11-07.
  3. ↑ Sahani DV, Samir AE (2016). Abdominal Imaging: Expert Radiology Series (2 ed.). Elsevier Health Sciences. p. 400. ISBN   9780323431613. Archived from the original on 2016-11-07.
  4. ↑ "Whonamedit – dictionary of medical eponyms". www.whonamedit.com. Archived from the original on 2016-11-07. Retrieved 2016-11-06.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Ala A, Walker AP, Ashkan K, Dooley JS, Schilsky ML (2007). "Wilson's disease". Lancet. 369 (9559): 397–408. doi:10.1016/S0140-6736(07)60196-2. PMID   17276780. S2CID   24663871.
  6. 1 2 3 Merle U, Schaefer M, Ferenci P, Stremmel W (2007). "Clinical presentation, diagnosis and long-term outcome of Wilson's disease: a cohort study". Gut. 56 (1): 115–20. doi:10.1136/gut.2005.087262. PMC   1856673 . PMID   16709660.
  7. ↑ "Wilson's disease - Symptoms and causes". Mayo Clinic. Retrieved 2022-10-05.
  8. 1 2 3 Lorincz MT (2010). "Neurologic Wilson's disease" (PDF). Annals of the New York Academy of Sciences. 1184 (1): 173–87. Bibcode:2010NYASA1184..173L. doi:10.1111/j.1749-6632.2009.05109.x. hdl: 2027.42/78731 . PMID   20146697. S2CID   2989668.
  9. ↑ Pagonabarraga J, Goetz, C (2012). Biller, J (ed.). Practical Neurology (4th ed.). Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins Heath. p. 282. ISBN   978-1451142631.
  10. 1 2 Pandey N, John S (21 June 2022). "Kayser-Fleischer Ring". StatPearls. Treasure Island, Florida: StatPearls Publishing. PMID   29083643 . Retrieved 30 November 2022.
  11. ↑ Roberts EA, Schilsky ML (2008). "Diagnosis and treatment of Wilson disease: An update". Hepatology. 47 (6): 2089–2111. doi: 10.1002/hep.22261 . PMID   18506894.
  12. ↑ Yanoff M, Jay S. Duker (2008). Ophthalmology (3rd ed.). Edinburgh: Mosby. p. 411. ISBN   978-0323057516.
  13. 1 2 3 4 Roberts EA, Schilsky ML (7 September 2023). "Current and Emerging Issues in Wilson's Disease". New England Journal of Medicine. 389 (10): 922–938. doi:10.1056/NEJMra1903585. PMID   37672695. S2CID   261581755.
  14. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Roberts EA, Schilsky ML (2003). "A practice guideline on Wilson disease". Hepatology. 37 (6): 1475–92. doi: 10.1053/jhep.2003.50252 . PMID   12774027. S2CID   263620.
  15. 1 2 3 4 5 6 7 de Bie P, Muller P, Wijmenga C, Klomp LW (November 2007). "Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes". J. Med. Genet. 44 (11): 673–88. doi:10.1136/jmg.2007.052746. PMC   2752173 . PMID   17717039.
  16. ↑ Kumar M, Gaharwar U, Paul S, Poojary M, Pandhare K, Scaria V, Bk B (2020-06-03). "WilsonGen a comprehensive clinically annotated genomic variant resource for Wilson's Disease". Scientific Reports. 10 (1): 9037. Bibcode:2020NatSR..10.9037K. doi:10.1038/s41598-020-66099-2. ISSN   2045-2322. PMC   7270127 . PMID   32493955.
  17. ↑ Grubenbecher S, Stüve O, Hefter H, Korth C (2006). "Prion protein gene codon 129 modulates clinical course of neurological Wilson disease". NeuroReport. 17 (5): 549–52. doi:10.1097/01.wnr.0000209006.48105.90. PMID   16543824. S2CID   37186426.
  18. ↑ Lee GR (1999). "Chapter 48: acquired hemolytic anaemias resulting from direct effects of infectious, chemical or physical agents". In Lee GR, Foerster J, Lukens J, et al. (eds.). Wintrobe's clinical hematology. Vol. 1 (10th ed.). Williams & Wilkins. pp.  1298. ISBN   978-0-683-18242-2.
  19. ↑ Shaver WA, Bhatt H, Combes B (1986). "Low serum alkaline phosphatase activity in Wilson's disease". Hepatology. 6 (5): 859–63. doi: 10.1002/hep.1840060509 . PMID   3758940. S2CID   24055787.
  20. ↑ Das SK, Ray K (September 2006). "Wilson's disease: an update". Nat Clin Pract Neurol. 2 (9): 482–93. doi:10.1038/ncpneuro0291. PMID   16932613. S2CID   205340375.
  21. ↑ Ferenci P (2006-06-22). "Regional distribution of mutations of the ATP7B gene in patients with Wilson disease: impact on genetic testing". Human Genetics. 120 (2): 151–159. doi:10.1007/s00439-006-0202-5. ISSN   0340-6717. PMID   16791614. S2CID   10124665.
  22. 1 2 Walshe JM (July 1996). "Treatment of Wilson's disease: the historical background". QJM. 89 (7): 553–55. doi: 10.1093/qjmed/89.7.553 . PMID   8759497.
  23. ↑ Brewer GJ, Askari FK (2005). "Wilson's disease: clinical management and therapy". Journal of Hepatology. 42 (Suppl 1): 13–21. doi: 10.1016/j.jhep.2004.11.013 . PMID   15777568.
  24. ↑ "Definition and Facts | NIDDK". National Institute of Diabetes and Digestive and Kidney Diseases. Retrieved 2019-02-01.
  25. ↑ Kinnier Wilson SA (1912). "Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver". Brain. 34 (1): 295–507. doi:10.1093/brain/34.4.295.
  26. 1 2 3 Robertson WM (February 2000). "Wilson's disease". Arch. Neurol. 57 (2): 276–77. doi:10.1001/archneur.57.2.276. PMID   10681092.
  27. ↑ Homén EA (1892). "Eine eigenthümliche bei drei Geschwistern auftretende typische Krankheit unter der Form einer progressiven Dementia in Verbindung mit ausgedehnten Gefässveränderungen (wohl Lues hereditaria tarda)". Archiv für Psychiatrie und Nervenkrankheiten. 24: 1–38.
  28. ↑ Cumings JN (1948). "The copper and iron content of brain and liver in the normal and in hepato-lenticular degeneration". Brain. 71 (Dec): 410–15. doi:10.1093/brain/71.4.410. PMID   18124738.
  29. ↑ McIntyre N, Clink HM, Levi AJ, Cumings JN, Sherlock S (February 1967). "Hemolytic anemia in Wilson's disease". N. Engl. J. Med. 276 (8): 439–44. doi:10.1056/NEJM196702232760804. PMID   6018274.
  30. ↑ Cumings JN (March 1951). "The effects of B.A.L. in hepatolenticular degeneration". Brain. 74 (1): 10–22. doi:10.1093/brain/74.1.10. PMID   14830662.
  31. ↑ Denny-Brown D, Porter H (December 1951). "The effect of BAL (2,3-dimercaptopropanol) on hepatolenticular degeneration (Wilson's disease)". N. Engl. J. Med. 245 (24): 917–25. doi:10.1056/NEJM195112132452401. PMID   14882450.
  32. ↑ Vilensky JA, Robertson WM, Gilman S (September 2002). "Denny-Brown, Wilson's disease, and BAL (British antilewisite [2,3-dimercaptopropanol])". Neurology. 59 (6): 914–16. doi:10.1212/wnl.59.6.914. PMID   12297577.
  33. ↑ Walshe JM (January 1956). "Wilson's disease; new oral therapy". Lancet. 270 (6906): 25–26. doi:10.1016/S0140-6736(56)91859-1. PMID   13279157.
  34. ↑ Walshe JM (March 1982). "Treatment of Wilson's disease with trientine (triethylene tetramine) dihydrochloride". Lancet. 1 (8273): 643–47. doi:10.1016/S0140-6736(82)92201-2. PMID   6121964. S2CID   205999334.
  35. ↑ Harper PL, Walshe JM (December 1986). "Reversible pancytopenia secondary to treatment with tetrathiomolybdate". Br. J. Haematol. 64 (4): 851–53. doi: 10.1111/j.1365-2141.1986.tb02250.x . PMID   3801328. S2CID   11546705.
  36. ↑ Brewer GJ (January 2000). "Recognition, diagnosis, and management of Wilson's disease". Proc. Soc. Exp. Biol. Med. 223 (1): 39–46. doi:10.1046/j.1525-1373.2000.22305.x (inactive 2024-07-31). PMID   10632959. Archived from the original on 2008-04-09. Retrieved 2008-05-20.{{cite journal}}: CS1 maint: DOI inactive as of July 2024 (link)
  37. ↑ Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW (1993). "The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene". Nat. Genet. 5 (4): 327–37. doi:10.1038/ng1293-327. PMID   8298639. S2CID   1236890.
  38. ↑ Tanzi RE, Petrukhin K, Chernov I, et al. (1993). "The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene". Nat. Genet. 5 (4): 344–50. doi:10.1038/ng1293-344. PMID   8298641. S2CID   610188.
  39. ↑ Sternlieb I, Twedt DC, Johnson GF, et al. (1977). "Inherited copper toxicity of the liver in Bedlington terriers". Proc. R. Soc. Med. 70 (Suppl 3): 8–9. PMC   1543595 . PMID   122681.
  40. ↑ van De Sluis B, Rothuizen J, Pearson PL, van Oost BA, Wijmenga C (2002). "Identification of a new copper metabolism gene by positional cloning in a purebred dog population". Hum. Mol. Genet. 11 (2): 165–73. doi: 10.1093/hmg/11.2.165 . PMID   11809725.
  41. ↑ Müller T, van de Sluis B, Zhernakova A, et al. (2003). "The canine copper toxicosis gene MURR1 does not cause non-Wilsonian hepatic copper toxicosis". J. Hepatol. 38 (2): 164–68. doi:10.1016/S0168-8278(02)00356-2. PMID   12547404.

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