Wilson disease and genetics
Wilson disease, also known as hepatolenticular degeneration, is a rare genetic disorder characterized by abnormal copper metabolism. It occurs due to mutations in the ATP7B gene, resulting in the inability to excrete excess copper, leading to its accumulation in the liver and other organs. This condition affects approximately one in 30,000 individuals, with symptoms typically manifesting in people under 40, often beginning around age four in children. Common symptoms include abdominal pain, jaundice, neurological issues, and distinctive eye changes known as Kayser-Fleischer rings.
Wilson disease is inherited in an autosomal recessive manner, meaning that both parents must carry the gene mutation for a child to be affected. Diagnosis can be challenging due to its rarity, and symptoms may be misattributed to other conditions. However, early detection and treatment are crucial to prevent severe organ damage and improve outcomes. Treatment options include medications to reduce copper levels, and in severe cases, a liver transplant may be necessary. Genetic testing and counseling can also play significant roles in managing the disease, especially for those with a family history of Wilson disease.
Wilson disease and genetics
ALSO KNOWN AS: Wilson’s disease
DEFINITION Wilson disease is a rare, inherited, genetic disorder of copper metabolism. It occurs in one out of every thirty thousand people.
Copper is a trace mineral that the human body needs in small amounts. Most people get a lot more copper from food than they need. However, most people are also able to excrete the excess copper. People with Wilson disease cannot excrete the copper they do not need because of a deficiency in ceruloplasmin, a copper-carrying protein. As a result, copper begins to build up in the liver right after birth and eventually damages the organ. When the liver can no longer hold the excess copper, the mineral goes into the bloodstream. It travels to other organs and may damage the brain, central nervous system, kidneys, and eyes. This disease is fatal unless it is treated before serious illness develops.
Risk Factors
The only known risk factor for Wilson disease is a family history of the disease. It tends to be most common in eastern Europeans, Sicilians, and southern Italians.
Etiology and Genetics
Wilson disease results from mutations in a gene called ATP7B, which is located on the long arm of chromosome 13 at position 13q14.3. This gene belongs to a family of genes called the ATPase superfamily, and it specifies a protein known as copper-transporting ATPase 2. Found mainly in the liver, this protein normally acts to transport copper from the liver to other parts of the body where it is needed in minute quantities as a cofactor for some enzymatic reactions. Additionally, if copper levels in the liver get too high, this protein can facilitate the transport of excess copper to bile sacs in the liver where it can be eliminated. If concentrations of this protein are drastically reduced or eliminated altogether because of mutations in the ATP7B gene, removal of the excess copper is compromised. Copper may then accumulate in tissues to toxic levels, causing the clinical symptoms characteristic of Wilson disease.
Mutations in a second gene, PRNP (found on chromosome 20 at 20p13), have been found that delay the age of onset of Wilson disease and ameliorate the symptoms somewhat. This gene encodes the protein, which is most active in the brain. In addition to its other functions, prion protein may also be involved in the intercellular transport of copper.
Wilson disease is inherited in a classic autosomal recessive manner, which means that both copies of the ATP7B gene must be deficient in order for the individual to be afflicted. Typically, an affected child is born to two unaffected parents, both of whom are carriers of the recessive mutant allele. The probable outcomes for children whose parents are both carriers are 75 percent unaffected and 25 percent affected.
Symptoms
Symptoms most commonly appear in people less than forty years of age. In children, the symptoms usually begin to be expressed around four years of age.
Symptoms of excess copper in the liver include jaundice, a swelled abdomen, pain in the abdomen, nausea, and vomiting blood. Symptoms of excess copper in the brain include depression, anxiety, mood swings, aggressive or other inappropriate behaviors, difficulty speaking and swallowing, tremors, rigid muscles, and problems with balance and walking. Symptoms of excess copper in the eyes include Kayser-Fleischer rings (rusty or brown-colored ring around the iris).
Screening and Diagnosis
Wilson disease is easy to diagnose when it is suspected. However, because it is relatively rare, common signs, such as psychiatric symptoms or hepatitis, may initially be attributed to other causes. A patient may appear healthy even while his or her liver is getting damaged. Sometimes the liver symptoms are mistaken for infectious hepatitis or mononucleosis. Doctors may not recognize psychiatric symptoms caused by Wilson disease. However, it is very important to get diagnosed and treated early to avoid organ damage and early death.
The doctor will ask about a patient’s symptoms and medical history and will perform physical and mental exams. Tests may include blood and urine tests to measure levels of copper and ceruloplasmin (a copper-carrying protein); an eye exam to look for brown, ring-shaped color in the cornea (Kayser-Fleischer rings); and a liver biopsy, in which a small sample of liver tissue is removed and tested for excess copper.
When there is a known family history of Wilson disease, early testing may prevent symptoms and organ damage. Genetic testing may be possible if a family member with the diagnosis of Wilson disease has identifiable changes in the gene. Because there are so many gene mutations that result in Wilson disease, there is no single, simple test for everyone.
Nonetheless, recent advances in the understanding of the ATP7B gene have increasingly allowed a diagnosis to be made by direct genetic analysis. This technique is particularly useful when other tests are negative or equivocal. The ATP7B gene is involved in making ATPase 2. Experts now think that when a condition known as “fatty liver” occurs in people who do not consume large amounts of alcohol (excessive alcohol intake is the most common cause of fatty liver), specific testing for Wilson disease is recommended.
Since diagnosis of this disease can be very difficult, experts have devised a scoring system that combines many of the available tests into a single score that is positive in over 90 percent of people who truly have the disease and negative in nearly 97 percent of people whose symptoms are caused by some other condition. Genetic counseling may be helpful to review risks and discuss appropriate testing and management.
Treatment and Therapy
The goals of treatment are to remove the excess copper, prevent copper from building up again, and improve all associated symptoms of copper overload. Treatment cannot cure the underlying problem of copper accumulation; therefore, patients must continue treatment throughout their lives.
Medications used to treat Wilson disease include zinc acetate, which blocks the absorption of copper in the intestinal tract; penicillamine (chelates, or binds, with copper, causing its increased urinary excretion); tetrathiomolybdolate (may be better than a similar drug called trientine); and dimercaprol. Penicillamine is probably the best-studied treatment and is commonly used, especially in severely symptomatic persons. Zinc has gained increasing importance in recent years because it is often effective in long-term maintenance and has fewer side effects than penicillamine. The role of tetrathiomolybdolate has not yet been clearly established.
If a patient has severe liver damage, he or she may need a liver transplant. Liver transplantation allows the body to correct its copper and can at least prevent the disease from worsening. Transplantation also affords an effective treatment for patients who cannot tolerate the sometimes serious side effects of penicillamine.
Prevention and Outcomes
Currently, there are no guidelines to prevent Wilson disease. However, when identified early, treatment can prevent the development of symptoms.
Bibliography
Brewer, G. J., et al. “Treatment of Wilson Disease with Ammonium Tetrathiomolybdate, IV: Comparison of Tetrathiomolybdate and Trientine in a Double-Blind Study of Treatment of the Neurologic Presentation of Wilson Disease.” Archives of Neurology 63.4 (2006): 521–27. Print.
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Ferenci, P. “Wilson’s Disease.” Clinical Gastroenterology and Hepatology 3.8 (2005): 726–33. Print.
Gupta, Sanjeev. "Cell Therapy to Remove Excess Copper in Wilson's Disease." Annals of the New York Academy of Sciences 1315.1 (2014): 70–80. Print.
Harada, Masaru. "Pathogenesis and Management of Wilson Disease." Hepatology Research 44.4 (2014): 395–402. Print.
Parker, James N. The Official Patient’s Sourcebook on Wilson’s Disease. San Diego: Icon Health, 2002. Print.
Patil, Mallikarjun, et al. "A Review and Current Perspective on Wilson Disease." Journ. of Clinical Experimental Hepatology 3.4 (2013): 321–36. Print.
Wakim-Fleming, Jamile, and Kevin D. Mullen. “Wilson’s Disease.” Practical Management of Liver Diseases. Ed. Zobair M. Younossi. New York: Cambridge UP, 2008. Print.
"Wilson Disease." National Library of Medicine, 11 July 2022, medlineplus.gov/genetics/condition/wilson-disease/. Accessed 5 Sept. 2024.