Synonyms

• Hepatolenticular Degeneration
• Lenticular Degeneration, Progressive

Disorder Subdivisions

• None

Related Disorders List

Information on the following diseases can be found in the Related Disorders section of this report:

• Chorea, Sydenham's
• Cirrhosis, Primary Biliary
• Heavy Metal Poisoning
• Levine-Critchley Syndrome
• Huntington's Disease
• Tourette Syndrome
• Cerebral Palsy

General Discussion

Wilson's disease is a rare genetic disorder characterized by excess copper stored in various body tissues, particularly the liver, brain, and corneas of the eyes. The disease is progressive and, if left untreated, it may cause liver (hepatic) disease, central nervous system dysfunction, and death. Early diagnosis and treatment may prevent serious long-term disability and life threatening complications. Treatment is aimed at reducing the amount of copper that has accumulated in the body and maintaining normal copper levels thereafter.

Symptoms

Wilson's disease is a rare genetic disorder beginning with liver dysfunction where damage begins by six years of age, but usually presents clinically in teenage years or early twenties. Common signs of associated liver disease include a yellow discoloration (jaundice) of the skin, mucous membranes and the membranes (sclera) that line the eye, swelling (edema) of the legs and abdomen (ascites) due to abnormal retention of fluid, presence of abnormal blood vessels in the esophagus that may bleed (esophageal varices), a tendency for bruising and prolonged bleeding, and excessive tiredness (fatigue). Some individuals with Wilson's disease may have only abnormalities of liver function test and may show no other symptoms until many years later.



A minority of affected individuals may experience severe liver failure. This happens most frequently in people with Wilson's disease during adolescence and more commonly in women. These individuals may rapidly develop signs and symptoms of liver disease, often associated with anemia due to breakdown of red blood cells (hemolysis) and mental confusion. In these young patients, the characteristic rusty-brown deposits in the corneas of the eyes (Kayser-Fleischer rings) may not yet be present.



In some patients, liver disease does not reveal itself, and the patient develops neurologic (brain-related) symptoms. Common neurological symptoms of Wilson's disease that may appear and progress with time include tremor, involuntary movements, difficulty swallowing (dysphagia), difficulty speaking and poor articulation (dysarthria), lack of coordination, spasticity, dystonic postures, and muscle rigidity. Almost all affected individuals with the neurological symptoms of Wilson's disease have Kayser-Fleischer rings in their eyes that can be identified by an ophthalmologist.



The psychiatric manifestations of Wilson's disease may vary widely from patient to patient. These symptoms may be confused with other disorders ranging from depression to schizophrenia, and are often misdiagnosed as substance abuse. Changes in personality or behavior may occur. Most affected individuals with psychiatric symptoms also have neurologic symptoms concurrently or will develop them within about three years and Kayser-Fleischer rings in the corneas of their eyes.



In young females, menstruation may not begin or ceases, until disease is treated. This is due to general disturbances in hormone metabolism due to the liver disease caused by Wilson's disease. Menstrual irregularity, loss of menstruation (ammenorrhea), miscarriages and infertility are also common.



Other signs and symptoms of Wilson's disease may include kidney stones and renal tubular damage, premature arthritis, and other joint and bone involvement including thinning of the bones (osteoporosis) and the appearance of bony outgrowths (osteophytes) at large joints. There may also be reduced spinal and extremity joint spaces.

Causes

Wilson's disease is inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.



In recessive disorders, the condition does not appear unless a person inherits two defective genes for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms or require treatment. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but will not show symptoms of the disorder or require treatment. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.



Researchers have determined that Wilson's disease is caused by disruption or changes (mutations) of the ATP7B gene, which plays an important role in the movement of excess copper from the liver to the bile to eventually be excreted from the body through the intestines. More than 300 different mutations of the ATP7B gene have been identified.

Affected Populations

Wilson's disease is a rare disorder that affects males and females in equal numbers. The disease is found in all races and ethnic groups. Although estimates vary, it is believed that Wilson's disease occurs in approximately one in 30,000 to 40,000 people worldwide. Approximately one in 90 people may be carriers of the disease gene. Although only about 2,000-3,000 cases have been diagnosed in the United States, other affected individuals may be misdiagnosed with other neurological, liver or psychiatric disorders. According to one estimate, there may actually be 6,000 people affected by Wilson's disease in the United States.

Related Disorders

Symptoms of the following disorders can be similar to those of Wilson's disease. Comparisons may be useful for a differential diagnosis:



Sydenham's Chorea is an acute, usually self-limited disorder that occurs after about 5 to 10 percent of cases of rheumatic fever. The disorder typically begins with jerky, uncontrollable, non-repetitive muscle movements on one or both sides of the body. Patients develop rapid, involuntary movements that can affect the manner or style of walking, arm movements and speech. Clumsiness and facial grimacing are common. (For more information on this disorder choose "Sydenham's Chorea" as your search term in the Rare Disease Database.)



Primary Biliary Cirrhosis is a chronic, progressive disease of the liver thought to be related to abnormalities in the immune system. The initial symptoms of this disorder usually include persistent, generalized itching, dark urine, pale stools and jaundice. Eventually, excessive amounts of copper accumulate in the liver and fibrous or granular hardening occurs in the soft tissue of the liver. (For more information on this disorder, choose "Primary Biliary Cirrhosis " as your search term in the Rare Disease Database.)



Heavy Metal Poisoning is generally caused by industrial exposure to a variety of toxins such as copper, aluminum, arsenic or mercury. Depending of the type and duration of exposure, the injury may occur in the lungs, nervous system, the skin or digestive system. The symptoms of the poisoning vary according to the type of metal that was involved in the overexposure. These include headache, nausea, dizziness, painful joints and muscles, delirium, seizures and a wide range of other symptoms. (For more information on these disorders, choose "Heavy Metal Poisoning" as your search term in the Rare Disease Database.)



Levine-Critchley Syndrome is a very rare genetic disorder of the neuromuscular and blood systems. Abnormal blood cells (acanthocytosis) are produced and there is a wasting away (atrophy) of muscles. The major symptom of this disorder is uncontrolled rapid muscular movements (amyotrophic chorea). Initially there are subtle involuntary movements (tics) of the face, mouth, and tongue. These slowly progress to severe, uncontrolled, rapid motions (chorea) of the trunk and limbs. Approximately 50 percent of people with Levine-Critchley Syndrome have seizures. (For more information on this disorder, please choose "Levine-Critchley" as your search term in the Rare Disease Database.)



Huntington's Disease (Huntington's Chorea) is an inherited, progressively degenerative neurological disorder. Initially there are personality changes and rapid jerky muscle movements that are involuntary. In time speech and memory become impaired and involuntary muscle movements become more frequent and pronounced. As Huntington's Disease progresses there is a further loss of cognitive abilities and dementia. The symptoms of this disorder usually begin during adulthood generally after the age of forty. (For more information on this disorder choose "Huntington" as your search term in the Rare Disease Database.)



Tourette Syndrome is a neurologic movement disorder that is characterized by repetitive motor and vocal tics. The first symptoms usually occur during childhood are rapid eye blinking or facial grimaces. Symptoms may also include involuntary movements of the extremities, shoulders, face and voluntary muscles. Some people with Tourette Syndrome may vocalize involuntarily; these may be inarticulate sounds or words. Tourette Syndrome is not a progressive or degenerative disorder; symptoms tend to be variable and follow a chronic waxing and waning course. Onset usually occurs before the age of 16. (For more information on this disorder, choose "Tourette" as your search term in the Rare Disease Database.)



Cerebral Palsy is a neuromuscular disorder that is the result of an injury to the brain during early development or at birth. The major symptom of this disorder is a lack of muscle control and coordination. Cerebral Palsy is not a progressive disorder. Generally infants may exhibit developmental delays during the first or second year and may have muscle weakness and abnormal muscle tone. The coordination and speech difficulties associated with Wilson's disease can resemble the symptoms of Cerebral Palsy. (For more information on this disorder, choose "Cerebral Palsy" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis

Wilson's disease may be diagnosed based upon a thorough clinical evaluation, a complete patient history, and specialized tests. Such tests may include slit-lamp examination of the eyes that reveals the presence of Kayser-Fleischer rings; tests of the fluid portion of the blood (serum) that demonstrate low levels of ceruloplasmin, a copper protein; and tests that reveal abnormally high levels of copper excreted in the urine. In some patients, a liver biopsy for copper analysis may be necessary to confirm a diagnosis of Wilson's disease. Molecular genetic studies that use DNA from blood cells to search for patterns of differences or similarities, a procedure called haplotype analysis may establish whether a full sibling of an affected patient has Wilson's disease, is a carrier of the Wilson's disease gene, or is not a carrier. This analysis is available for family members of individuals identified as having Wilson's disease.



It is important to diagnose Wilson's disease as early as possible. Permanent neurologic dysfunction and serious liver disease may be avoided with early diagnosis and treatment.



Treatment

Treatment for Wilson's disease is life-long and aimed at preventing the progression of the disease and trying to reverse any signs and symptoms that have appeared because of copper accumulation in the body. Treatment may be divided into two phases: treatment of symptomatic patients and maintenance therapy after copper has been reduced in affected tissues.



Treatment for Wilson's disease includes medications that remove (chelate) copper from the body by urinary excretion such as penicillamine (Cuprimine) and trientine dihydrochloride (Syprine), zinc salts to prevent the gut from absorbing copper from the diet. Tetrathiomolybdate both prevents absorbing copper and binds up toxic copper in the blood making it nontoxic.



Patients who present symptomatically with mild to moderate liver failure can be effectively treated with a combination of trientine and zinc for 4-6 months, and then go on maintenance therapy with zinc or trientine alone. A second choice would be penicillamine and zinc, but penicillamine has more side effects than zinc. Patients with severe liver failure usually require liver transplantation. Patients who present neurologically can best be treated with tetrathiomolybdate, but it is not commercially available as yet. The second choice is zinc alone. Zinc is rather slow acting but doesn't cause the drug catalyzed worsening so common with trientine and penicillamine. Trientine and penicillamine are poor choices to treat neurologically presenting patients because of the high frequency of neurological worsening, from which many patients never recover.



Zinc Acetate (Galzin) has been approved for the maintenance treatment for patients.



For affected individuals without symptoms (asymptomatic) or for individuals initially treated with chelating agents, zinc acetate (Galzin manufactured by the Gate division of Teva Pharmaceuticals) is used to prevent copper absorption from the gut. Zinc therapy is often preferred in children and pregnant women because of limited side effects. For some patients intolerant of zinc due to gastric irritation, maintenance therapy with trientine may be preferable.



Monitoring of chronic drug therapy includes follow-up physical examinations, measurement of copper (and zinc for those on zinc therapy) in 24-hour urine collection, blood tests to determine the amount of copper not bound to ceruloplasmin (free copper), periodic measurement of liver functions, and blood counts. For those on chelating agents, periodic urinalysis should be to look for the presence of cells or protein in the urine. Repeat liver biopsies are usually not necessary to follow the progress of drug therapy.



Discontinuation of medication for Wilson's disease may cause rapid build up of copper and life threatening events. It is important that patients taking zinc acetate use the prescription version of this drug (Galzin) because nutritional supplements are not bioequivalent and may be ineffective.



Liver transplantation may be lifesaving for individuals presenting with severe liver failure.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com





Researchers at the University of Michigan are currently looking into several treatment options for Wilson's disease. The University has been designated a Wilson's Disease Center of Excellence by the Wilson's Disease Association. For information about studies being conducted there, contact:



George J. Brewer, MD

Emeritus Professor of Human Genetics and Internal Medicine

Department of Human Genetics

University of Michigan

G061X MBNI

Ann Arbor, Michigan 48109-5720

Phone: 734-764-5499

Fax: 734-615-2048

Email: brewergj@umich.edu



Or



Frederick Askari, MD, PhD

Associate Professor of Medicine

University of Michigan

3912 Taubman Center

Ann Arbor, MI 48109-0362

Phone: 734-936-4780, Toll-Free 800-395-6431 Email: faskari@umich.edu

References

TEXTBOOKS

Brewer GJ. Wilson Disease. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:506.



Schilsky ML. Wilson's Disease. In: Diseases of the Liver; Lippincott-Raven. 1999:1091-1106.



Beers MH, Berkow R., eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:56-8.



Kanski JJ., ed. Clinical Ophthalmology, 4th ed. Woburn, MA: Butterworth-Heinemann; 1999:142.



Fauci AS, et al., eds. Harrison's Principles of Internal Medicine, 14th Ed. New York, NY: McGraw-Hill, Inc; 1998:2166-69.



Adams, RD, et al., eds. Principles of Neurology. 6th ed. New York, NY: McGraw-Hill, Companies; 1997:969-71.



Bennett JC, Plum F., eds. Cecil Textbook of Medicine. 20th ed. Philadelphia, PA: W.B. Saunders Co; 1996:1131-2.



Schilsky ML. Wilson's Disease -- Genetic Basis of Copper Toxicity and Natural History. In: Seminars in Liver Disease. Thieme Medical Publishers, Inc. 1996:83-95.



Behrman RE, ed. Nelson Textbook of Pediatrics, 15th ed. Philadelphia, PA: W.B. Saunders Company; 1996:1139-40.



Scriver CR, et al., eds. The Metabolic and Molecular Basis of Inherited Disease. 7th Ed. New York, NY; McGraw-Hill Companies, Inc; 1995:2217-23.



Menkes JH., au., Pine JW, et al., eds. Textbook of Child Neurology, 5th ed. Baltimore, MD: Williams & Wilkins; 1995:118-25.



Leevy CM, et al., eds. Diseases of the Liver and Biliary Tract: Standardization of Nomenclature, Diagnostic Criteria and Prognosis. New York, NY: Raven Press; 1994:112-3.



JOURNAL ARTICLES

El-Youssef M, Wilson disease. Mayo Clin Proc. 2003;78:1126-36.



Ferenci P, et al., Diagnosis and phenotypic classification of Wilson disease. Liver Int. 2003;23:139-42.



Pellecchia MT, et al., Clinical presentation and treatment of Wilson?'s disease: a single-centre experience. Eur Neurol. 2003;50:48-52.



Brewer GJ, et al., Treatment of Wilson disease with ammonium tetrathiomolybdate: III. Initial therapy in a total of 55 neurologically affected patients and follow-up with zinc therapy. Arch Neurol. 2003;60:379-85.



Bacon BR, et al., New knowledge of genetic pathogenesis of hemochromatosis and Wilson?'s disease. Adv Intern Med. 1999;44:91-116.



Sturniolo GC, et al., Zinc therapy increases duodenal concentrations of metallothionein and iron in Wilson?'s disease patients. Am J Gastroenterol. 1999;94:334-38.



Schaefer M, et al., Hepatocyte-specific localization and copper-dependent trafficking of the Wilson?'s disease protein in the liver. 1999;276:639-46.



Brewer GJ, et al., Treatment of Wilson's disease with zinc: XV. Long-term follow-up studies. J Lab Clin Med. 1998;132:264-78.



Brewer GJ, et al., Treatment of Wilson disease with ammonium tetrathiomolybdate. Arch Neurol. 1996;53:1017-25.



Demirkiran M, et al., Neurologic presentation of Wilson disease without Kayser-Fleischer rings. Neurology. 1996;46:1040-3.



Scheinberg IH, et al., Treatment of the neurologic manifestations of Wilson?'s disease. Arch Neurol. 1995; 52:339-40.



Schilsky ML, et al., Hepatic transplantation for Wilson?'s disease: indication and outcome. Hepatology. 1994;19:583-7.



Yarse JC, et al., Wilson's disease: current status. Am J Med. 1992;92:643-54.



Brewer GJ, et al., Initial therapy of patients with Wilson's disease with tetrathiomolybdate. Arch Neurol. 1991;48:42-7.



Tankanow RM, Pathophysiology and treatment of Wilson's disease. Clin Pharm. 1991;10:839-49.



Schilsky ML, et al., Prognosis of Wilsonian chronic active hepatitis. Gastroenterology. 1991;100:762-7.



Woods SE, Wilson's disease. Am Family Physician. 1989;40:171-8.



McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 277900; Last Update:7/9/2003.

Resources

WE MOVE (Worldwide Education and Awareness for Movement Disorders)

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New York, NY 10024

USA

Tel: (212)875-8312

Fax: (212)875-8389

Email: wemove@wemove.org

Internet: http://www.wemove.org



Wilson's Disease Association

5572 N Diversey Blvd

Milwaukee, WI 53217

USA

Tel: (414)961-0533

Fax: (414)962-3886

TDD: (540)743-1415

Email: info@wilsondisease.org

Internet: http://www.wilsonsdisease.org



March of Dimes Birth Defects Foundation

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Fax: (301)402-2186

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