Wilson disease (WD) is an inherited disorder of copper metabolism, transmitted as an autosomal recessive trait. This type of inheritance means unaffected parents who each carry the WD gene have a 25% risk in each pregnancy of having an affected child. The disorder is caused by a defective copper-binding protein found primarily in the liver, which leads to excess copper circulating through the bloodstream. Over time, the copper is deposited and increased to toxic levels in various body tissues, especially the liver, brain, kidney, and cornea of the eye. Left untreated, WD is invariably fatal.
In 1912, Dr. Samuel Kinnear Wilson described a disorder he called "progressive lenticular degeneration." He noted the familial nature of the condition, and also that it was likely to be caused by a toxin affecting the liver. The toxin was later discovered to be excess copper. Another,
little-used name for the disorder is "hepatolenticular degeneration" (degeneration of the liver and lens), which omits the contribution of neurological symptoms.
The classic triad of signs for WD includes lenticular degeneration, cirrhosis of the liver, and neuropsychiatric symptoms. Errors in a specific gene produce a defective copper-binding protein in the liver, which results in an inability to excrete excess copper. While some copper is necessary for normal metabolic processes in the body, too much can be toxic. The disease is present at birth, but symptoms typically do not show until years later. WD is progressive because the underlying cause cannot be corrected. Effective treatments are available, but without treatment, people with WD will eventually die of liver failure.
WD has an incidence of about one in 30,000, which means one in 90 individuals is a silent carrier of the WD gene. There seems to be no specific ethnic group or race that has a higher frequency of the disease. Only a man and woman who are both silent carriers of the WD gene can have a child with the condition. Unlike a disease with dominant inheritance, which usually implies a definite family history, WD only rarely has occurred in a previous family member.
Causes and symptoms
WD is caused by errors in a gene located on chromosome 13, which produces a protein named ATP7B. Errors in the ATP7B gene produce a protein with decreased ability to bind copper. Unused copper is then absorbed back into the bloodstream where it is transported to other organs. A person who is a carrier of WD has one normally functioning copy of the ATP7B gene, and this produces enough functional protein to rid the body of excess copper.
A little more than half of all patients with WD first show symptoms of hepatitis. In addition, those who have liver-related symptoms first, do so at a younger age than do those who first present with neuropsychiatric symptoms—15 years and 25 years on average, respectively. However, the symptoms and their severity are quite variable, and the diagnosis of WD has been made in children as young as three years old, and in adults in their 60s.
Neurological symptoms are primarily the result of copper's toxic effects in the basal ganglia, a portion of the brain that controls some of the subconscious aspects of
- Dystonia. Prolonged muscular contractions that may cause twisting (torsion) of body parts, repetitive movements, and increased muscular tone.
- Dysarthria. Difficulty in articulating words, sometimes accompanied by drooling.
- Dysphagia. Difficulty swallowing.
- Pseudosclerosis. Symptoms similar to multiple sclerosis.
While the diagnosis of WD may be suspected on clinical grounds, it can only be confirmed using laboratory tests. An easily detectable physical sign is the presence of Kayser-Fleisher rings in the eye, which are bluish rings around the iris, caused by copper deposition in the cornea.
The easiest biochemical test is measurement of ceruloplasmin, a blood protein that is nearly always decreased in patients with WD. While low levels of ceruloplasmin are highly suggestive, a liver biopsy to detect excess copper levels is much more accurate. Testing for mutations in the ATP7B gene is nearly definitive, but the large number of mutations catalogued in the gene means that only certain individuals may benefit from testing. A consultation with a genetics professional is always recommended.
A gastroenterologist will treat and monitor liver disease, while a neurologist and psychiatrist (or neuropsychiatrist) should evaluate and treat neuropsychiatric symptoms. Since many individuals achieve remission of their neurologic symptoms once treatment is started, neuropsychiatric consultations may only be short term. If necessary, periodic consultations with a geneticist can provide updated information on genetic testing.
Treatment of WD revolves around the process of copper chelation. A chelating agent binds to excess copper in the bloodstream so that it can be excreted from the body. Penicillamine is the most effective and commonly used medication, but about 20% of all patients suffer serious side effects, which may include joint pain, blood disorders, fever, an increase in neurologic symptoms, and systemic lupus erythematosus.
Trientine and zinc salts given orally are somewhat less effective, but have fewer side effects than penicillamine. In addition, zinc salts may take several months to have any noticeable effect. A diet low in copper will also have some preventive effect. Finally, for those patients in advanced stages of liver disease, liver transplantation may be the only method of averting liver failure and death.
Recovery and rehabilitation
The earlier in the course of the disorder that treatment is started, the more beneficial the effects will be. For some individuals, liver function may return to near normal, and often dramatic improvements in the neuropsychiatric symptoms can be seen shortly after beginning treatment. For others who have gone untreated for longer periods, or who have a more severe form of the disease, only modest improvements may be seen. Treatment must be lifelong.
A newer copper chelating agent currently being investigated is tetrathiomolybdate. The hope is that it will prove to have fewer side effects than penicillamine, yet be more effective than Trientine. Possible suppression of bone marrow function may yet be a risk for some patients.
For those who begin treatment early in the progression of the disorder, or even before symptoms are noted, the prognosis is excellent, as long as the patients comply with the treatment regimen. For others, the prognosis may be more difficult to predict, but nearly every patient with WD sees at least some improvement once treatment is begun. For those who go untreated, the prognosis is very poor.
The rarity of WD, combined with its diverse and varied symptoms that can mimic other conditions, makes it difficult to diagnose. This is of special concern because it is a progressive fatal condition; yet it can be easily and effectively treated if caught early. The autosomal recessive nature of the condition means that there is almost never a previous family history (other than a diagnosed sibling) to alert anyone to the risk. Because the diagnosis is easily established by measuring serum ceruloplasmin levels, with subsequent liver biopsy for copper levels, anyone contracting hepatitis or cirrhosis with no obvious cause, with or without neuropsychiatric symptoms, should be tested for WD.
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"NINDS Wilson's Disease Information Page." The National Institute of Neurological Disorders and Stroke. December 27, 2001 (April 4, 2004). <http://www.ninds.nih.gov/health_and_medical/disorders/wilsons_doc.htm>.
Wilson's Disease Association. 4 Navaho Drive, Brookfield, CT 06804-3124. (800) 399-0266; Fax: (203) 775-9666. <http://www.wilsondisease.org>.
National Center for the Study of Wilson's Disease. 432 West 58th Street, Suite 614, New York, NY 10019. (212) 523-8717; Fax: (212) 523-8708.
Scott J. Polzin, MS, CGC