Wilson disease

Other Names: Hepatolenticular degeneration; WND; WDcopper storage disease hepatolenticular degeneration syndrome WD Wilson's disease

Wilson disease is a rare inherited disorder that is characterized by the accumulation of copper in the body. Because high levels of copper are toxic to tissues and organs, this buildup can lead to damage of the liver, brain and eyes. The signs and symptoms of Wilson disease usually first appear between the ages of 6 and 45, but they most often begin during the teenage years. The features of this condition include a combination of liver disease and neurological and psychiatric problems.

Epidemiology

Wilson disease is a rare disorder that affects approximately 1 in 30,000 individuals.

Cause

Wilson disease is caused by mutations in the ATP7B gene. This gene provides instructions for making a protein called copper-transporting ATPase 2, which plays a role in the transport of copper from the liver to other parts of the body. Copper is necessary for many cellular functions, but it is toxic when present in excessive amounts. The copper-transporting ATPase 2 protein is particularly important for the elimination of excess copper from the body. Mutations in the ATP7B gene prevent the transport protein from functioning properly. With a shortage of functional protein, excess copper is not removed from the body. As a result, copper accumulates to toxic levels that can damage tissues and organs, particularly the liver and brain.

Research indicates that a normal variation in the PRNP gene may modify the course of Wilson disease. The PRNP gene provides instructions for making prion protein, which is active in the brain and other tissues and appears to be involved in transporting copper. Studies have focused on the effects of a PRNP gene variation that affects position 129 of the prion protein. At this position, people can have either the protein building block (amino acid) methionine or the amino acid valine. Among people who have mutations in the ATP7B gene, it appears that having methionine instead of valine at position 129 of the prion protein is associated with delayed onset of symptoms and an increased occurrence of neurological symptoms, particularly tremors. Larger studies are needed, however, before the effects of this PRNP gene variation on Wilson disease can be established.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

Wilson disease can affect many different systems of the body. Affected people often develop signs and symptoms of chronic liver disease in their teenaged years or early twenties. These features may include jaundice; abnormal fluid retention which can lead to swelling of the legs and/or abdomen; weight loss; nausea and vomiting; and/or fatigue. Unfortunately, some people may not experience any signs until they suddenly develop acute liver failure. Affected people often experience a variety of neurologic (central nervous system-related) signs and symptoms, as well. Neurologic features often develop after the liver has retained a significant amount of copper; however, they have been seen in people with little to no liver damage. These symptoms may include tremors; muscle stiffness; and problems with speech, swallowing and/or physical coordination. Almost all people with neurologic symptoms have Kayser-Fleisher rings - a rusty brown ring around the cornea of the eye that can best be viewed using an ophthalmologist's slit lamp. About a third of those with Wilson disease will also experience psychiatric (mental health-related) symptoms such as abrupt personality changes, depression accompanied by suicidal thoughts, anxiety, and/or psychosis. In many individuals with Wilson disease, copper deposits in the front surface of the eye (the cornea) form a green-to-brownish ring, called the Kayser-Fleischer ring, that surrounds the colored part of the eye. Abnormalities in eye movements, such as a restricted ability to gaze upwards, may also occur. Other signs and symptoms may include:

• Menstrual period irregularities, increased risk of miscarriage and infertility in women
• Anemia
• Easy bruising and prolonged bleeding
• Kidney stones
• Early-onset arthritis
• Osteoporosis

Symptoms may include:

• Abnormal posture of arms and legs
• Arthritis
• Confusion or delirium
• Dementia
• Difficulty moving arms and legs, stiffness
• Difficulty walking (ataxia)
• Emotional or behavioral changes
• Enlargement of the abdomen due to accumulation of fluid (ascites)
• Personality changes
• Phobias, distress (neuroses)
• Slow movements
• Slow or decreased movement and expressions of the face
• Speech impairment
• Tremors of the arms or hands
• Uncontrollable movement
• Unpredictable and jerky movement
• Vomiting blood
• Weakness
• Yellow skin (jaundice) or yellow color of the white of the eye (icterus)

Diagnosis

A slit-lamp eye exam may show: Limited eye movement Rusty or brown-colored ring around the iris (Kayser-Fleischer rings)

A physical exam may show signs of: Damage to the central nervous system, including loss of coordination, loss of muscle control, muscle tremors, loss of thinking and IQ, loss of memory, and confusion (delirium or dementia) Liver or spleen disorders (including hepatomegaly and splenomegaly)

Lab tests may include:

• Complete blood count (CBC)
• Serum ceruloplasmin
• Serum copper
• Serum uric acid
• Urine copper

If there are liver problems, lab tests may find:

• High AST and ALT
• High bilirubin
• High PT and PTT
• Low albumin

Other tests may include:

• 24-hour urine copper test
• Abdominal x-ray
• Abdominal MRI
• CT scan of the abdomen
• Head CT scan
• Head MRI
• Liver biopsy
• Upper GI endoscopy

The gene that causes Wilson disease has been found. It is called ATP7B. DNA testing is available for this gene. Talk to your health care provider or a genetic counselor if you would like to have gene testing performed.

Treatment

The goal of treatment is to reduce the amount of copper in the tissues. This is done by a procedure called chelation. Certain medicines are given that bind to copper and help remove it through the kidneys or gut. Treatment must be lifelong.

The following medicines may be used:

• Penicillamine (such as Cuprimine, Depen) binds to copper and leads to increased release of copper in the urine.
• Trientine (such as Syprine) binds (chelates) the copper and increases its release through the urine.
• Zinc acetate (such as Galzin) blocks copper from being absorbed in the intestinal tract.

• Vitamin E supplements may also be used.

Sometimes, medicines that chelate copper (such as penicillamine) can affect the function of the brain and nervous system (neurological function). Other medicines under investigation may bind copper without affecting neurological function.

A low-copper diet may also be recommended. Foods to avoid include:

• Chocolate
• Dried fruit
• Liver
• Mushrooms
• Nuts
• Shellfish

You may want to drink distilled water because most tap water flows through copper pipes. Avoid using copper cooking utensils.

Symptoms may be managed with exercise or physical therapy. People who are confused or unable to care for themselves may need special protective measures.

A liver transplant may be considered in cases where the liver is severely damaged by the disease.

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• Zinc acetate (Brand name: Galzin)For maintenance treatment of patients with Wilson's disease who have been initially treated with a chelating agent.
• Trientine HCl (Brand name: Syprine )Treatment of patients with Wilson's disease who are intolerant, or inadequately responsive to penicillamine.

Prognosis

The long-term outlook (prognosis) for people with Wilson disease varies and largely depends on timely diagnosis and treatment. If the condition is detected early and treated appropriately, people with Wilson disease can usually enjoy normal health and a normal lifespan. Unfortunately, untreated Wilson disease is associated with severe brain damage, liver failure, and death.

NIH genetic and rare disease info

• NIH info on Wilson disease

Wilson disease is a rare disease.

Wilson disease Resources
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