Wilson Disease

What Causes Wilson Disease?

Wilson disease is caused by a deficiency of an enzyme called ATPase 2. This enzyme is responsible for transporting copper from the liver to other parts of the body and removing copper from inside cells. When there is not enough ATPase 2 in the body, copper accumulates to toxic levels.

Copper is essential for normal cell function, but excess levels of the metal have a toxic effect. As a result, affected cells eventually die, causing the symptoms characteristic of the disease. Cells in the liver, eyes, and brain are most susceptible to damage from abnormally high copper levels.

Is Wilson Disease Hereditary?

Wilson disease is caused by an abnormal variation (mutation) in the ATP7B gene, which carries the instructions for making ATPase 2. The disease-causing mutations impair the production of ATPase 2, beginning a chain reaction that leads to copper accumulation.

A parent who possesses a disease-causing mutation can pass the mutation on to their children. The disease follows an autosomal recessive inheritance pattern, meaning that a child must inherit a copy of the mutation from both parents to develop the disease. A person who inherits the mutation from only one parent is unlikely to develop symptoms, but they will carry the mutation and potentially pass it on to their children.

When two people who are carriers of the gene have a child, there is a 25% chance that the child will inherit two copies of the mutation and be affected by the disease. There is a 50% chance the child will inherit only one copy of the mutation and be a disease carrier. There is a 25% chance that the child will inherit two normal copies of the gene and be free of the mutation.

How Is Wilson Disease Detected?

The earliest signs of Wilson disease may vary depending on the age of onset. In children and adolescents, the first symptoms are often associated with liver disease. These signs include:

• Fatigue
• Yellowing of the skin
• Yellowing of the whites of the eyes
• Swelling in the abdomen or legs
• Loss of appetite
• Bleeding in the esophagus
• Easy bruising or prolonged bleeding

People with later-onset forms of the disease may not initially show signs of liver dysfunction. Instead, the first symptoms may be brain-related. These symptoms can include:

• Muscle tremors
• Involuntary muscle movements
• Speech difficulties
• Problems swallowing
• Problems with coordination
• Rigid muscles

How Is Wilson Disease Diagnosed?

A diagnosis of Wilson disease can be achieved using a variety of tests and exams. Possible diagnostic steps may include:

• Blood and urine tests. These tests may show elevated copper levels or other indicators of the disease.
• Eye exams. An eye exam may identify the Kayser-Fleischer ring, which is present in almost all people who show neurological effects of the disease.
• Liver biopsy. This test examines a sample of liver tissue to look for excess copper levels.
• Molecular genetic tests. These tests can identify whether the individual has a disease-causing mutation of the ATP7B gene.

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Wilson Disease Treated?

Wilson disease is treatable. Treatment approaches focus on removing excess copper from the body and preventing more copper from being absorbed. Treatment programs are life-long for people with the disease.

Medications to treat Wilson disease include:

• Chelating agents. These medications remove copper from the body and allow it to be excreted through the urine. This is typically the first step in a treatment plan. Commonly used medications include penicillamine and trientine dihydrochloride. These drugs can have significant side effects.
• Zinc salts. These medications prevent the patient’s body from absorbing copper from food. These drugs are usually used as a maintenance step after chelating agents have reduced copper levels.
• Tetrathiomolybdate. This medication is also used for maintenance.

How Does Wilson Disease Progress?

Wilson disease is treatable, and most people with the disease do not experience life-threatening or debilitating complications if the condition is diagnosed and treated early. However, the disease can produce severe complications if left untreated.

Long-term complications can include:

• Liver damage and liver failure. In some cases, a liver transplant might be necessary.
• Neurological damage. Some people experience permanent neurological effects such as tremors or difficulty walking.
• Anemia or jaundice
• Kidney damage or kidney stones
• Depression
• Anxiety
• Mood swings or irritability

How Is Wilson Disease Prevented?

There is no way to prevent the development of Wilson disease in individuals who carry two copies of the mutated ATP7B gene. However, people who have a relative with the disease are encouraged to undergo testing to determine whether they carry the gene mutation. A genetic counselor can help prospective parents assess their risk if they are discovered to be carriers of the disease-causing mutation.

Wilson Disease Caregiver Tips

Most people with Wilson disease also suffer from other brain and mental health-related issues, a condition called co-morbidity. Here are a few of the disorders commonly associated with Wilson disease:

• Between 20% and 60% of people with Wilson disease suffer from depression.
• Suicide attempts are more common among people with WD.
• People with WD are at increased risk of bipolar disorder.
• WD may sometimes be associated with attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), or eating disorders.
• Some people may experience dementia as a long-term complication of WD.

Wilson Disease Brain Science

Because Wilson disease causes widespread effects in various parts of the body in addition to psychiatric symptoms, researchers have studied the mental-health manifestations of the disorder in search of the best combination of treatments for all the disorder’s symptoms.

Although WD often affects the liver first, the brain is commonly involved in the disease’s progression. As a result, almost a third of people with the condition have psychiatric symptoms as their first sign of the disease, and one in five have already seen a psychiatrist by the time they’re diagnosed with WD.

A challenge in treating the psychiatric symptoms of WD is finding a treatment plan that is safe and effective. The liver’s involvement rules out some common psychiatric medications because they are metabolized by the liver and could be unsafe. In addition, some studies have suggested that standard treatments are not as effective in disorders that affect the basal ganglia, the part of the brain most impacted by WD.

Wilson Disease Research

Title: Clinical Study of UX701 AAV-Mediated Gene Transfer for the Treatment of Wilson Disease

Stage: Recruiting

Ultragenyx Pharmaceutical, Inc.

Los Angeles, CA

The primary objectives of this study are to evaluate the safety of single IV doses of UX701 in patients with Wilson disease, to select the UX701 dose with the best benefit/risk profile based on the totality of safety and efficacy data to evaluate the effect of UX701 on copper regulation.

This study is a randomized, double-blind, placebo-controlled, seamless, adaptive Phase 1/2/3 clinical study of UX701 in patients with Wilson disease.

Stage 1 (Phase 1/2) is designed to evaluate the safety and efficacy of 3 dose levels of UX701 to establish the initial safety of UX701 and select a safe and efficacious dose for further evaluation. Stage 2 (Phase 3) is designed to evaluate the safety and efficacy of UX701 using the dosage selected in Stage 1. Stage 3 (long-term follow-up) is designed to evaluate the long-term safety, efficacy, and clinical benefit of UX701. All participants will be monitored for at least five years from the time of UX701 administration.

Participants who receive UX701 will receive prophylactic oral corticosteroids. Participants who receive a placebo will receive placebo oral corticosteroids to maintain the study blind.

Title: Natural History of Wilson Disease

Stage: Recruiting

Principal investigator: Michael Schilsky, MD

Yale University

New Haven, CT

The purpose of the registry/repository is to provide a mechanism to store data and specimens to support the conduct of future research about Wilson disease (WD). The overall aim is to determine the optimal testing for diagnosis and parameters for monitoring treatment of WD that will aid product utilization and development.

There are three aims outlined as part of this research study.

Aim 1 is to study the natural history of a carefully characterized cohort of patients with WD followed longitudinally at the Centers of Excellence for WD in the United States and the United Kingdom.

Aim 2 seeks to evaluate parameters for diagnosis and treatment monitoring for patients on chelation therapy and zinc treatment for their WD. Data gathered in Specific aim one will be used for analyzing the components of the diagnostic scores for patients.

Aim 3 is intended to determine whether a composite index or a biomarker can be used as a surrogate marker for treatment monitoring for current patients on therapy that can be used for future patient treatment trials.

Title: Clinical Evaluation and Assessment of Instruments and Biomarkers in Subjects With Wilson Disease

Stage: Recruiting

Ultragenyx Pharmaceutical, Inc.

New Haven, CT

The study’s primary objective is to determine the relevance and appropriateness of outcome assessments, including biomarkers, within the Wilson disease population to inform study design and endpoint selection for future clinical studies.

Given the limited information on the frequency and spectrum of disease manifestations and clinical course of Wilson disease, the UX701-CL001 study aims to assess the utility and feasibility of various assessments and biomarkers to inform endpoint selection for future clinical studies, better understand the relationship between biomarkers and potential clinical outcomes, and characterize the clinical presentation of Wilson disease. UX701-CL001 is a clinical survey study. Subjects will complete assessments at the study site and at home to evaluate the clinical manifestations of Wilson disease in clinical and real-world environments.