Wilson Disease: Symptoms, Types, Causes and Treatment

Wilson disease is a rare, inherited disorder that disrupts copper metabolism, leading to toxic copper accumulation in vital organs—especially the liver, brain, and eyes. Understanding its symptoms, types, causes, and available treatments is crucial for timely diagnosis and effective management. This detailed overview brings together the latest research to offer a comprehensive look at Wilson disease.

Symptoms of Wilson Disease

Recognizing the symptoms of Wilson disease early can be life-saving, as the disorder is treatable if diagnosed in time. However, its diverse manifestations—affecting the liver, nervous system, psyche, eyes, and other organs—often mimic other diseases and can lead to misdiagnosis. Symptoms frequently emerge between ages 6 and 45, most commonly during adolescence, and vary widely between individuals and organ systems involved.

System	Key Symptoms	Typical Age at Onset	Source
Liver	Jaundice, hepatitis, liver failure	Childhood–teen years	1 3 12
Neurologic	Tremor, dystonia, clumsiness, dysarthria, gait disturbance	Teens–adults	3 4 12
Psychiatric	Depression, personality changes, psychosis	Any age	2 16
Ophthalmic	Kayser-Fleischer rings, sunflower cataracts	Usually with neuro symptoms	5 7
Other	Osteopenia, arthralgia, renal symptoms, anemia	Variable	5 7

Table 1: Key Symptoms

Liver Involvement

Liver symptoms are often the earliest and most prominent manifestations, especially in children and adolescents. These may include:

• Jaundice (yellowing of the skin and eyes)
• Hepatitis-like symptoms
• Fatigue and malaise
• Acute or chronic liver failure
• Abdominal swelling (ascites) and pain

In severe cases, acute hepatic failure can develop rapidly—sometimes within weeks of onset—leading to life-threatening complications if not promptly treated 1 3 12.

Neurological Symptoms

Neurologic signs usually appear later, often in young adults, and are primarily due to copper buildup in the brain, especially the basal ganglia. Key features include:

• Tremors (shaking)
• Dystonia (involuntary muscle contractions)
• Dysarthria (slurred speech)
• Clumsiness and gait disturbances
• Drooling and swallowing difficulties

Movement disorders are common, and combinations of symptoms are typical, rather than a single isolated problem 4 7. MRI scans frequently reveal changes in the basal ganglia and other regions 4 7.

Psychiatric Manifestations

Psychiatric symptoms can be subtle, precede other symptoms, or develop at any stage of the disease. They are highly variable and may include:

• Depression and mood swings
• Personality changes, irritability, or impulsivity
• Anxiety and panic attacks
• Cognitive decline or psychosis

These symptoms can be mistaken for primary psychiatric disorders, sometimes delaying the correct diagnosis by years 2 16.

Eye and Other Systemic Findings

The most distinctive eye sign is the Kayser-Fleischer ring—a golden-brown ring at the edge of the cornea, visible on slit-lamp examination. Sunflower cataracts and retinal degeneration are less common 5 7.

Other organ involvement includes:

• Osteoarticular: Osteopenia, osteoporosis, joint pain (knees, wrists), fractures
• Renal: Tubular dysfunction, kidney stones
• Cardiac: Increased risk of arrhythmias and heart failure
• Hematologic: Hemolytic anemia, leukopenia, low platelets
• Skin: Hyperpigmentation of the legs, xerosis, azure lunulae (blue nails)
• Endocrine: Infertility, menstrual irregularities, growth disturbances 5

Types of Wilson Disease

Wilson disease does not present uniformly; it encompasses several clinical types based on the dominant symptoms and organs involved. Recognizing these types facilitates targeted diagnosis and therapy.

Type	Core Features	Typical Age Group	Source
Hepatic	Liver dysfunction, hepatitis, or failure	Children/teens	3 6 7
Neurologic	Movement disorders, dysarthria, psychiatric symptoms	Teens/adults	3 4 6 7
Psychiatric	Behavioral/mood disturbances (with/without liver/neurologic signs)	Any age	2 16 18
Mixed	Both hepatic and neurologic/psychiatric	Variable	3 6
Asymptomatic	No symptoms, abnormal labs only	Any (often siblings)	7 18

Table 2: Clinical Types

Hepatic Type

This type is most prevalent among children and adolescents. It ranges from mild, chronic liver dysfunction (often misdiagnosed as hepatitis) to acute liver failure. Some patients may present solely with liver symptoms, without any neurologic or psychiatric features 3 6.

Neurologic Type

Typically seen in teenagers and young adults, the neurologic type is marked by movement disorders (tremors, dystonia, parkinsonism), dysarthria, and gait disturbances. These symptoms may be the initial or dominant features, especially if liver disease is mild or clinically silent 3 4 6.

Psychiatric Type

Psychiatric presentations can occur at any age and sometimes precede other symptoms by months or years. Patients may display mood or personality changes, depression, psychosis, or cognitive impairment. In some cases, psychiatric symptoms are the only initial manifestation, potentially leading to misdiagnosis 2 16 18.

Mixed Type

Many patients experience overlapping liver, neurologic, and psychiatric symptoms—sometimes sequentially. This mixed presentation complicates diagnosis but is common in Wilson disease 3 6.

Asymptomatic and Other Forms

Some individuals, often siblings of diagnosed patients, are discovered through family screening before symptoms appear. These asymptomatic cases may show only abnormal laboratory values (e.g., low ceruloplasmin, elevated urinary copper) 7 18. Rarely, patients may present with atypical features such as osteoarticular, renal, or cardiac symptoms 5 7.

Causes of Wilson Disease

At the heart of Wilson disease is a genetic defect affecting copper metabolism. Understanding the root cause helps explain its clinical variability and guides both diagnosis and family counseling.

Cause	Mechanism/Impact	Genetic Inheritance	Source
ATP7B mutation	Impaired copper export from liver	Autosomal recessive	11 12 13
Copper accumulation	Toxic buildup in liver, brain, eyes	Variable	1 12 14
Cellular toxicity	Oxidative stress, mitochondrial injury	Multisystem	12 14
Prevalence	~1/7,000 (birth prevalence)	Universal ethnicities	10

Table 3: Causes and Mechanisms

Genetic Defect: ATP7B Mutation

Wilson disease is caused by mutations in the ATP7B gene, which encodes a copper-transporting ATPase required for copper excretion into bile and incorporation into ceruloplasmin, the main copper-carrying protein in blood 11 12 13. Inheritance is autosomal recessive—both parents must pass on a mutated gene for a child to be affected.

Pathogenesis: Copper Accumulation and Toxicity

Due to defective ATP7B, copper cannot be efficiently exported from liver cells or bound to ceruloplasmin. This leads to:

• Progressive copper buildup in the liver, causing inflammation, fibrosis, and eventually liver failure.
• Release of excess copper into the bloodstream, which then deposits in other organs, most notably the brain and eyes.
• In the brain, copper primarily affects the basal ganglia, leading to movement and psychiatric disorders 12 14.

Cellular toxicity is driven by oxidative stress, disruption of mitochondrial function, inhibition of crucial proteins and enzymes, and altered gene expression. These effects underlie the multisystem nature of Wilson disease 12 14.

Prevalence and Genetic Diversity

Recent genetic studies estimate a birth prevalence of about 1 in 7,000 individuals worldwide, making Wilson disease more common than previously thought. Over 700 pathogenic mutations in ATP7B have been identified across all ethnicities, explaining the variability in clinical presentation 10 11.

Treatment of Wilson Disease

Timely treatment of Wilson disease can halt or even reverse organ damage, making it one of the few treatable inherited movement disorders. The main strategies involve removing excess copper, preventing reaccumulation, and managing symptoms. Treatment must be lifelong and tailored to each patient’s disease stage and symptoms.

Treatment	Main Approach	Indications	Source
Chelators	Penicillamine, trientine, dimercaprol, tetrathiomolybdate	Initial/main therapy	13 15 17
Zinc salts	Block copper absorption	Maintenance, presymptomatic, mild cases	15 18
Liver transplant	Replace failing liver	Acute/severe liver failure	15 18
Symptomatic	Movement disorder, psychiatric, liver failure treatments	As needed	4 16 18
Emerging	New chelators, gene/cell therapy	Refractory/experimental	17

Table 4: Main Treatment Approaches

Chelation Therapy

Chelating agents are the cornerstone of Wilson disease treatment. They bind copper and promote its elimination via urine or bile:

• D-penicillamine: Most widely used, effective for most patients but may cause adverse reactions (rash, bone marrow suppression). Can worsen neurologic symptoms in some cases.
• Trientine: Alternative for those intolerant to penicillamine; fewer side effects, but may also cause neurological worsening.
• Dimercaprol and Dimercaptopropane sulfonate: Used less commonly, typically for severe or acute cases.
• Tetrathiomolybdate: Newer agent, appears to cause less neurologic deterioration and is under active investigation 13 15 17.

Treatment is usually started at diagnosis and continued for life. Regular monitoring for efficacy and side effects is essential.

Zinc Salts

Zinc interferes with copper absorption in the intestine, lowering copper uptake from food. It is often used:

• As maintenance therapy after initial chelation
• In asymptomatic, presymptomatic, or mildly affected patients
• For patients intolerant to chelators

Zinc is well-tolerated and suitable for long-term use, especially in children or during pregnancy 15 18.

Liver Transplantation

In cases of acute liver failure or advanced liver disease unresponsive to medical therapy, liver transplantation is life-saving. It cures the underlying metabolic defect, as the new liver provides functional ATP7B 15 18.

Symptomatic and Supportive Management

• Neurological symptoms: Managed with physical therapy, occupational therapy, and medications used for movement disorders (e.g., anticholinergics, dopaminergic agents) 4.
• Psychiatric symptoms: Treated according to general psychiatric guidelines, though response may be variable; careful choice of medications is necessary due to potential hepatic or neurological side effects 16.
• Other complications: Anemia, bone disease, cardiac or renal issues are addressed as they arise.

Emerging and Future Therapies

Limitations of current treatments—such as irreversible neurological damage, adverse drug effects, and poor adherence—have spurred research into:

• Newer chelators (e.g., CNS-penetrant trientine, tetrathiomolybdate)
• Non-chelating copper-removal drugs (e.g., methanobactin)
• Cell-based and gene therapies targeting ATP7B defects 17.

Gene sequencing is increasingly used for diagnosis and family screening, enabling earlier intervention 18.

Conclusion

Wilson disease is a complex, multisystem genetic disorder. While its manifestations are diverse and sometimes elusive, timely recognition and treatment can dramatically alter the prognosis. A multidisciplinary approach—incorporating hepatology, neurology, psychiatry, and genetics—is key to optimal care.

Key Takeaways:

• Wilson disease is caused by ATP7B mutations leading to copper overload, mainly affecting the liver, brain, and eyes 1 11 12.
• Symptoms are highly variable and include hepatic, neurologic, psychiatric, ophthalmologic, and other systemic features 1 3 4 5 7.
• Clinical types are based on the dominant organ systems involved: hepatic, neurologic, psychiatric, mixed, or asymptomatic 3 6 7.
• Diagnosis relies on clinical, biochemical, genetic, and imaging findings—early detection is crucial 7 10 18.
• Lifelong copper chelation or zinc therapy prevents disease progression; liver transplantation is reserved for severe cases 13 15 17 18.
• Ongoing research aims to improve neurological outcomes and explore gene/cell therapies 14 17.

Early diagnosis and individualized treatment can turn a potentially fatal disease into a manageable chronic condition, enabling most patients to lead full, productive lives.