Wilson Disease (Morbus Wilson): A Genetic Disorder of Copper Metabolism

By SWA

Introduction

Wilson disease (also known as Morbus Wilson or Wilson-Krankheit in German) is a rare, autosomal recessive genetic disorder caused by mutations in the ATP7B gene. This gene encodes a protein responsible for transporting copper out of liver cells and into bile for excretion. In individuals with Wilson disease, defective ATP7B function leads to the accumulation of toxic levels of copper in the liver, brain, eyes, and other organs. If untreated, the disease can cause severe hepatic, neurological, and psychiatric complications. Early diagnosis and appropriate therapy can significantly improve prognosis.

Genetics of Wilson Disease: The Role of ATP7B and rsIDs

Wilson disease is caused by pathogenic variants in the ATP7B gene, located on chromosome 13q14.3. These variants impair copper transport, leading to its accumulation in tissues.

In genetic studies and clinical databases, single nucleotide polymorphisms (SNPs) are cataloged with RefSNP ID numbers (rsIDs), which are used to identify specific genetic variations. Here are some key ATP7B mutations associated with Wilson disease:

Common ATP7B rsIDs in Wilson Disease

  1. rs76151636

    • Mutation: c.3207C>A (p.His1069Gln)

    • Prevalence: Most common in European populations

    • Effect: Missense mutation that disrupts copper transport

    • Clinical relevance: Strongly associated with Wilson disease

  2. rs121907998

    • Mutation: c.2333G>T (p.Arg778Leu)

    • Common in: East Asian populations

    • Effect: Missense mutation

    • Pathogenicity: Well-established cause of Wilson disease

  3. rs137853261

    • Mutation: c.2304dupC

    • Effect: Frameshift mutation leading to premature stop codon and truncated protein

    • Pathogenic: Yes; results in non-functional ATP7B

More than 600 different mutations have been reported in ATP7B, many of which are available for review in genetic databases such as:

Diagnostic Approach

Early diagnosis is essential to prevent irreversible organ damage. The diagnostic process includes laboratory tests, eye examinations, imaging, and genetic testing.

Laboratory Diagnostics

  • Ceruloplasmin (a copper-carrying protein)

    • Normal: 20–60 mg/dL

    • Wilson disease: Typically low (<20 mg/dL)

  • Total Serum Copper

    • May be low or normal

    • Not reliable alone due to binding with ceruloplasmin

  • Free Serum Copper

    • Calculated as total copper minus ceruloplasmin-bound copper

    • Increased in Wilson disease

  • Liver Enzymes (ALT, AST)

    • May be elevated, even in asymptomatic patients

  • 24-hour Urinary Copper Excretion

    • Elevated in Wilson disease (>100 µg/24h)

    • Also used to monitor treatment response

Ophthalmological Findings

  • Kayser-Fleischer Rings

    • Brownish-green ring around the cornea due to copper deposits in Descemet's membrane

    • Common in patients with neurological involvement

  • Sunflower Cataracts

    • Rare

    • Star-shaped copper deposits in the lens

    • Usually asymptomatic but indicative of copper overload

Additional Diagnostics

  • Liver Biopsy

    • Direct measurement of hepatic copper concentration

  • Genetic Testing

    • Identifies mutations in the ATP7B gene

  • Brain Imaging (MRI)

    • Used when neurological symptoms are present

Clinical Manifestations

Wilson disease can manifest with hepatic, neurological, and psychiatric symptoms. The type and severity of symptoms vary greatly among individuals.

Psychiatric Symptoms

  • Personality changes: Irritability, reduced empathy

  • Depression: Common early symptom

  • Bipolar disorder: Extreme mood swings may occur

  • Psychosis: Hallucinations, delusions in advanced cases

  • Loss of behavioral control: Aggression or self-harm may result

Neurological Symptoms

  • Coordination problems: Ataxia affecting gait and fine motor skills

  • Speech disturbances: Slurred or slowed speech

  • Tremor: Involuntary shaking, often of hands or fingers

  • Muscle weakness: Difficulty with movement or physical activity

  • Dysphagia: Difficulty swallowing

Treatment

Treatment aims to remove excess copper, prevent its reaccumulation, and manage symptoms.

Pharmacologic Therapy

  • Chelating agents (e.g., D-penicillamine, trientine): Bind copper and promote urinary excretion

  • Zinc salts: Inhibit copper absorption from the gut

Dietary Modifications

  • Low-copper diet (avoid organ meats, shellfish, nuts, chocolate, mushrooms)

Monitoring

  • Regular follow-up to assess copper levels, liver function, and treatment adherence

Liver Transplantation

  • Considered in cases of acute liver failure or advanced liver disease unresponsive to medical therapy

Conclusion

Wilson disease is a treatable but potentially life-threatening genetic disorder. Its wide range of symptoms, especially psychiatric and neurological, can often lead to misdiagnosis. Understanding the genetic underpinnings, such as ATP7B mutations and relevant rsIDs, enables early diagnosis through genetic testing. With timely intervention, including chelation therapy, dietary management, and regular monitoring, patients with Wilson disease can live long and healthy lives.

Early recognition is crucial — especially in young individuals presenting with unexplained liver, neurological, or psychiatric symptoms.

References: 

Mutation analysis in patients of Mediterranean descent with Wilson disease: identification of 19 novel mutations
https://pubmed.ncbi.nlm.nih.gov/10544227/

Other citations: https://www.ncbi.nlm.nih.gov/snp/rs60986317#publications

© 2000-2025 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right. Library of Congress Card Number: LCN 00-192742

 

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