eMedicine Specialties > Neurology > Movement and Neurodegenerative Diseases

Wilson Disease

Author: Celia H Chang, MD, Associate Health Sciences Clinical Professor, Department of Neurology, University of California at Davis
Contributor Information and Disclosures

Updated: Nov 26, 2008

Introduction

Background

Wilson disease, or hepatolenticular degeneration, is a neurodegenerative disease of copper metabolism. In 1912, Wilson first described it as a familial disorder associated with neurologic symptoms and cirrhosis. In 1956, Walshe first treated patients with the chelating agent penicillamine.

Although the animal models are not human equivalents of Wilson disease, they are helpful in studying copper metabolism and potential treatments. The Bedlington terrier has an autosomal recessive inherited disease characterized by copper toxicosis.1 The Bedlington terrier does not develop neurologic symptoms, but its liver pathology is similar to that of Wilson disease. Canine copper toxicosis is caused by a mutation of the MURR1 gene, which is also believed to be essential for copper excretion. The MURR1 gene is downstream of the gene that causes Wilson disease.

The Long Evans Cinnamon (LEC) rat and toxic milk mouse both develop autosomal recessive inherited diseases associated with copper overload. LEC rats are reported to develop neurologic symptoms, though hemolysis and hepatitis are the usual presenting symptoms. However, the liver histologic findings in the LEC rats and toxic milk mice are substantially different from those of Wilson disease.

Tetrathiomolybdate (TM) was initially developed to treat chronic nutritional copper poisoning in sheep and is now used for Wilson disease. The Menkes disease gene (MNK) was cloned in January 1993 and identified as a P-type adenosine triphosphatase (ATPase), which led to the identification of the Wilson disease gene (WND) at the end of 1993.

Pathophysiology

Wilson disease involves loss of the ability to export copper from the liver into bile and to incorporate copper into hepatic ceruloplasmin. As a consequence, copper accumulates in the liver, brain, kidney, and cornea. The gene for Wilson disease encodes a cation-transporting P-type ATPase with 14 domains: 6 copper binding, 4 transmembrane, 1 phosphatase, 1 transduction, 1 phosphorylation, and 1 adenosine triphosphate (ATP) binding. About 24.6% of all mutations involve the ATP-binding domain.

A patient with a mutation causing a deletion of transmembrane domain 8 and entire the C-terminal cytoplasmic tail was reported to have liver disease and Kayser-Fleisher rings without neurologic symptoms. The Menkes and Wilson genes have 55% identity in amino acids. The Menkes and Wilson ATPases use common biochemical mechanisms, but their tissue-specific expression differs. The ATPase affected in Wilson disease, ATP7B, is predominantly in the liver and transports copper in the hepatocyte, allowing for the incorporation of copper into ceruloplasmin and its subsequent excretion into the bile. This is the only important pathway for copper removal.

ATP7B, also known as Wilson disease protein or WNDP, delivers copper to ferroxidase ceruloplasmin in Purkinje neurons. WNDP is active during development and adulthood but seems to be downregulated with age. About 58.2% of mutations in the Wilson disease gene are missense mutations, 27% are small deletions or insertions, 7.4% are splice-site mutations, and 7.4% are nonsense mutations. Of the point mutations in Wilson disease, 58.2% are missense mutations, 7.4% are at the splice site, 7.4% are nonsense and 27% are small insertions and/or deletions. Individuals in the same family who have the same genetic mutation in ATP7B may have different phenotypes.

Accumulation of copper in the cytoplasm of hepatocytes results in cellular necrosis and leakage of copper into the plasma. The excess copper then collects in extrahepatic tissues, including the basal ganglia and the limbus of the cornea. All copper-transporting ATPases have a histidine residue in the large cytoplasmic loop, adjacent to the ATP-binding domain. The histidine residue is essential for function, and it is the most common mutation in Wilson disease. The Wilson protein is synthesized as a single-chain polypeptide and is localized to the trans-Golgi network of cells.

ATP7B transports copper into the secretory pathway of the cell for incorporation into the cuproenzymes and excretion from the cell. An increase in the intracellular copper level causes ATP7B to move to a cytoplasmic vesicular compartment. As the copper is concentrated into vesicles for excretion from the cell, the cytosolic copper concentration decreases, and ATP7B returns to the trans-Golgi network. The movement of ATP7B appears to involve amino acid sequences in its carboxyl terminus. The copper concentration is higher in brains of people with Wilson disease than in other people or animals with diseases of copper overload.

Frequency

International

Incidence is 1 in 35,000-100,000 live births, with a gene frequency of 0.56%; the incidence in Sardinia may be higher.

Mortality/Morbidity

  • After patients become symptomatic, Wilson disease is lethal if untreated.
  • Patients who present with fulminant liver failure have a mortality rate as high as 70%.

Age

  • The onset of liver disease is usually at the age of 8-16 years.
  • Neurologic symptoms are rare before the age of 12 years.

Clinical

History

  • Liver disease is the most common initial manifestation in children.
  • Older individuals often present with neuropsychiatric symptoms.
  • About 40-50% of patients present with liver disease, and 35-50%, with neurologic or psychiatric symptoms.
  • KF rings are almost always present when the patient has neurologic symptoms.
  • Wilson disease can be divided into 4 stages: presymptomatic, symptomatic, symptomatic but treated, and maintenance.

Physical

  • Neurologic signs
    • Parkinsonian symptoms - Rigidity, bradykinesia
    • Dysarthria
    • Tremor at rest or with action
    • Dystonia mainly of the face
    • Dysdiadochokinesia
    • Poor handwriting
    • Incoordination
    • Abnormal eye movements
    • Respiratory dyskinesia which can present as an unusual cough
    • Polyneuropathy (may be initial manifestation and reversible with treatment)
  • Psychiatric signs
    • Hyperkinetic behavior
    • Irritability or anger
    • Emotional lability
    • Psychosis
    • Mania
    • Difficulty concentrating
    • Abnormal behavior
    • Personality changes
    • Depression
    • Schizophrenia
  • Skeletal abnormalities
    • Osteoporosis
    • Osteomalacia
    • Chondrocalcinosis
    • Osteoarthritis
    • Joint hypermobility
  • Ophthalmic findings
    • KF rings are greenish yellow or brown rings seen at the limbus of the cornea. They are best seen on slitlamp examination and usually progress from just the superior pole to both the superior and inferior poles and then finally to a full circle. They may not be present in children or other individuals without neurologic symptoms.
    • Sunflower cataracts are brilliantly multicolored and visible only by slitlamp examination. They do not impair vision.
    • Other relatively uncommon findings include exotropic strabismus, optic neuritis or pallor of the optic disc, and nightblindness.
  • Other physical findings
    • Azure lunulae of the fingernails
    • Arthropathy

Causes

Wilson disease is an autosomal recessive inherited condition caused by mutations or deletions of the ATP7B protein encoded by chromosome subbands 13q14.3-q 21.1. This gene encodes a 1411–amino acid protein that is a P-type ATPase. The gene is found predominantly in liver, kidney, and placenta but also in the heart, brain, lung, muscle, and pancreas. The most common genetic mutations are single–base pair changes or frame-shift mutations due to small deletions. On occasion, splicing errors are found. Genetic testing may be helpful in diagnosing the disease in a patient's asymptomatic relatives, but it has not replaced the traditional laboratory studies because of the large number (>200) of mutations that have been identified.

About 95% of serum copper is bound to ceruloplasmin. The serum ceruloplasmin level is usually low in Wilson disease, not because copper levels affect the synthesis of apoceruloplasmin but because the half-life of apoceruloplasmin decreases from 4-5 days to 4-5 hours in the absence of copper. The copper in liver cells is not excreted and is thought to cause oxyradical damage.

More on Wilson Disease

Overview: Wilson Disease
Differential Diagnoses & Workup: Wilson Disease
Treatment & Medication: Wilson Disease
Follow-up: Wilson Disease
References
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Further Reading

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Keywords

Wilson's disease, hepatolenticular degeneration, liver cirrhosis, copper overload, Kayser-Fleischer rings, KF rings, Bedlington terrier, disease of copper metabolism, Long Evans Cinnamon rat, LEC rat, toxic milk mouse, MNK, WND

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Contributor Information and Disclosures

Author

Celia H Chang, MD, Associate Health Sciences Clinical Professor, Department of Neurology, University of California at Davis
Celia H Chang, MD is a member of the following medical societies: American Academy of Neurology and Child Neurology Society
Disclosure: Nothing to disclose.

Medical Editor

Christopher Luzzio, MD, Clinical Assistant Professor, Department of Neurology, University of Wisconsin at Madison
Christopher Luzzio, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Nestor Galvez-Jimenez, MD, MSc, MHA, Chairman, Department of Neurology, Program Director, Movement Disorders, Department of Neurology, Division of Medicine, Cleveland Clinic Florida
Nestor Galvez-Jimenez, MD, MSc, MHA is a member of the following medical societies: American Academy of Neurology, American College of Physicians, and Movement Disorders Society
Disclosure: Nothing to disclose.

CME Editor

Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital
Matthew J Baker, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

 
 
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