Wilson disease is a rare, autosomal recessive, inherited disorder that affects copper metabolism, leading to the excessive accumulation of copper in the body’s tissues, especially the liver, brain, and eyes.1 

Genetics of Wilson Disease

Homozygous or compound heterozygous mutations in the ATP7B gene result in the development of Wilson disease.2 ATP7B encodes a P-type, cation, transmembrane, copper-transporting ATPase protein. Normally, this ATPase functions by using energy obtained from adenosine triphosphate (ATP) to transport copper through hepatic cell membranes and secrete excess copper into the biliary system. ATPase also loads ceruloplasmin with copper.2-4 

Mutations in the ATP7B gene result in the production of a dysfunctional ATPase that cannot sufficiently remove copper from the liver in bile, leading to excessive copper deposition within the liver, brain, and other body tissues.3

Wilson disease can be inherited when both parents carry an abnormal copy of the ATP7B gene. A child has a 25% chance of inheriting abnormal copies of this gene from both parents.1 

Over 600 genetic variations in the ATP7B gene have been identified. The most frequent ATP7B pathogenic variants involve single-nucleotide missense and nonsense mutations followed by insertions or deletions. Splice-site mutations are the most uncommon.2

The most common genetic variation causing Wilson disease in white individuals results in a histidine-to-glutamate substitution at the amino acid 1069 (p.H1069Q), which changes the orientation of the ATPase catalytic binding site for ATP, impairing ATP hydrolysis.2,5,6 Researchers have demonstrated that ATP7B mutations that cause substitutions of histidine at the amino acid 1069 for alanine, cysteine, or glutamine all directly impair ATP-dependent phosphorylation.6 

Pathogenesis of Wilson Disease

Humans ingest approximately 1.5 to 2.5 mg of dietary copper per day. Approximately 50% to 75% of dietary copper is absorbed from the stomach and intestines, especially the duodenum, and is transported via circulating albumin to hepatocytes for regulation and excretion.2,5 Copper is an important component for metabolic enzymes such as lysyl oxidase, superoxide dismutase, cytochrome c oxidase, and dopamine beta-hydroxylase. In the liver, copper is incorporated into these metabolic enzymes and loaded onto copper-binding proteins, including ceruloplasmin.5 

Ceruloplasmin is a serum ferroxidase that transports copper from the liver through the circulatory system to other tissues in the body that require copper for normal functioning.7 ATPase sequesters 6 copper molecules in the trans-Golgi network, packaging them into apoceruloplasmin and secreting this into the bloodstream.2

ATPase transmembrane proteins sequester the excess copper remaining in the cytoplasm of hepatocytes into vesicles and secretes these vesicles by transporting them across the apical canalicular membrane into the biliary system—the main route for copper excretion to achieve normal copper balance in the body.2,5

Patients with Wilson disease have impaired copper excretion via the biliary system and impaired incorporation of copper into ceruloplasmin.5 

Excess copper accumulation within the liver causes damage to the hepatocytes secondary to free radical formation, resulting in lipid and protein oxidation. Signs of hepatic disease such as steatosis, hepatitis, liver fibrosis, and acute liver failure are often the initial manifestations of Wilson disease.3 

Excess copper accumulation is toxic, resulting in oxidative stress, gene expression modification, protein inhibition, and mitochondrial impairment.3 As copper gradually accumulates and reaches certain levels in the liver, copper levels in the bloodstream also eventually increase, allowing copper deposition to occur throughout other organ systems, such as the brain and the cornea of the eyes.1,5,8 

Copper accumulates in astrocytes in the brain, disrupting the blood-brain barrier and leading to neuronal and oligodendrocyte injury, particularly in the brainstem and basal ganglia, which are the most susceptible to copper toxicity. Damage to these brain regions results in symptoms indicative of movement and psychiatric disorders.3

Kayser-Fleischer rings are dark greenish or brownish rings surrounding the irises of the eyes that form secondary to copper deposition within Descemet’s membrane and are often indicative of liver diseases. Most patients with neurological involvement due to Wilson disease also exhibit Kayser-Fleischer rings.9


  1. Wilson disease. National Organization for Rare Disorders (NORD). Accessed September 9, 2022.
  2. Chang IJ, Hahn SH. The genetics of Wilson disease. Handb Clin Neurol. 2017;142:19-34. doi:10.1016/B978-0-444-63625-6.00003-3
  3. Scheiber IF, Brůha R, Dušek P. Pathogenesis of Wilson disease. Handb Clin Neurol. 2017;142:43-55. doi:10.1016/B978-0-444-63625-6.00005-7
  4. ATP7B ATPase copper transporting beta [Homo sapiens (human)]. National Center for Biotechnology Information (NCBI). Updated August 12, 2022. Accessed September 9, 2022.
  5. Gilroy RK. Wilson disease: etiology. Medscape. Updated February 14, 2019. Accessed September 9, 2022.
  6. Tsivkovskii R, Efremov RG, Lutsenko S. The role of the invariant His-1069 in folding and function of the Wilson’s disease protein, the human copper-transporting ATPase ATP7B. J Biol Chem. 2003;278(15):13302-13308. doi:10.1074/jbc.M300034200
  7. Ceruloplasmin test. MedlinePlus. Updated September 15, 2021. Accessed September 9, 2022.
  8. Pfeiffer RF. Wilson’s disease. Handb Clin Neurol. 2011;100:681-709. doi:10.1016/B978-0-444-52014-2.00049-5
  9. Pandey N, John S. Kayser-Fleischer ring. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated June 21, 2022. Accessed September 9, 2022.

Reviewed by Hasan Avcu, MD, on 9/19/2022.