Wilson Disease

Basics

Description

Wilson disease (WD), also known as hepatolenticular degeneration, is an autosomal recessive disorder of copper transport affecting several organs, most notably the liver, brain, and cornea.

Epidemiology

Children usually present with hepatic manifestations; adolescents and young adults may present with neurologic symptoms.

  • Worldwide carrier rate is 1:100.
  • Prevalence is 1:30,000 to 40,000.
  • Most cases present between ages 5 and 35 years.
  • No gender predilection
  • Worldwide distribution with higher risk in Sardinia (1:7,000 to 10,000) and Costa Rica (1:20,400)

Risk Factors

Genetics

  • Autosomal recessive inheritance with 1 of >500 known defects of the WD gene (ATP7B) on chromosome 13q14.3 membrane (ATPase)
  • The affected protein facilitates biliary excretion of excess copper; incorporates copper into apoceruloplasmin for transport
  • Heterozygotes are generally asymptomatic.
  • Siblings have 25% risk of disease, 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Clinical phenotype of WD is modified by mutations in other genes, including MTHFR, COMMD1, ATOX1, and XIAP.
  • Use of direct mutational analysis to phenotype WD is limited by the high number of mutations.

Pathophysiology

  • Loss of ATP7B function causes; (i) impaired biliary copper excretion (the only route for elimination of copper) and (ii) failure to incorporate copper to apoceruloplasmin during ceruloplasmin biosynthesis, leading to ceruloplasmin deficiency
  • Copper accumulates preferentially in the liver, leading to cirrhosis.
  • After liver is saturated, copper overflows and settles in the brain (primarily in the basal ganglia leading to impaired motor control), as well as other tissues including kidneys, heart, blood, and cornea.
  • Excess copper damages mitochondria, causing oxidative damage to cells. In addition, toxic intracellular copper deposition promotes apoptotic cell death by the inhibition of inhibitor of apoptosis proteins (IAPs).

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