1. Background

• Copper is an essential trace element and is acquired from dietary sources. Dietary copper is ingested and 50% passes into the feces while 30% is absorbed then lost through the skin. The remaining 20% is absorbed then excreted with bile via the biliary system into the feces.
• There are 3 inherited disorders known to be caused by genetic defects in copper metabolism:
  • Wilson Disease
  • Menkes Disease
  • Occipital Horn Syndrome
• Wilson Disease was first described by Kinnear-Wilson in 1912
• Isolation of the Wilson Disease gene (Cu-binding P-type ATPase) was first reported in 1993 by three groups (Bull et al., Petrukhin et al., Tanzi et al., Nature Genetics 5:327-350, 1993) and is a member of a cation-transporting P-type ATPase subfamily.
• The gene is about 7.5 kb with the gene product being about 1,411 amino acids in length and has about a 60% homology to the copper-binding P-type ATPase which is defective in Menkes Disease.
• Expression of this Cu-binding P-type ATPase occurs primarily in the liver, kidney, and placenta (Chelly and Monaco, Nature Genetics 5:317-318, 1993).

2. Genetic Defect

• genetic defect -> defect in the Cu-binding ATPase protein -> defective liver-specific copper transportion -> defective copper excretion into the bile -> accumulation of copper in the liver (cytosol of hepatocytes) -> hepatic overload -> toxic copper accumulation in other tissues:
  • brain (basal ganglia and thalamus)
  • renal (proximal renal tubules)
  • cornea (Kayser-Fleischer rings)
• accumulation of copper in tissues acts to inhibit various enzymatic reactions (glycolysis, microsomal membrane ATPases, pyruvate oxidase), oxidize proteins and lipids in membranes, bind to proteins and nucleic acids, and enhance free-radial generation (i.e., is toxic to the cells)
• the main difference in the pathogenesis between Menkes Disease and Wilson Disease is that in the latter there is a toxic accumulation of copper throughout the body and no dysfunction of numerous copper-dependent enzyme systems
• several disease-specific mutations have been identified including transversions, base pair deletions, and frame shift mutations (Bull et al., Nature Genetics 5:327-337, 1993; Petrukhin el al., Nature Genetics 5:338-343, 1993)

1. Hepatic Manifestations

• all patients will have liver involvement
• predominate before age 20
• asymptomatic hepatomegaly +/- splenomegaly is usually the presenting sign
• may present as acute hepatitis, chronic active hepatitis, cirrhosis, or fulminant hepatic failure
• acute hepatits:
  • patients may initially mimic acute hepatits with complete recovery followed later by liver, CNS disease, and/or in fulminant hepatic failure
• chronic active hepatitis:
  • insidious onset of abdominal pain, fatigue, abdominal distension, hepatomegaly, splenomegaly, and jaundice
• cirrhosis:
  • palmar erythema
  • spider nevi
  • portal hypertension with hematemesis
  • digital clubbing
• fulminant hepatic failure:
  • ascites and edema
  • jaundice
  • coagulation defects
  • encephalopathy

2. Neurologic Manifestations

• reflects degeneration of the basal ganglia
• predominate after age 20 but can present in the first decade
• develop insidiously or precepitously
• movement disorders
  • progressive dystonia is often the initial presenting sign
  • intention tremor is initially unilateral then becomes coarse generalized, and incapacitating ("wing-beat" tremor)
  • difficulty with fine motor tasks
  • chorea, choreathetosis
  • rigidity, contractures
  • gait disturbances
• dysphonia, dysarthria, drooling
• retraction of the upper lip - "fixed smile"
• mask-like facies

3. Ophthalmologic Manifestations

4. Renal Manifestations (Fanconi Syndrome)

• episodes of vomiting, dehydration, weakness, & unexplained fever
• anorexia, constipation, polydipsia and polyuria, failure to thrive, growth failure, rickets
• urolithiasis (bladder stones)
• improve with proper therapy

5. Psychiatric Manifestations

• deterioration in school performance
• behavioural changes:
  • compulsive, impulsive, aggressive
  • depression, phobias

6. Skeletal Manifestations

• arthritis and arthropathy
• osteoarthritis
• osteochondritis dissecans

7. Other Manifestations

• hemolytic anemia
  • may be due to oxidative injury of the RBC membrane from excess copper
  • may be a presenting complaint
• cardiomyopathy and/or arrhythmias
• endocrinopathies (hypoparathyroidism)
• cholelithiasis

1. Diagnostic (Indicies of Copper Metabolism)

2. Serum

3. Urine

4. Liver Biopsy

5. Imaging Studies

1. Diet

• restrict copper intake to less than 1 mg/day
  • eliminate liver, kidney, shellfish, nuts, chocolate, dried beans, peas, and unprocessed wheat
  • demineralize water if copper content > 0.1 mg/L

2. Medications

3. Surgery

• liver transplantation with end stage liver failure
• 77% survival rate at 2.7 years post transplantation

4. Prognosis

• progressive dementia, loss of ambulation, coma, and death within a few years of onset if untreated
• depends on the time of initiation of therapy and response to chelation

1. Altschuler, S.M., and C.A. Liacouras. Clinical Pediatric Gastroenterology (1st Edition), p. 451-455, 1998.