A 22-year-old man is brought to the physician by his parents due to concerning changes in his behavior over the past year. He has become increasingly irritable, impulsive, and his academic performance at college has significantly declined. He also complains of a fine tremor in his hands and difficulty coordinating his movements when walking. Past medical history is negative, and he does not take any medications. Physical examination reveals scleral icterus and a firm, enlarged liver edge palpable 2 cm below the right costal margin. Slit-lamp examination demonstrates brownish-green deposits in the Descemet membrane of the cornea.
Which of the following is the most likely underlying cause of this patient's condition?
A) Defective hepatocyte copper transport
This patient presents with the classic triad of hepatic (hepatomegaly, jaundice), neurologic (tremor, ataxia), and psychiatric (personality changes) dysfunction associated with Wilson disease (hepatolenticular degeneration). The pathognomonic finding is the presence of Kayser-Fleischer rings, which are copper deposits in the cornea. Wilson disease is caused by an autosomal recessive mutation in the ATP7B gene, which codes for a copper-transporting ATPase in hepatocytes. This defect leads to impaired biliary excretion of copper and impaired incorporation of copper into ceruloplasmin, resulting in the accumulation of toxic free copper in the liver, brain, and cornea.
Answer choice B: Defective intestinal copper absorption, is incorrect. This is the pathophysiology of Menkes disease, an X-linked recessive disorder caused by a mutation in the ATP7A gene. Menkes disease presents in infancy with "kinky" hair, growth retardation, and hypotonia due to copper deficiency, not copper overload.
Answer choice C: Increased serum ceruloplasmin levels, is incorrect. In Wilson disease, because copper cannot be incorporated into apoceruloplasmin to form stable ceruloplasmin, the unstable apoceruloplasmin is degraded. Therefore, serum ceruloplasmin levels are typically decreased, not increased.
Answer choice D: Mutation in the ATP7A gene, is incorrect. As noted above, mutations in ATP7A cause Menkes disease ("Menkes is Absent copper"). Wilson disease is caused by a mutation in ATP7B ("Wilson is Bad copper transport").
Answer choice E: Mutation in the HFE gene, is incorrect. Mutations in the HFE gene are associated with hereditary hemochromatosis, which leads to iron overload. While hemochromatosis can cause cirrhosis, skin pigmentation ("bronze diabetes"), and cardiomyopathy, it does not present with the specific neurologic findings or Kayser-Fleischer rings seen in this patient.
Key Learning Point
Wilson disease is caused by an autosomal recessive mutation in the ATP7B gene, which leads to defective hepatocyte copper transport. This results in a failure to excrete copper into bile and a failure to incorporate copper into ceruloplasmin, leading to low serum ceruloplasmin. The excess copper deposits in the liver resulting in cirrhosis, in the brain resulting in basal ganglia degeneration, and in the cornea causing Kayser-Fleischer rings.
