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Not All Absent Serum Ceruloplasmin Is Wilson Disease: A Review of Aceruloplasminemia
  1. Leah Z. Harris
  1. From the Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, Md.
  1. Address correspondence to: Z. Leah Harris, MD, Division of Pediatric Anesthesiology and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Blalock 904B, Baltimore, MD 21287. Email: zharris1{at}

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Human copper enzymes reflect, by nature of their function and tissue specificity, an essential family of proteins. These enzymes are 1) cytochrome c oxidase, which is required for mitochondrial respiration; 2) Cu, Zn-superoxide dismutase (SOD), a ubiquitous antioxidant; 3) dopamine β hydroxylase, which is essential for catecholamine production; 4) lysyl oxidase, which is integral for collagen cross-linking and elastin formation; 5) peptidyl glycine α-amidating monooxygenase, which is responsible for neuropeptide and peptide hormone processing; 6) tyrosinase, which is essential for melanin synthesis, and 7) ceruloplasmin and hephaestin, members of the multicopper oxidase family, which are critical for efficient iron efflux through their action as ferroxidases. Recent identification of the inherited disorder aceruloplasminemia—a triad of diabetes, retinal degeneration, and neurodegeneration with an absence of detectable serum ceruloplasmin—associated with an altered iron metabolism has revealed an important link between copper and iron homeostasis.1,2

A review of hepatic copper homeostasis reveals that ingested copper, either bound to albumin or histidine, enters the hepatocyte via the copper transporter (CTR1), where its fate is determined by a family of copper chaperones or is stored in a metallothionein pool. Copper may be trafficked via cyclooxygenase-17 to the mitochondria for incorporation into cytochrome oxidase. Alternatively, it may be shuttled via CCS (the copper chaperone for SOD) for copper delivery to Cu, Zn-SOD. Finally, copper may be transported by HAH1, the copper chaperone for the Wilson disease P-type adenosine triphosphatase (ATPase), to the trans-Golgi network. It is here that the Wilson disease P-type ATPase is responsible for transporting copper into the secretory pathway, where it can either be incorporated into the cuproprotein ceruloplasmin or trafficked into a vesicular compartment that is excreted into bile.3

A mutation in the Wilson disease P-type ATPase gene prevents copper from being appropriately deposited within the secretory compartment and, hence, prevents …

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