(Yazaki et al. 1998). Tissue copper concentrations, however, tend to be unchanged and total iron-binding capacity and erythrocyte counts are normal. ⁵⁹Fe administered as a trace dose tends to accumulate in the brain, heart, kidney, and liver of patients with aceruloplasminemia, confirming the biopsy reports. ⁶⁴Cu administered intravenously, however, shows no such tendency, and tissue copper remains basically normal (Logan et al. 1994). Intravenous injections of human ceruloplasmin raise the serum iron in these patients (Logan et al. 1994). The lack of cardinal copper-related symptoms in aceruloplasminemic individuals challenges what has been considered the essential role of ceruloplasmin in copper transport and homeostasis and has increased the focus on its role.

Despite similarities with hemosiderosis and other iron-overload disorders, aceruloplasminemia is unusual in showing major alterations in neurological functions. Patients with aceruloplasminemia eventually succumb to the effects of increased iron in the tissues, particularly the basal ganglia (Miyajima et al. 1998). An increased susceptibility to lipid peroxidation is believed to contribute substantially to the neuropathology, which suggests that free-radical-mediated tissue injury is responsible for the basal-ganglia degeneration (Miyajima et al. 1996, 1998). Ceruloplasmin has recently been shown to function as an antioxidant in neutralizing nitric oxide via nitrosothiol formation (Inoue et al. 1999). A membrane-bound (GPI anchor) form of ceruloplasmin has been found in glia cells, which might have cytoprotective function in brain (Patel and David 1997). Lack of that form of ceruloplasmin in the aceruloplasminemic patient could also result in neurodegeneration.

Molecular genetic studies of DNA from cells from aceruloplasminemic individuals have detected specific mutations in the ceruloplasmin mRNA. Mutations that occur often lead to splicing errors and abridged forms of ceruloplasmin that cannot support normal ferroxidase function (Yazaki et al. 1998). In one patient with the disease, a 5-bp insertion in exon 7 caused an out-of-frame shift that generated a stop codon that aborted the protein from the ribosome before synthesis was completed (Harris et al. 1995). In another, a guanine-to-adenine transition at a splice acceptor site caused a similar premature termination of the protein during biosynthesis (Yoshida et al. 1995).

Despite careful clinical investigations of afflicted individuals, it is still unclear how ceruloplasmin controls iron homeostasis and tissue distribution. Copper-deficiency studies in which ceruloplasmin is lowered never achieve a total absence of the protein, as is observed in aceruloplasminemia. Such studies are further confounded by a disrupted copper status. A mouse knockout model, however, has recently been developed, and preliminary studies show no abnormalities in cellular iron uptake but do show a pronounced impairment in the movement of iron out of the reticu-

Front Matter (R1-R14)

Executive Summary (1-8)

1 Introduction (9-15)

2 Physiological Role of Copper (16-32)

3 Health Effects of Copper Deficiencies (33-50)

4 Disorders of Copper Homeostasis (51-77)

5 Health Effects of Excess Copper (78-126)

6 Risk Characterization (127-147)