in copper excretion by preventing the reabsorption of copper (Iyengar et al. 1988). That hypothesis is supported by evidence of a high-molecular-weight protein in the bile that reacts with antibodies to ceruloplasmin, and contains enough copper to account for the excess copper (Iyengar et al. 1988; Chowrimootoo et al. 1996; Davis et al. 1996). There is no evidence of immunoreactive ceruloplasmin in the bile of most Wilson patients (Iyengar et al. 1988), and Wilson patients usually have low blood ceruloplasmin levels (Brewer and Yuzbasiyan-Gurkan 1992). It is not known, however, how the genetic defect in ATP7B and the effects on ceruloplasmin in Wilson patients are related. It is important to note that patients with aceruloplasminemia have normal copper concentrations (Harris et al. 1998).

Although diets low in copper have been prescribed for patients with Wilson disease in the past, more recent measurements of food copper content have indicated that only liver and shellfish are high enough in copper to warrant restriction (Brewer and Yuzbasiyan-Gurkan 1992). If the concentration of copper in drinking water at home, school, or work is greater than 0.1 mg per liter (L), most clinicians recommend that alternate sources be used in the management of Wilson disease (Brewer et al. 1998).

The genetic mutations responsible for the loss of copper homeostasis are well characterized for Menkes and Wilson diseases. As a result, both diseases have provided insight into the genetic factors that regulate copper bioavailability and transport to organs and tissues.

The identification, sequencing, cloning, and characterization of the Wilson gene and mutations of the gene (Bull et al. 1993; Tanzi et al. 1993; Petrukhin et al. 1993; Thomas et al. 1995) and the Menkes gene (Vulpe et al. 1993; Chelly et al. 1993; Mercer et al. 1993) reveal that both genes encode P-type Cu-ATPases that are specific for copper transport (Solioz and Vulpe 1996). Cu-ATPases are complex integral membrane proteins that are part of a family of ion-transporting proteins that include the Ca²⁺ and Na⁺/K⁺ transport proteins. The Wilson protein (ATP7B) and the Menkes protein (ATP7A) share 57% amino acid sequence homology (Vulpe and Packman 1995) and show remarkable similarity to bacteria copper-binding proteins (Silver et al. 1993).

The Menkes gene, MNK, spans about 140–150 kb (Tumer et al. 1995; Dierick et al. 1995) and gives rise to a 8.5-kb mRNA. The Menkes mRNA encodes a protein (ATP7A) of exactly 1,500 amino acids, but additional nucleotide sequences at the 5' end are also known to occur (Tumer et al. 1995). High levels of MNK mRNA are found in muscle, kidney, lung, and

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)