Pathophysiology

In almost all normal cells, except for hepatocytes, ATP7A is localized in the trans-Golgi membrane. ATP7A acts to transport copper from the cytosol into the Golgi apparatus and then serves to excrete copper. In the cells of individuals with MNK, copper accumulates in the cytosol and cannot be excreted from the cells. Copper accumulation in the intestine results in a failure of copper absorption, leading to copper deficiency, especially in the serum, liver, and brain. The characteristic features of MNK can be explained by decreases in activity of copper-dependent enzymes (Fig. 2 and Table 3). These decreases in enzyme activity are caused by defective copper absorption and/or disturbances in intracellular copper transport. In patients with MNK and in the animals serving as a model of this disease, the levels of activity of several copper-dependent enzymes, including dopamine P-hydroxy-

Cu Intestinal lumen

Fig. 2. Disruption of copper homeostasis in Menkes disease, with decreases and increases in copper levels shown.

Table 3

Reduced Activities of Copper-Dependent Enzymes and Clinical Findings of Menkes Disease

Reduced copper-dependent enzyme activities

Findings in Menkes disease

Cytochrome-c oxidase

Dopamine P-hydroxylase

Peptidylglycine a-amidating monooxygenase Lysyl oxidase

Tyrosinase Sulfhydryl oxidase Ceruloplasmin

Copper-zinc superoxide dismutase

Mitochondrial abnormalities, neurological damage, hypothermia, muscle weakness Abnormalities in catecholamines in the serum and cere-

brospinal fluid, hypotension Unknown

Decreased strength of collagen and elastin (arterial abnormalities, bladder diverticula, loose skin and joints) Reduced pigmentation of hair and skin Pili torti

Decreased levels of circulating copper Failure of free radical detoxification lase, cytochrome-c oxidase, and Cu/Zn superoxide dismutase, are improved by parenteral administration of copper, indicating that the decreased levels of activity of these enzymes are the result of only the defective copper absorption (30-32). However, the level of activity of lysyl oxidase seems not to be improved by copper administration. The level of lysyl oxidase activity is significantly reduced in cultured fibroblasts from patients with MNK, even in the presence of a high copper concentration (33,34). These findings suggest that the incorporation of copper into lysyl oxidase is disturbed in the affected cells.

On the other hand, significant accumulation of copper occurs in cells of the proximal tubules of the kidney, in which copper metabolism seems to occur in a manner similar to that in intestinal cells (35,36).

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