Menkes Disease

Menkes' syndrome is an X-linked (Xq13.3) recessive disorder associated to copper deficiency, lethal in the early childhood (27). The most striking feature of this disease is the coarse and hypopigmented hair; therefore, it is also called "kinky or steely hair disease." Menkes' children show impaired synthesis of collagen and elastin. Furthermore, they are severely mentally retarded: altered brain development and neurodegeneration have been detected by postmortem histological assay (28). In particular, diffuse atrophy, focal degeneration of gray matter, and prominent neuronal loss has been detected in the cerebellum. Purkinje cells show abnormal dendridic arborization and focal axonal swelling. These features are present at birth, indicating that copper is essential for prenatal growth and development of the central nervous system. The molecular basis of this syndrome has recently been discovered, by identifying a mutated gene (ATP7A) encoding for a P-type cation-transporting ATPase (29-31). All types of mutations have been found: nonsense, missense, duplications, and deletion. Approximately 200 mutations have been identified, responsible for classical or milder form of the disease. As a primary effect, the impairment of the copper ATPase results in defective copper export from intestinal cells, leading to systemic copper deficiency. Thus, copper accumulates in intestine, kidney, and cultured fibroblasts, whereas brain and liver are copper deficient. Systemic depletion of copper-dependent enzymes may justify the phenotype and the symptoms of Menkes patients.

Fig. 1. Mitochondrial impairment and markers of apoptosis in the brain of mottled/brindled mice. Fourteen-day-old mice were used. (A) Cytochrome-c oxidase activity in total brain homogenates was assayed spectro-photometrically; (B) ATP levels were assessed by a luminescent method; (C) Cytochrome-c in the cytosol was measured by Western blotting using a monoclonal antibody; (D) Bcl-2 protein was measured by Western blotting using a polyclonal antibody. Lanes 1 and 3: healthy control mice; Lane 2: mottled/brindled. For details, see ref. 34.

Fig. 1. Mitochondrial impairment and markers of apoptosis in the brain of mottled/brindled mice. Fourteen-day-old mice were used. (A) Cytochrome-c oxidase activity in total brain homogenates was assayed spectro-photometrically; (B) ATP levels were assessed by a luminescent method; (C) Cytochrome-c in the cytosol was measured by Western blotting using a monoclonal antibody; (D) Bcl-2 protein was measured by Western blotting using a polyclonal antibody. Lanes 1 and 3: healthy control mice; Lane 2: mottled/brindled. For details, see ref. 34.

The cause of the neurological abnormalities observed in Menkes disease is still to be ascertained. As mentioned earlier, copper content is particularly low in the brain, because ATPase also transports copper across the blood-brain barrier and lower activities of copper-dependent enzymes may strongly contribute to the altered development of the central nervous system (32). However, the mechanisms accounting for prenatal cerebral and cerebellar degeneration remain unknown, implying the existence of an as yet unidentified copper-dependent factor, which plays an essential role in neuronal growth and differentiation.

In the brain of the Mobr/Y mouse, the closest animal model of Menkes' disease (32,33), we have recently shown (34) that copper deficiency leads to specific decrease in brain of cytochrome-c oxidase and Cu,Zn superoxide dismutase activities. In addition, a dramatic change of markers for apoptosis were detected in the brain: loss of the antioxidant Bcl-2 protein, which also plays a fundamental role in brain development and morphogenesis (35), release of cytochrome-c from the mitochondria, and depletion of ATP (Fig. 1). Histological analysis of brain revealed a high percentage of apoptotic cells in the neocortex and the hippocampus (34). These results clearly show that a copper deficit may cause mitochondrial damage in the brain consequent to inactivation of cytochrome-c oxidase. In turn, this event may trigger leakage of oxygen radicals out of damaged mitochondria, leading to neurodegeneration via oxidative stress-mediated apoptosis. Treatment of Menkes' disease consists in intravenous administration of the copper-histidine complex (27). The crucial role of cytochrome-c oxidase alteration in neurodegeneration is demonstrated by studies on the timing of treatment of Mobr/Y with copper, showing that delayed treatment results in irreversible changes of cytochrome-c oxidase of the brain, leading to irresponsiveness to the treatment (36).

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