Drug targets in Menkes disease - prospective developments.

Menkes disease (MNK) is an X-linked recessive disorder characterised by a copper-transporting ATPase defect. In the affected cells, copper transport from the cytosol to the Golgi apparatus is disturbed, resulting in a reduction of copper efflux. Orally-administered copper, which accumulates in the intestine, cannot be absorbed and thus a copper deficiency arises. The characteristic features of MNK are progressive neurological degeneration, connective tissue disorders and hair abnormalities, which are caused by a reduction in the activity of several copper-dependent enzymes, due to concomitant copper deficiency. Subcutaneous injections of copper-histidine complex, which currently forms the accepted mode of treatment, prevent the neurological degeneration in some patients when the treatment is initiated soon after birth. However, when the treatment is started later, the neurological degenerative processes are not prevented. Moreover, the treatment does not improve the connective tissue disorders that are caused by the low activity of lysyl oxidase. In order to solve these problems, a form of the treatment aimed at delivering copper into the Golgi apparatus should be studied. An attempt is made in this review to present what is currently known about MNK and its variants, the efficacy and problems of currently accepted treatments and finally therapeutic targets in MNK.