In 1962, pediatrician John Menkes described a condition that he had found in five related boys—all of whom died before the age of 3. In each case, the child was born without incident but gained little weight postpartum. Their hair was coarse, brittle, and ivory-white, the result of depigmentation. Under the microscope, the hair fibers were twisted helically or broken in several places. In the first year of life, each of the infants developed seizures; and postmortem analysis showed cerebral and cerebellar degeneration. The condition was named Menkes disease, and over the next few years, other clinical symptoms would be added, including hypothermia, thrombosis, poor bone development, and an increased tendency toward aneurysms.

By the early 1970s, it was determined that the condition was due to a copper deficiency. Attempts to introduce copper orally met with limited success, but intravenous injection of copper did elevate the serum copper levels. The efficacy of intravenous administration suggested that the problem lay in copper absorption by the intestine. Later work, however, suggested that intracellular copper transport was a bigger problem, because the mucosa cells lining the intestine contained high levels of copper bound to metallothionein protein. Rather than being transported to the bloodstream, the copper remained in the mucosa and was lost when the intestinal cells were naturally sloughed off.

Serum copper is known to be critical to the proper function of several enzymes, many of which are involved in the metabolic processes that are debilitated in Menkes disease. Lysyl oxidase is important for the cross-linking of collagen and elastin, such that deficiencies lead to problems in connective tissue, such as bone. Other enzymes that require copper include cytochrome c oxidase, which is involved in temperature maintenance, and tyrosinase, which is necessary for pigmentation.

Copper binding. The ATP7A protein responsible for Menkes disease contains several transmembrane segments and six sequences that bind copper (Cu1–6). (Adapted from DiDonato and Sarker, 1997.)

The inheritance pattern of the disease in boys indicated that the gene for Menkes disease was located on the X chromosome, and the gene was eventually isolated to the centromeric portion of the long arm. In 1993, three research groups independently isolated the gene (MNK). The amino acid sequence of MNK suggests that the enzyme is a member of the P-type ATPases and is similar to bacterial proteins involved in metal transport across membranes. Almost 20% of the mutations that cause Menkes disease are deletions, whereas milder forms of the disease seem to be due to single base-pair changes.

The protein generated by MNK, ATP7A, contains eight transmembrane segments, four of which connect amino acid sequences involved in ATP binding and signals for phosphatase and phosphorylation activities. The protein’s N-terminal region carries six 30-residue repeats, each bearing the heptad GMXCXXC (where G = glycine, M = methionine, C = cyteine, and X = any amino acid), which has been shown to bind copper.

Copper–histidine. In the most efficacious treatment for Menkes disease, two histidine molecules coordinate around a copper atom. (Adapted from Sarker, 1999.)

The protein normally functions by moving copper from the intestinal mucosa cells into the bloodstream, where it is bound by proteins such as albumin and transported to organs and tissues. Mutations of the gene block this function, and thus the copper does not leave the mucosa cells. Mutations in a very similar protein, ATP7B, lead to problems in the transport of copper from the cytoplasm of cells into the Golgi apparatus, where it normally becomes bound to proteins. This defect results in a condition known as Wilson’s disease.

Although the isolation and characterization of MNK gives hope for future treatments, current efforts concentrate on diagnosis and early treatment with copper formulations, the most efficacious of which is copper–histidine, which was developed in 1973 at Toronto’s Hospital for Sick Children. Copper–histidine is the natural form of non-ceruloplasmin-bound copper in the bloodstream and is important to proper copper transport and uptake. Regardless of the formulation used, though, early administration is critical, because the prognosis of infants who begin treatment after the first month of life is poor. Thus, efforts are being made to improve in utero diagnosis and possible treatment. The use of such protocols has increased the lifespan of patients from 3 to 12 or more years.

Sources:

• DiDonato, M.; Sarkar, B. Biochim. Biophys. Acta 1997, 1360, 3–16
• Sarkar, B. Chem. Rev. 1999, 99, 2535–2544.