Deadly copper disease in infants targeted

October 03, 2001

COLLEGE STATION, - Cells in the placenta, brain and intestine are linked to Menkes' disease in babies, researchers at the Texas Agricultural Experiment Station discovered.

In addition to determining the cause of a deadly disease, the findings will help researchers learn more about genes that control copper and, more specifically, render a potentially dangerous metal safe for bodily functions, according to Dr. Ed Harris, Experiment Station biochemist.

Menkes' disease is a fatal illness in which the inability to absorb copper in the intestines deprives the brain and other tissues of this essential mineral. Though rare in occurrence - perhaps only one in 200,000 births - it strikes male infants typically, causing death by age 3. The disease is caused by a defective gene in the X-chromosome.

The placental cells, called "BeWo" cells, "clearly have the gene that is involved in the development of Menkes' disease," said Harris. Researchers now will study what the normal function of the gene is and what happens when it is absent or defective. Harris said an important question is what causes the gene to turn off - causing Menkes' disease - or turn on to enable healthy development in the baby.

The disease is named for John Menkes who first described it at Columbia University in 1962. He called it "kinky hair disease" because the hair of afflicted children takes on a brittle, steel wool-like texture, Harris noted. Ten years after it was described, workers in Australia connected Menkes' disease to improper management of the mineral copper, particularly copper absorption in the intestine and brain.

In 1993, the gene causing the disease was isolated and shown to be a major factor in controlling copper movement and distribution throughout the body. Despite these major advancements, the disease still has no permanent cure and prognosis for recovery is practically non-existent, Harris said.

"A baby boy will sit in his crib all day, not looking at anything in particular. You can put a mobile in front of him and he doesn't notice," said Harris, whose lab is the only one in the world studying the "on-off signals" of the disease's gene. "He doesn't smile. He has low body temperature and sometimes he has convulsions. And, the hair is greyish-red and so brittle that it will break off when touched. These children also usually have very high cheekbones."

Copper, a trace mineral not given much thought by most people, has been called the "Jekyll-Hyde" of the human body. Most diets contain sufficient amounts of copper, found in seafood, liver, beans, nuts, seeds and whole-grained breads. Copper is required to form pigment in the body and support sound bone, connective tissue and brain development.

Copper deficiencies can cause dramatic impacts - especially in the development of unborn children whose mothers' diets are deficient in the element. Usually a person with copper deficiencies, however, can simply alter the diet or take supplements.

But Menkes' disease cannot be treated. That's because normally when people eat, food goes to the intestine where it is digested and passed through the absorbing cells into liver and eventually into the various organs. When the copper in food goes into a cell, a protein in the cell allows the mineral to leave and enter the blood for its passage to the liver and the brain.

In those with Menkes' disease, however, the protein that would normally pass the copper out of the intestine is missing because the gene that would make it is defective, Harris explained. So copper is taken into a cell but can not get out.

"It is like being locked in a room with no key to open the door," he said.

His research looked for the necessary protein in "very young cells, because there is evidence that the disease develops as the embryo develops in the mother's womb.

"The placental 'BeWo' cells exist in both young and adult stages, which allows us to determine how development factors control the express of the Menkes' gene," Harris explained. "Older cells of the placenta form a 'syncytium' or a mass of multi-nucleated cytoplasm without dividing into separate cells."

Younger cells remain in clumps, he said, and for reasons not yet understood, do not express the gene while in this state. That indicated something was happening during development that impacted on the normal expression of the Menkes' gene, Harris said.

"The question now is what is it between the time the 'BeWo'cells exist as clumps until they form syncytia that turns on the gene," he said.

Harris noted that humans have about 32,000 genes, and not all of them are "turned on" at the same time. Finding out what turns Menkes' genes on and off, he said, will require more detective work.

Ultimately, he said, Menkes' disease will most likely be treated with gene therapy - possibly putting a functioning gene into a patient.

"But we're doing the basic research now, and the hurdles that must be overcome for its success," he said. "We can get the engine running but will let the factory build the car," indicating that medical and pharmaceutical companies would be the entities to take his findings further toward treatment.

Texas A&M University

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