Gene Tied to Deadly Lung Problem in Newborns

Mutations found in babies with respiratory distress

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HealthDay Reporter

WEDNESDAY, March 24, 2004 (HealthDayNews) -- Scientists have identified genetic mutations that are responsible for an often fatal respiratory condition occurring in newborns.

The condition happens when babies are born without surfactant, a fluid that lets the air sacs of the lungs expand and prevents the organs from collapsing. The mutations, found on the ABCA3 gene, are responsible for the lack of surfactant.

"It's very rare, but it's about the most horrible thing I've heard," says senior study author Michael Dean, chief of the human genetics section at the National Cancer Institute. "The pregnancy goes to term and everything seems normal until the child is born and can't breathe."

The study appears in the March 25 issue of the New England Journal of Medicine, along with another article finding that children with respiratory distress syndrome at birth who received a particular steroid treatment had later developmental problems.

According to an accompanying perspective article, administering surfactant at birth has resulted in a dramatic decrease in mortality. There are still some cases, however, that resist treatment. If scientists knew what caused them, they might know how to prevent or treat them.

To that end, the researchers analyzed blood DNA from 21 racially and ethnically diverse infants with severe respiratory distress, all of whom seemed to have surfactant deficiency. Most of the babies, who were from 14 families, died within a month of being born. Lung tissue was examined by high-resolution light and electron microscopy.

Sixteen of the 21 babies (76 percent) had mutations in the ABCA3 gene. Siblings had the same mutation, and each mutation was found only in one family.

The ABCA3 gene is involved in producing surfactant, but scientists are not sure exactly how it does that.

While children with this condition may one day be candidates for gene therapy, the authors suggest that, in the meantime, families with the mutation may benefit from genetic counseling.

The fact that some babies with surfactant deficiency did not have ABCA3 mutations suggests that other genes are also involved. "It is actually very complicated," Dean says.

The second study, done in Taiwan, concluded that the steroid dexamethasone should not be given to babies to prevent or treat lung disease because it can lead to neuromotor and cognitive problems when the children reach school age.

The researchers, based in Taiwan, looked at 146 children, part of an original group of 262, who had had severe respiratory distress syndrome and who had been randomized within 12 hours after birth to receive either dexamethasone therapy or a placebo.

Although dexamethasone, a steroid, has a long history of use in newborns, there is little data to support this practice. The problem with using many medications in newborns is that they have not been tested in that particular population. "There are virtually no FDA-approved drugs for treating preterm infants," says Dr. Alan H. Jobe, author of an accompanying editorial and a professor of pediatrics at Cincinnati Children's Hospital Medical Center.

In this investigation, the researchers assessed the children's growth, neurologic and motor function, cognition and school performance.

As it turned out, children who had received dexamethasone had poorer motor skills, motor coordination and visual-motor integration. They also had lower IQ scores, verbal IQ scores and performance IQ scores. Thirty-nine percent of children in the dexamethasone group had clinically significant disabilities vs. only 22 percent in the control group. The dexamethasone children were also shorter in stature and had smaller head circumference than the controls.

It is possible that lower doses and shorter durations than were used in this study might be of benefit without the drawbacks, Jobe says, but experts do not know for sure.

"There's a bit of a conundrum," admits Jobe. "The bad outcomes that were compelling demonstrations for this study, one would hope, are not going to be occurring with low-dose, short duration, later treatment."

Jobe argues for a "more careful, more considered approach."

"What we do basically is wait until we see how the disease progresses," he says. "If you just hang with them, a lot of these kids will do OK."

More information

For more on respiratory distress syndrome, visit the American Lung Association or the University of Wisconsin.

SOURCES: Alan H. Jobe, M.D., Ph.D., professor, pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati; Michael Dean, Ph.D., chief, human genetics section, National Cancer Institute, Frederick, Md.; March 25, 2004, New England Journal of Medicine

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