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Gene for Fatal Childhood Disorder Found

After decades of work, scientists at NIH have identified a gene alteration associated with the fatal childhood cholesterol disorder Niemann-Pick type C (NPC). Learning how the gene functions may lead to the first effective treatment for the disease and to a fundamental new understanding of how cholesterol is processed in the body.

The gene, known as NPC1, is located on human chromosome 18. NPC causes progressive deterioration of the nervous system by blocking the movement of cholesterol within cells. The finding opens the door to improved diagnosis and understanding of this neurological disorder, which is usually fatal by age 25, and to the design of therapies that may correct the underlying problem. The finding also may contribute to the understanding of atherosclerosis, a more common killer associated with cholesterol buildup. Atherosclerosis is an accumulation of fatty tissue inside arteries that blocks blood flow, leading to heart disease and stroke.

"This discovery is an excellent example of how research on rare brain disorders often pays off in other ways," said Dr. Zach W. Hall, NINDS director. "By identifying this gene, we not only take a crucial step forward in understanding this devastating disorder, but also gain insights into problems that affect every one of us."

The NPC1 finding is the first step toward developing a cure for NPC. "This gene reveals a new way that cells handle cholesterol," noted Dr. Peter G. Pentchev of NINDS. "It provides a fundamental understanding of a previously undefined pathway of cholesterol metabolism. Like motor mechanics, we have to know what's wrong before we can fix it." Pentchev and his colleagues at NINDS have studied NPC for almost 20 years. Other key members of the team that identified the human gene include Drs. Eugene D. Carstea, formerly of NINDS, Jill A. Morris of NINDS, and Danilo A. Tagle and Melissa A. Rosenfeld of the National Human Genome Research Institute.

Collaborating scientists, led by NHGRI's Dr. William J. Pavan, identified the same gene in a mouse model for NPC. The human and mouse gene findings appear in back-to-back reports in the July 1 issue of Science.

NPC develops when a person receives two altered copies of the gene -- one from each parent. Carriers of the disease, who possess a single copy of the altered gene, sometimes develop subtle abnormalities in cholesterol metabolism. However, they remain healthy, and most do not know they are carriers until they have an affected child. NPC often appears at random in families with no history of the disorder, and it occurs in individuals from many ethnic groups.

Calcium Doesn't Stop Preeclampsia

Contrary to prevailing medical opinion, taking high doses of calcium during pregnancy does not prevent preeclampsia in women who do not have any risk factors for the disease, according to the largest, most comprehensive clinical trial of its kind to date.

Preeclampsia is a disorder of pregnancy that can strike without warning, causing protein in the urine and high blood pressure. In turn, preeclampsia may progress to eclampsia -- hypertension and generalized convulsions -- which may be fatal.

The trial, reported in the July 10 New England Journal of Medicine, was conducted by researchers at the National Institute of Child Health and Human Development and several other academic and research institutions. Funding was provided by NICHD and by the National Heart, Lung, and Blood Institute.

"Clearly, women need some calcium during pregnancy," said the study's principal investigator, Dr. Richard J. Levine of the Division of Epidemiology, Statistics, and Prevention Research, NICHD. "But in light of the results of our study, the high doses of calcium thought to prevent preeclampsia at best provide no apparent benefit, and at worst, could cause complications in certain high-risk women."

Preeclampsia is a potentially life-threatening complication of pregnancy in which a woman may develop dangerously high blood pressure and begin excreting protein in the urine. About 5 percent of first-time mothers and 1 to 2 percent of mothers having subsequent pregnancies develop the condition. The authors note that preeclampsia is a leading cause of maternal death. Even in cases where the condition does not progress to eclampsia, the children born to mothers with preeclampsia may be small for their gestational age or may be born prematurely. This may, in turn, place them at risk for a variety of other complications of birth.

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