Genetic testing of pregnant women with liver illness could save infant lives

June 03, 1999

St. Louis, June 3, 1999 -- In the third trimester of pregnancy, some women are struck suddenly by swelling, severe nausea, vomiting or jaundice -- symptoms of an illness called acute fatty liver of pregnancy (AFLP). These women and their partners sometimes have passed on a genetic mutation that prevents their babies from processing certain fats for energy. In severe cases, the genetic defect can result in a baby's death.

To save lives, researchers at Washington University School of Medicine in St. Louis are recommending that women with AFLP be screened, along with their partners and children, for this mutation, which is called E474Q. They published their study in the June 3 issue of the New England Journal of Medicine.

"The main message here is that families should be tested before the babies are born so that the babies can be appropriately treated and death can be prevented," said Arnold W. Strauss, M.D., professor of pediatrics, who headed the study. "It's also important to test families so they can be appropriately advised about the risk of the mothers having the same sort of liver disease with future pregnancies."

Babies born with this mutation usually get acutely ill when they are a few months old. They suffer from a variety of conditions, ranging from liver failure to heart muscle and skeletal muscle disorders to sudden death. Each baby has a defect in an enzyme called long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD). When faulty, this enzyme can't complete its mission of breaking down fatty acids. Sugars provide fuel for four or five hours following a meal, then the body uses fatty acids as an energy source. For babies with the mutation, this is not possible.

The E474Q mutation is recessive, which means that a baby with the disorder needs to inherit one copy of the defective gene from each parent in order to develop the disease. A mother who carries just one defective copy is healthy until she becomes pregnant with a baby who has inherited the mutated gene from both parents.

AFLP occurs in approximately one in every 14,000 pregnancies. Strauss and colleagues identified the E474Q mutation in 1995. Prior to this discovery, no one knew the cause of liver problems in pregnant women once hepatitis was ruled out.

There were still many unanswered questions about AFLP, however. Mothers whose children carried the E474Q mutation did not always get sick, and the incidence of this mutation in mothers with AFLP remained unknown. These puzzles spurred Strauss and colleagues to study 24 families whose children were known to have an LCHAD deficiency or a deficiency in the large protein complex that contains LCHAD.

Analyzing the gene for the protein subunit where LCHAD is found, the researchers discovered that 19 children who became very ill had a defect in LCHAD. Eight had two doses of E474Q. The remaining 11 children had this mutation on one chromosome and a different mutation in the same gene on the other chromosome. So they were unable to make a functional enzyme. Seventy-nine percent of the mothers developed AFLP or another liver disorder called HELLP -- hemolysis, elevated liver enzymes and low platelets. But five children didn't have the E474Q mutation, and none of their mothers developed liver disease during pregnancy.

One of the families in the study, Jennifer and John Carroll of Prairie-du-Sac, Wis., lost their first child, Sarah, when she was 5 months old. Sarah had developed an ear infection and a week later was diagnosed with the flu. She had a poor appetite and, over a two-week period, developed low blood sugar and lethargy, common symptoms of the deficiency. She died on the way to the emergency room. "The autopsy said she had a fatty liver, but the doctors couldn't tell us what she died of," said Jennifer Carroll.

When Jennifer was almost seven months pregnant with Sarah, she experienced liver problems and was incorrectly diagnosed with hepatitis. She was sent home and later had to be rushed to the hospital for an emergency Cesarean section.

Six months after Sarah died, the Carrolls decided to have another child. Jennifer's doctor told her not to worry about having the same problems during her second pregnancy. But during the sixth month of her second pregnancy, Jennifer began feeling nauseated. She was admitted to the hospital, and doctors found that her liver enzymes again were elevated and her platelets were low. She underwent an emergency Cesarean, and her daughter, Jane, was born almost three months early.

After Jane's birth, a genetic counselor called the Carrolls and asked if they wanted to participate in a study involving LCHAD deficiency. When Strauss tested the Carrolls' blood, he found the defective form of the LCHAD gene in both parents. Jane, now 5, is doing well. She is fed a special formula every three hours to keep her energy up. In April, Jennifer gave birth to another daughter, Megan. Through genetic testing before birth, the Carrolls found out Megan hadn't inherited the mutation.

"It was a huge relief," said John Carroll. "A child with this mutation is a lot of work, with the round-the-clock feedings and watching and worrying about them all the time."

Educating physicians and the public about these findings is important, Strauss believes, because of the potential impact on people's lives. "We now know that if the fetus carries the E474Q mutation, the mother runs the risk of life-threatening liver disease and the baby also can die," Strauss said. "So it's essential to screen pregnant women who develop AFLP and their families for this mutation."
The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC Health System.

Washington University School of Medicine

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