Studies Shed Light on Multiple Miscarriages of Boys,
& Girls With Duchenne Muscular Dystrophy

Girls with the Duchenne form of muscular dystrophy (DMD) and boys who perish during fetal life can sometimes be conceived by the same parents. Now, geneticist Eric Hoffman, a longtime research grantee of the Muscular Dystrophy Association, says the two problems can be related and aren't just coincidental.

Studies being conducted by Hoffman, who is at the Center for Genetic Medicine at Children's Hospital National Medical Center in Washington, with colleagues at Magee Women's Hospital in Pittsburgh, have revealed part of the solution to this rare but troubling genetic puzzle.

The clue lies among parents who pass on to their children an unfortunate combination of two genetic problems at the same time, Hoffman says. One is a mutation in the gene for DMD on an X chromosome, and the other is a second genetic mutation, one of a class of "X-linked lethal" genetic mutations, on another X chromosome.

The "X-linked lethal" mutation, when inherited by a boy, causes him to die as a fetus and the mother to miscarry. In fact, Hoffman notes, it's the first major genetic cause that's been found to underlie "unexplained multiple miscarriages" in the population in general, probably accounting for some 15 percent of cases of unexplained multiple miscarriages. These findings are published in the September 2001 issue of the American Journal of Obstetrics and Gynecology.

Here's what happens:

Boys, who normally have only one X chromosome, die before birth if they inherit the lethal defect.

Girls, who normally have two X chromosomes, don't die from inheriting the defect. In fact, they may not even know they have it as long as their second X chromosome is free of disease-causing genetic flaws.

However, if they also inherit a nonlethal, X-linked disorder, such as Duchenne muscular dystrophy, they'll develop that disorder. Usually, a girl would only become a "carrier" of an X-linked disorder and not show the disease herself. She would normally be protected by her second X.

The X-linked lethal defect causes female fetuses to rely solely on their other X chromosome — even if it's one that carries a disease-causing mutation, such as the one for DMD.

There are other circumstances in which the protection of a "backup" X chromosome is wholly or partially lost, leading to symptoms of DMD in girls. For more on this subject, see www.mda.org/publications/Quest/q56girlsdmd.html.

Parents with a history of miscarriage of male fetuses who have also had a girl with DMD or another X-linked disorder, such as X-linked hemophilia, may wish to have themselves tested for the presence of this X-linked lethal defect and to undergo genetic counseling in interpreting the results of the test.

Hoffman's laboratory can perform genetic testing for the defect using a blood sample. For now, the test is free as part of a government-funded research study.

For further information, contact Cheryl Scacheri at (202) 884-6013 or cscacheri@cnmcresearch.org, or visit www.cnmcresearch.org/xcis. Other labs perform the test for a fee, Hoffman says.