MEDICINE / GAUCHER’S DISEASE : Study Finds a 2nd Genetic Link to Illness
La Jolla scientists have identified the second major genetic defect that causes Gaucher’s disease, a debilitating, inherited disorder that is most common among Jews of European descent.
The discovery makes it possible for the first time to identify carriers of Gaucher’s disease--an estimated one of every 12 Ashkenazic Jews--with full confidence that virtually all affected individuals will be identified. It also makes possible effective prenatal screening.
Researchers at the National Institutes of Health reported in 1988 that they had identified the genetic defect responsible for nearly 75% of the cases of Gaucher’s (pronounced go-SHAYS), which affects as many as 15,000 Americans. Researchers have identified at least 14 other mutations in the same gene, but each of those accounts for only a fraction of a percent of victims.
Hematologist Ernest Beutler and his colleagues at the Scripps Research Institute report today in the Proceedings of the National Academy of Sciences that they have identified another defect, in the same gene, that accounts for most of the remaining 25% of the cases.
Although the discovery makes prenatal testing possible, the decision to abort a fetus with the disorder will be ethically difficult--and most likely controversial--because it is not yet possible to predict the severity of the disorder in a child.
Nonetheless, the discovery is “very significant” even if the parents do not choose an abortion, said family practitioner Dr. Robin Berman, medical director of the National Gaucher Foundation. “We can detect people who will be affected at a much earlier stage and allow them to get treatment before they have any bad symptoms of the disorder. That’s extremely valuable.”
Gaucher’s is characterized by a severely enlarged liver or spleen, anemia, bleeding, significant bone and joint pain, fatigue, and orthopedic complications, such as repeated fractures and bone erosion.
Its severity varies widely. In some people, it is very mild and causes few problems. In the most severe form, the affected individual typically dies in the womb or in the first year of life. Typically, the later in life the disorder strikes, the less severe it is.
The disorder is caused by abnormalities in an enzyme, called glucocerebrosidase, that normally degrades a fatty compound called glucocerebroside. Because it is not destroyed, the fatty compound accumulates in the liver, bone marrow and spleen, where it is toxic.
Gaucher’s afflicts both men and women and occurs in all racial and ethnic groups, but about two-thirds of American victims are Jews of European descent. In that ethnic group, about one child in 500 now develops the disorder.
The first successful therapy for Gaucher’s was approved by the U.S. Food and Drug Administration in April of this year. The treatment is based on a form of the enzyme isolated from placental tissue, but it must be chemically modified before use so that it reaches the affected tissues intact.
Treatment with the modified enzyme, called Ceredase and manufactured by Genzyme Corp. of Cambridge, Mass., is highly effective, but it is also quite expensive. Isolating enough of the chemical to bring one patient under control requires more than a ton of placental tissue, and the resultant drug can cost as much as $500,000. Some insurance companies have started paying for the therapy since the FDA approved Ceredase, but many still do not, Berman said.
Once the disorder is under control, however, the patient requires much smaller quantities of the drug, and the yearly cost drops to between $30,000 and $50,000. Early treatment reduces the initial amount of the drug necessary to bring the disorder under control--and thus the cost of treatment--and may reduce the complications associated with the disorder.
Genzyme is now close to manufacturing the enzyme through genetic engineering technology, and researchers hope that feat will bring a sharp drop in prices. Further in the future, researchers hope to use gene therapy to provide a cure for the disorder by inserting a healthy gene into the patient so his or her body produces the needed enzyme. Most researchers agree that this will not happen for another 10 years.
Beutler said in a telephone interview that identification of the new gene will enable physicians to offer premarital screening and genetic counseling for young Jews in particular. This testing would indicate the likelihood that a couple would conceive a Gaucher’s child. Such counseling is already widely used for Tay-Sachs disease, another genetic disorder that is most common among Ashkenazic Jews.
It is now also possible to perform prenatal screening for Gaucher’s once a woman is pregnant, he said, but the ethics of doing so are much more complicated. Tay-Sachs disease is uniformly fatal, and most couples who learn they have a fetus with the disorder choose to have an abortion.
In sharp contrast, Gaucher’s has a very broad range of severity and the genetic testing is not yet able to tell how severely a child will be affected. “No physician, armed with this information (from genetic testing), would recommend an abortion,” said Berman, who has three children with Gaucher’s.
