Opens Way for Diagnostic Tests, Possible Treatment : Nerve Disorder Linked to Genetic Defect

Two independent teams of medical researchers announced Thursday that they have succeeded in mapping the approximate location on human chromosomes of a genetic defect responsible for the most common inherited disease of the nervous system.

The scientists, at Harvard University and Massachusetts General Hospital in Boston and at the University of Utah, said the discovery opens the way for the eventual development of diagnostic tests and possibly for treatment of neurofibromatosis, or NF.

The discovery of a distinctive genetic “flag” on human chromosome No. 17 signifying the presence of NF also marks the latest instance in recent years that advanced techniques for manipulating DNA, the basic material of heredity, have been used to link an inherited disease to a defect on one of the 46 human chromosomes.

Rare Brain Disorder

Others are Huntington’s disease, a relatively rare brain disorder that progressively destroys a patient’s mind and motor control, and a “familial” form of Alzheimer’s disease, which attacks the thinking functions of the brain. Earlier this year, separate groups of researchers reported evidence linking some cases of one of the most common mental afflictions, manic-depressive illness, to a defect on chromosome No. 11.

Neurofibromatosis, also known as Elephant Man’s disease, afflicts about 100,000 people in the United States and an estimated 1 million worldwide. It is characterized by the growth of highly pigmented patches of cafe au lait skin and numerous small tumors that develop under the skin and in the brain and spinal cord. Although usually benign, the tumors, which may number in the thousands, can be gravely disfiguring and often lead to blindness, paralysis or a variety of brain disorders.

“So far there is no diagnostic test, no cure, no clue to a defective protein” that might underlie the disease, Dr. Bernd Seizinger, a member of the Massachusetts team, said in a telephone interview. He said the discovery of a characteristic genetic marker--a deviant gene that is not itself the cause of the disease--should make it possible in a relatively short time to develop a diagnostic test to identify even before birth those who will develop NF.

Important Implications

More important, he said, the marker is known to lie near the still-unidentified gene responsible for the disease. Isolation of a marker gene “dramatically enhances the prospect of finding the (disease) gene itself,” a step that would carry important implications for understanding both the normal and abnormal development of the human nervous system, Seizinger said.

Using a technique known as genetic linkage analysis, involving a painstaking construction of patients’ family trees and a search among them for a persistent, shared defect, researchers focused on a gene that carries the code or instructions for making a protein called nerve growth factor.

It was thought at first that the disease was caused by a defect in the sequence of amino acids that make up the DNA of the nerve growth factor gene, but that turned out not to be the case. But the NF gene was found to contain a distinctively abnormal--but apparently harmless--sequence that always travels from one generation to the next in people who develop the disease. This, Seizinger said, means the disease gene itself must lie nearby on chromosome 17, and that a genetic “flag” has been found that signals its presence.

Preserving Vision

“If you’re aware that someone has this gene, you keep a very close eye on the person, and you can act much earlier to try to preserve vision or nerve functions,” Seizinger said.

Seizinger, an instructor in neurology at Harvard medical school and a geneticist at Massachusetts General Hospital, collaborated with Dr. James F. Gusella, also a geneticist at Massachusetts General. A report of their work is to be published in this week’s issue of the journal Science.

The simultaneous work of Dr. David Barker and Dr. Mark Skolnick, of the human genetics department at the University of Utah medical school in Salt Lake City, is to be published in next Friday’s issue of the journal Cell.

Both teams were supported by the National Neurofibromatosis Foundation Inc. in New York City and by the federal government’s National Institutes of Health.