UAB (University of Alabama at Birmingham) researchers collaborated on a study that discovered gene mutations responsible for most cases of a rare and usually fatal neurological disorder called Alexander’s disease.

Posted on January 2, 2001 at 2:05 p.m.

BIRMINGHAM, AL — UAB (University of Alabama at Birmingham) researchers collaborated on a study that discovered gene mutations responsible for most cases of a rare and usually fatal neurological disorder called Alexander’s disease. This disease most often occurs in infants under the age of one, but can also attack older children and adults. Only about 100 cases have ever been diagnosed worldwide.

In the January 3 issue of the journal Nature Genetics, the scientists report sequencing the gene for glial fibrillary acidic protein (GFAP) and finding mutations in 9 out of the 10 cases examined. “GFAP is a component of astrocytes, one of the major cell types of the central nervous system,” says Michael Brenner, Ph.D., an associate professor of neurobiology at the University of Alabama at Birmingham (UAB), who performed the sequencing analyses. “This is the first time we have ever been able to link a disorder in astrocyte cells to a specific disease.”

The research team was headed by Albee Messing, Ph.D., professor of pathobiological sciences at the University of Wisconsin-Madison’s School of Veterinary Medicine. Messing and UAB’s Brenner had previously developed a transgenic mouse with a high expression of GFAP to study brain injury response. Unexpectedly, the mice showed traits of Alexander’s disease, which led to the discovery of GFAP’s role in the disease. Brenner says the discovery of the GFAP mutations have led to a genetic test for the disease, but that possible treatments remain many years in the future.

The gene mutations cause production of an abnormal protein, which leads to a buildup of fibers that damage the nervous system, a process known as “protein aggregation.” Protein aggregation is also present in other neurological conditions such as Alzheimer’s and Parkinson’s diseases. Brenner says this first discovery of disease-causing mutations in astrocytes could open the door to a better understanding of the role of protein aggregation in these diseases.

“We don’t know if protein aggregation is a cause of these diseases, or an effect of the disease on the nervous system,” says Brenner. “But we can build off this discovery to take a closer look at this question as well as the function of astrocytes in health and disease. For example, our findings now show that the original defect in Alexander’s disease occurs in astrocytes, but intriguingly, in most cases of this disorder there is severe damage to the myelin sheath that provides a protective insulation for nerves, although the myelin is made by a different kind of cell. This tells us that astrocytes are critical for the proper functioning of other types of brain cells, something we know little about but will now be in a better position to study.”

“I think parents who have had children with Alexander's disease will be relieved by finally knowing its cause,” said Messing. “It’s such a rare disorder that they have felt very isolated, thinking that no one was working to find answers.”

Other collaborators on the research include: Anne B. Johnson at Albert Einstein College of Medicine in New York; Odile Boespflug-Tanguay of the Clermont-Ferrand Medical School in France; Diana Rodriguez of St. Vincent de Paul Hospital in Paris; and James Goldman of Columbia University. The research is supported by the National Institutes of Health.