17 Jan 2001

The cause of Alexander's disease, a very rare, inherited CNS disorder, has been traced to the gene for glial fibrillary acidic protein (GFAP), according to a report published in this month's Nature Genetics. The disease results in catastrophic damage throughout the nervous system. Symptoms appear in infancy, and most children with the disease do not survive past age 6. The team that made the discovery, led by Albee Messing at the University of Wisconsin, Madison, carried out a genetic analysis of 13 cases of the disease, and was aided by the earlier discovery that overexpression of GFAP in mouse astrocytes was fatal. The mouse cells contained inclusions indistinguishable from a hallmark of Alexander's disease known as Rosenthal fibers, cytoplasmic inclusions in astrocytes that contain the intermediate filament protein GFAP in association with small heat-shock proteins. Analysis of the GFAP gene in the human patients revealed that most of the patients had mutations in the coding region of the gene. "Alexander disease, therefore, represents the first example of a primary genetic disorder of astrocytes," the authors note. It also adds to a growing body of heritable degenerative brain disorders, including Alzheimer's, Parkinson's, frontal-temporal dementia and Huntington's, characterized by abnormal aggregates of a mutant protein.—Hakon Heimer