Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease

Alexander disease is a rare disorder of the central nervous system of unkno wn etiology(1,2). Infants with Alexander disease develop a leukoencephalopa thy with macrocephaly, seizures and psychomotor retardation, leading to dea th usually within the first decade; patients with juvenile or adult forms t ypically experience ataxia, bulbar signs and spasticity, and a more slowly progressive course. The pathological hallmark of all forms of Alexander dis ease is the presence of Rosenthal fibers, cytoplasmic inclusions in astrocy tes that contain the intermediate filament protein GFAP in association with small heat-shock proteins(3,4). We previously found that overexpression of human GFAP in astrocytes of transgenic mice is fatal and accompanied by th e presence of inclusion bodies indistinguishable from human Rosenthal fiber s(5). These results suggested that a primary alteration in GFAP may be resp onsible for Alexander disease. Sequence analysis of DNA samples from patien ts representing different Alexander disease phenotypes revealed that most c ases are associated with non-conservative mutations in the coding region of GFAP. Alexander disease therefore represents the first example of a primar y genetic disorder of astrocytes, one of the major cell types in the verteb rate CNS.