Infantile Alexander disease: Spectrum of GFAP mutations and genotype-phenotype correlation

Heterozygous, de novo mutations in the glial fibrillary acidic protein (GFA P) gene have recently been reported in 12 patients affected by neuropatholo gically proved Alexander disease. We searched for GFAP mutations in a serie s of patients who had heterogeneous clinical symptoms but were candidates f or Alexander disease on the basis of suggestive neuroimaging abnormalities. Missense, heterozygous, de novo GFAP mutations were found in exons 1 or 4 for 14 of the 15 patients analyzed, including patients without macrocephaly . Nine patients carried arginine mutations (four had R79H; four had R239C; and one had R239H) that have been described elsewhere, whereas the other fi ve had one of four novel mutations, of which two affect arginine (2R88C and 1R88S) and two affect nonarginine residues (1L76F and 1N77Y). All mutation s were located in the rod domain of GFAP, and there is a correlation betwee n clinical severity and the affected amino acid. These results confirm that GFAP mutations are a reliable molecular marker for the diagnosis of infant ile Alexander disease, and they also form a basis for the recommendation of GFAP analysis for prenatal diagnosis to detect potential cases of germinal mosaicism.