title: Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease.
abstract: Alexander disease is a progressive, usually fatal neurological disorder defined by the widespread and abundant presence in astrocytes of protein aggregates called Rosenthal fibers. The disease most often occurs in infants younger than 2 years and has been labeled a leukodystrophy because of an accompanying severe myelin deficit in the frontal lobes. Later onset forms have also been recognized based on the presence of abundant Rosenthal fibers. In these cases, clinical signs and pathology can be quite different from the infantile form, raising the question whether they share the same underlying cause. Recently, we and others have found pathogenic, de novo missense mutations in the glial fibrillary acidic protein gene in most infantile patients examined and in a few later onset patients. To obtain further information about the role of glial fibrillary acidic protein mutations in Alexander disease, we analyzed 41 new patients and another 3 previously described clinically, including 18 later onset patients. Our results show that dominant missense glial fibrillary acidic protein mutations account for nearly all forms of this disorder. They also significantly expand the catalog of responsible mutations, verify the value of magnetic resonance imaging diagnosis, indicate an unexpected male predominance for the juvenile form, and provide insights into phenotype-genotype relations.
authors.affiliation: Department of Neurobiology and Civitan International Research Center, University of Alabama-Birmingham, Birmingham, AL, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.forename: Anne B
authors.initials: AB
authors.lastname: Johnson
authors.forename: Gajja
authors.initials: G
authors.lastname: Salomons
authors.forename: James E
authors.initials: JE
authors.lastname: Goldman
authors.forename: Sakkubai
authors.initials: S
authors.lastname: Naidu
authors.forename: Roy
authors.initials: R
authors.lastname: Quinlan
authors.forename: Bruce
authors.initials: B
authors.lastname: Cree
authors.forename: Stephanie Z
authors.initials: SZ
authors.lastname: Ruyle
authors.forename: Brenda
authors.initials: B
authors.lastname: Banwell
authors.forename: Marc
authors.initials: M
authors.lastname: D'Hooghe
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Siebert
authors.forename: Cristin M
authors.initials: CM
authors.lastname: Rolf
authors.forename: Helen
authors.initials: H
authors.lastname: Cox
authors.forename: Alyssa
authors.initials: A
authors.lastname: Reddy
authors.forename: Luis González
authors.initials: LG
authors.lastname: Gutiérrez-Solana
authors.forename: Amanda
authors.initials: A
authors.lastname: Collins
authors.forename: Roy O
authors.initials: RO
authors.lastname: Weller
authors.forename: Albee
authors.initials: A
authors.lastname: Messing
authors.forename: Marjo S
authors.initials: MS
authors.lastname: van der Knaap
authors.forename: Michael
authors.initials: M
authors.lastname: Brenner
mesh_terms: D000293:Adolescent; D018268:Adrenocortical Carcinoma; D000328:Adult; D000367:Age Factors; D017668:Age of Onset; D038261:Alexander Disease / Q000145:classification / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D016296:Mutagenesis / Q000502:physiology; D020125:Mutation, Missense; D014162:Transfection / Q000379:methods
chemical_list: D005904:Glial Fibrillary Acidic Protein