Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease.
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.
Li
Rong
R
Department of Neurobiology and Civitan International Research Center, University of Alabama-Birmingham, Birmingham, AL, USA.
Johnson
Anne B
AB
Salomons
Gajja
G
Goldman
James E
JE
Naidu
Sakkubai
S
Quinlan
Roy
R
Cree
Bruce
B
Ruyle
Stephanie Z
SZ
Banwell
Brenda
B
D'Hooghe
Marc
M
Siebert
Joseph R
JR
Rolf
Cristin M
CM
Cox
Helen
H
Reddy
Alyssa
A
Gutiérrez-Solana
Luis González
LG
Collins
Amanda
A
Weller
Roy O
RO
Messing
Albee
A
van der Knaap
Marjo S
MS
Brenner
Michael
M
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
D005904:Glial Fibrillary Acidic Protein