title: Molecular findings in symptomatic and pre-symptomatic Alexander disease patients.
abstract: OBJECTIVE
  Alexander disease is a slowly progressive CNS disorder that most commonly occurs in children. Until recently, the diagnosis could only be established by the histologic finding of Rosenthal fibers in brain specimens. Mutations in the glial fibrillary acidic protein (GFAP) gene have now been shown in a number of biopsy- or autopsy-proven patients with Alexander disease. A prospective study on patients suspected to have Alexander disease was conducted to determine the extent to which clinical and MRI criteria could accurately diagnose affected individuals, using GFAP gene sequencing as the confirmatory assay.
  
  
  METHODS
  Patients who showed MRI white matter abnormalities consistent with Alexander disease, unremarkable family history, normal karyotype, and normal metabolic screening were included in this study. Genomic DNA from patients was screened for mutations in the entire coding region, including the exon-intron boundaries, of the GFAP gene.
  
  
  RESULTS
  Twelve of 13 patients (approximately 90%) were found to have mutations in GFAP. Seven of those 12 patients presented in infancy with seizures and megalencephaly. Five were juvenile-onset patients with more variable symptoms. Two patients in the latter group were asymptomatic or minimally affected at the time of their initial MRI scan. The mutations were distributed throughout the gene, and all involved sporadic single amino acid heterozygous changes that changed the charge of the mutant protein. Four of the nine changes were novel mutations.
  
  
  CONCLUSIONS
  In symptomatic and asymptomatic patients with a predominantly frontal leukoencephalopathy by MRI, GFAP gene mutation analysis should be included in the initial diagnostic evaluation process for Alexander disease.
authors.affiliation: Research Center for Genetic Medicine, Children's National Medical Center, Washington DC 20010, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Gorospe
authors.forename: S
authors.initials: S
authors.lastname: Naidu
authors.forename: A B
authors.initials: AB
authors.lastname: Johnson
authors.forename: V
authors.initials: V
authors.lastname: Puri
authors.forename: G V
authors.initials: GV
authors.lastname: Raymond
authors.forename: S D
authors.initials: SD
authors.lastname: Jenkins
authors.forename: R C
authors.initials: RC
authors.lastname: Pedersen
authors.forename: D
authors.initials: D
authors.lastname: Lewis
authors.forename: P
authors.initials: P
authors.lastname: Knowles
authors.forename: R
authors.initials: R
authors.lastname: Fernandez
authors.forename: D
authors.initials: D
authors.lastname: De Vivo
authors.forename: M S
authors.initials: MS
authors.lastname: van der Knaap
authors.forename: A
authors.initials: A
authors.lastname: Messing
authors.forename: M
authors.initials: M
authors.lastname: Brenner
authors.forename: E P
authors.initials: EP
authors.lastname: Hoffman
mesh_terms: D000293:Adolescent; D001921:Brain / Q000473:pathology; D002493:Central Nervous System Diseases / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics; D011446:Prospective Studies
chemical_list: D005904:Glial Fibrillary Acidic Protein