title: GFAP mutations, age at onset, and clinical subtypes in Alexander disease.
abstract: OBJECTIVE
  To characterize Alexander disease (AxD) phenotypes and determine correlations with age at onset (AAO) and genetic mutation. AxD is an astrogliopathy usually characterized on MRI by leukodystrophy and caused by glial fibrillary acidic protein (GFAP) mutations.
  
  
  METHODS
  We present 30 new cases of AxD and reviewed 185 previously reported cases. We conducted Wilcoxon rank sum tests to identify variables scaling with AAO, survival analysis to identify predictors of mortality, and χ(2) tests to assess the effects of common GFAP mutations. Finally, we performed latent class analysis (LCA) to statistically define AxD subtypes.
  
  
  RESULTS
  LCA identified 2 classes of AxD. Type I is characterized by early onset, seizures, macrocephaly, motor delay, encephalopathy, failure to thrive, paroxysmal deterioration, and typical MRI features. Type II is characterized by later onset, autonomic dysfunction, ocular movement abnormalities, bulbar symptoms, and atypical MRI features. Survival analysis predicted a nearly 2-fold increase in mortality among patients with type I AxD relative to those with type II. R79 and R239 GFAP mutations were most common (16.6% and 20.3% of all cases, respectively). These common mutations predicted distinct clinical outcomes, with R239 predicting the most aggressive course.
  
  
  CONCLUSIONS
  AAO and the GFAP mutation site are important clinical predictors in AxD, with clear correlations to defined patterns of phenotypic expression. We propose revised AxD subtypes, type I and type II, based on analysis of statistically defined patient groups.
authors.affiliation: Children's National Medical Center, 111 Michigan Ave. NW, Washington, DC 20010, USA.
authors.forename: M
authors.initials: M
authors.lastname: Prust
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: H
authors.initials: H
authors.lastname: Morizono
authors.forename: A
authors.initials: A
authors.lastname: Messing
authors.forename: M
authors.initials: M
authors.lastname: Brenner
authors.forename: E
authors.initials: E
authors.lastname: Gordon
authors.forename: T
authors.initials: T
authors.lastname: Hartka
authors.forename: A
authors.initials: A
authors.lastname: Sokohl
authors.forename: R
authors.initials: R
authors.lastname: Schiffmann
authors.forename: H
authors.initials: H
authors.lastname: Gordish-Dressman
authors.forename: R
authors.initials: R
authors.lastname: Albin
authors.forename: H
authors.initials: H
authors.lastname: Amartino
authors.forename: K
authors.initials: K
authors.lastname: Brockman
authors.forename: A
authors.initials: A
authors.lastname: Dinopoulos
authors.forename: M T
authors.initials: MT
authors.lastname: Dotti
authors.forename: D
authors.initials: D
authors.lastname: Fain
authors.forename: R
authors.initials: R
authors.lastname: Fernandez
authors.forename: J
authors.initials: J
authors.lastname: Ferreira
authors.forename: J
authors.initials: J
authors.lastname: Fleming
authors.forename: D
authors.initials: D
authors.lastname: Gill
authors.forename: M
authors.initials: M
authors.lastname: Griebel
authors.forename: H
authors.initials: H
authors.lastname: Heilstedt
authors.forename: P
authors.initials: P
authors.lastname: Kaplan
authors.forename: D
authors.initials: D
authors.lastname: Lewis
authors.forename: M
authors.initials: M
authors.lastname: Nakagawa
authors.forename: R
authors.initials: R
authors.lastname: Pedersen
authors.forename: A
authors.initials: A
authors.lastname: Reddy
authors.forename: Y
authors.initials: Y
authors.lastname: Sawaishi
authors.forename: M
authors.initials: M
authors.lastname: Schneider
authors.forename: E
authors.initials: E
authors.lastname: Sherr
authors.forename: Y
authors.initials: Y
authors.lastname: Takiyama
authors.forename: K
authors.initials: K
authors.lastname: Wakabayashi
authors.forename: J R
authors.initials: JR
authors.lastname: Gorospe
authors.forename: A
authors.initials: A
authors.lastname: Vanderver
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D017668:Age of Onset; D038261:Alexander Disease / Q000145:classification* / Q000235:genetics* / Q000401:mortality; D001499:Bayes Theorem; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics*; D006801:Humans; D016015:Logistic Models; D008297:Male; D009154:Mutation / Q000235:genetics*; D012189:Retrospective Studies; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D005904:Glial Fibrillary Acidic Protein