title: Archetypal and new families with Alexander disease and novel mutations in GFAP.
abstract: OBJECTIVE
  To describe genetic analyses of the 2 most thoroughly studied, historically seminal multigenerational families with Alexander disease described prior to the identification of GFAP as the related gene, as well as 1 newly discovered family.
  
  
  METHODS
  Clinical histories were obtained and DNA was analyzed from blood, cheek epithelial cells, or fixed paraffin-embedded surgical samples.
  
  
  METHODS
  Affected and unaffected adult members of 3 families and affected children were included.
  
  
  METHODS
  Mutations in GFAP and behavior of mutant protein in cellular transfection assays.
  
  
  RESULTS
  Family A contains 4 siblings in whom we found a novel p.Ser247Pro mutation that was paternally inherited. The phenotypes of these siblings include 1 unaffected adult, 1 individual with juvenile-onset disease, and 2 individuals with adult-onset disease. Family B spans 4 generations, including the first described patient with adult-onset disease originally reported in 1968. Analysis of members of the later generations revealed a novel p.Asp417Ala mutation. Family C contains 3 generations. We detected a novel p.Gln426Leu mutation that, to our knowledge, is the farthest C-terminal mutation known.
  
  
  CONCLUSIONS
  These families display clear evidence of variable phenotypes but do not support recessive inheritance. While germline mosaicism cannot be excluded for 1 family (A), we propose that for genetic counseling purposes the risk of germline mosaicism should be described as less than 1%.
authors: Waisman Center, Department of Comparative Biosciences, University of Wisconsin-Madison, 1500 Highland Ave, Madison, WI 53705, USA. messing@waisman.wisc.edu
authors: Albee
authors: A
authors: Messing
authors: Rong
authors: R
authors: Li
authors: Sakkubai
authors: S
authors: Naidu
authors: J Paul
authors: JP
authors: Taylor
authors: Lital
authors: L
authors: Silverman
authors: Daniel
authors: D
authors: Flint
authors: Marjo S
authors: MS
authors: van der Knaap
authors: Michael
authors: M
authors: Brenner
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D038261:Alexander Disease / Q000235:genetics*; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D020233:Gait Disorders, Neurologic / Q000209:etiology; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D048631:Micronucleus, Germline; D008875:Middle Aged; D018908:Muscle Weakness / Q000209:etiology; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D055815:Young Adult
chemical_list: D005904:Glial Fibrillary Acidic Protein; D004247:DNA