Archetypal and New Families With Alexander Disease and Novel Mutations in GFAP

A. Messing, R. Li, S. Naidu, J.P. Taylor, L. Silverman, D. Flint, M.S. van der Knaap, M. Brenner

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23 Citations (Scopus)


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. Clinical histories were obtained and DNA was analyzed from blood, cheek epithelial cells, or fixed paraffin-embedded surgical samples. Affected and unaffected adult members of 3 families and affected children were included. Mutations in GFAP and behavior of mutant protein in cellular transfection assays. 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. 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%
Original languageEnglish
Pages (from-to)208-214
JournalArchives of neurology
Issue number2
Publication statusPublished - 2012

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