Archetypal and new families with Alexander disease and novel mutations in GFAP

Albee Messing, Rong Li, Sakkubai Naidu, J. Paul Taylor, Lital Silverman, Daniel Flint, Marjo S. Van Der Knaap, Michael Brenner

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


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. Design: Clinical histories were obtained and DNA was analyzed from blood, cheek epithelial cells, or fixed paraffin-embedded surgical samples. Subjects: Affected and unaffected adult members of 3 families and affected children were included. Main Outcome Measures: 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%.

Original languageEnglish (US)
Pages (from-to)208-214
Number of pages7
JournalArchives of neurology
Issue number2
StatePublished - Feb 2012

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Clinical Neurology


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