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

作者：Messing Albee^*; Li Rong; Naidu Sakkubai; Taylor J Paul; Silverman Lital; Flint Daniel; van der Knaap Marjo S; Brenner Michael

来源：Archives of Neurology, 2012, 69(2): 208-214.

DOI：10.1001/archneurol.2011.1181

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. %26lt;br%26gt;Design: Clinical histories were obtained and DNA was analyzed from blood, cheek epithelial cells, or fixed paraffin-embedded surgical samples. %26lt;br%26gt;Subjects: Affected and unaffected adult members of 3 families and affected children were included. %26lt;br%26gt;Main Outcome Measures: Mutations in GFAP and behavior of mutant protein in cellular transfection assays. %26lt;br%26gt;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. %26lt;br%26gt;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%.

• 出版日期2012-2