TY - JOUR
T1 - Archetypal and new families with Alexander disease and novel mutations in GFAP
AU - Messing, Albee
AU - Li, Rong
AU - Naidu, Sakkubai
AU - Taylor, J. Paul
AU - Silverman, Lital
AU - Flint, Daniel
AU - Van Der Knaap, Marjo S.
AU - Brenner, Michael
PY - 2012/2
Y1 - 2012/2
N2 - 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%.
AB - 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%.
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U2 - 10.1001/archneurol.2011.1181
DO - 10.1001/archneurol.2011.1181
M3 - Article
C2 - 21987397
AN - SCOPUS:84863393001
SN - 0003-9942
VL - 69
SP - 208
EP - 214
JO - Archives of neurology
JF - Archives of neurology
IS - 2
ER -