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Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease

Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease
Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease
Alexander disease is a progressive, usually fatal neurological disorder defined by the widespread and abundant presence in astrocytes of protein aggregates called Rosenthal fibers. The disease most often occurs in infants younger than 2 years and has been labeled a leukodystrophy because of an accompanying severe myelin deficit in the frontal lobes. Later onset forms have also been recognized based on the presence of abundant Rosenthal fibers. In these cases, clinical signs and pathology can be quite different from the infantile form, raising the question whether they share the same underlying cause. Recently, we and others have found pathogenic, de novo missense mutations in the glial fibrillary acidic protein gene in most infantile patients examined and in a few later onset patients. To obtain further information about the role of glial fibrillary acidic protein mutations in Alexander disease, we analyzed 41 new patients and another 3 previously described clinically, including 18 later onset patients. Our results show that dominant missense glial fibrillary acidic protein mutations account for nearly all forms of this disorder. They also significantly expand the catalog of responsible mutations, verify the value of magnetic resonance imaging diagnosis, indicate an unexpected male predominance for the juvenile form, and provide insights into phenotype-genotype relations.
0364-5134
310-326
Li, Rong
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Johnson, Anne B.
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Salomons, Gajja
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Goldman, James E.
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Naidu, Sakkubai
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Quinlan, Roy
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Cree, Bruce
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Ruyle, Stephanie Z.
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Banwell, Brenda
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D'Hooghe, Marc
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Siebert, Joseph R.
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Rolf, Cristin M.
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Cox, Helen
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Reddy, Alyssa
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Gutierrez-Solana, Luis Gonzalez
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Collins, Amanda
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Weller, Roy O.
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Messing, Albee
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van der Knaap, Marjo S.
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Brenner, Michael
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Li, Rong
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Johnson, Anne B.
98693c35-071a-45ca-881d-9e7fa11be431
Salomons, Gajja
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Goldman, James E.
f1e8516d-7789-4bfa-baba-bb8752f129b3
Naidu, Sakkubai
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Quinlan, Roy
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Cree, Bruce
fa55c77e-f5c2-4d7d-9a5e-62da79f3d32b
Ruyle, Stephanie Z.
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Banwell, Brenda
d578436f-5f2a-4f53-b4ca-79f11f56b45d
D'Hooghe, Marc
fae7f28c-e437-40f9-aba7-c29f1308e80d
Siebert, Joseph R.
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Rolf, Cristin M.
21e84553-d715-4734-80be-71eafc1c2768
Cox, Helen
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Reddy, Alyssa
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Gutierrez-Solana, Luis Gonzalez
922d7fc4-4285-45ed-adf0-df3bb2778d81
Collins, Amanda
c314bd0c-2043-471a-8db2-7b7a1a008ce0
Weller, Roy O.
4a501831-e38a-4d39-a125-d7141d6c667b
Messing, Albee
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van der Knaap, Marjo S.
b46a8973-a464-464c-a35d-5e0c600749c3
Brenner, Michael
cb1f55d6-6aba-435d-9d76-77f76db33906

Li, Rong, Johnson, Anne B., Salomons, Gajja, Goldman, James E., Naidu, Sakkubai, Quinlan, Roy, Cree, Bruce, Ruyle, Stephanie Z., Banwell, Brenda, D'Hooghe, Marc, Siebert, Joseph R., Rolf, Cristin M., Cox, Helen, Reddy, Alyssa, Gutierrez-Solana, Luis Gonzalez, Collins, Amanda, Weller, Roy O., Messing, Albee, van der Knaap, Marjo S. and Brenner, Michael (2005) Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease. Annals of Neurology, 57 (3), 310-326. (doi:10.1002/ana.20406).

Record type: Article

Abstract

Alexander disease is a progressive, usually fatal neurological disorder defined by the widespread and abundant presence in astrocytes of protein aggregates called Rosenthal fibers. The disease most often occurs in infants younger than 2 years and has been labeled a leukodystrophy because of an accompanying severe myelin deficit in the frontal lobes. Later onset forms have also been recognized based on the presence of abundant Rosenthal fibers. In these cases, clinical signs and pathology can be quite different from the infantile form, raising the question whether they share the same underlying cause. Recently, we and others have found pathogenic, de novo missense mutations in the glial fibrillary acidic protein gene in most infantile patients examined and in a few later onset patients. To obtain further information about the role of glial fibrillary acidic protein mutations in Alexander disease, we analyzed 41 new patients and another 3 previously described clinically, including 18 later onset patients. Our results show that dominant missense glial fibrillary acidic protein mutations account for nearly all forms of this disorder. They also significantly expand the catalog of responsible mutations, verify the value of magnetic resonance imaging diagnosis, indicate an unexpected male predominance for the juvenile form, and provide insights into phenotype-genotype relations.

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Published date: March 2005

Identifiers

Local EPrints ID: 27639
URI: http://eprints.soton.ac.uk/id/eprint/27639
ISSN: 0364-5134
PURE UUID: ccd7526d-d8f1-4386-a23c-13e060222e6d

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Date deposited: 25 Apr 2006
Last modified: 15 Mar 2024 07:20

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Contributors

Author: Rong Li
Author: Anne B. Johnson
Author: Gajja Salomons
Author: James E. Goldman
Author: Sakkubai Naidu
Author: Roy Quinlan
Author: Bruce Cree
Author: Stephanie Z. Ruyle
Author: Brenda Banwell
Author: Marc D'Hooghe
Author: Joseph R. Siebert
Author: Cristin M. Rolf
Author: Helen Cox
Author: Alyssa Reddy
Author: Luis Gonzalez Gutierrez-Solana
Author: Amanda Collins
Author: Roy O. Weller
Author: Albee Messing
Author: Marjo S. van der Knaap
Author: Michael Brenner

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