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

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

Research output: Contribution to journalArticlepeer-review

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 farther 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.

Original languageEnglish (US)
Pages (from-to)310-326
Number of pages17
JournalAnnals of neurology
Volume57
Issue number3
DOIs
StatePublished - Mar 2005

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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