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

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.

Infantile Onset Alexander Disease with Normal Head Circumference: A Genetically Proven Case Report

“…Rosenthal fibers are protein aggregates containing GFAP, ubiquitin, heat shock protein hsp-27, and B-crystallin [2]. Mutation in the GFAPgene encodes GFAP protein has been proven to cause AD [3,4]. Three forms are recognized according to the age of clinical presentations: infantile, juvenile, and adult.…”

“…ManiSha Goyal 1 , SuMit Mehndiratta 2 , MohaMMed Faruq 3 , ManiSh KuMar dwivedi 4 , SeeMa KaPoor 5 amplified products were subjected for Sanger method of sequencing using ABI-BigDye terminator sequencing chemistry and ABI3130xl capillary sequencer [1]. It revealed a de novo heterozygous mutation c.716G>A of p.Arg239His in the exon 4 of GFAPgene.…”

Ceftriaxone for Alexander’s Disease: A Four-Year Follow-Up

“…Some adverse effects, as the self-limiting myoclonic jerks, indicate that ceftriaxone may lower the epileptogenic threshold. This adverse event needs long-term supervision, and an eventual lowering of ceftriaxone dosages, mainly in the infantile form of AxD, which is frequently characterized by the occurrence of epileptic seizures (Li et al 2005).…”

“…Alexander's disease (AxD) is a rare, usually fatal, primary disorder of astroglial cells in the central nervous system (CNS) related to dominant mutations in the gene encoding the type III intermediate filament protein, glial fibrillary acidic protein (GFAP) (Brenner et al 2001;Mignot et al 2004;Li et al 2005). The prevalent pathophysiological hypothesis regarding AxD is based on the occurrence of a toxic gain-of-function of mutated GFAP, which causes intracytoplasmic aggregates in astrocytes (Rosenthal fibers), containing GFAP, aB-Crystallin, the heat shock protein 27, and ubiquitin (Mignot et al 2004;Li et al 2005), and on the occurrence of excitotoxicity related to impairment of the buffering capacity of dystrophic astrocytes and of their ability to metabolize extracellular glutamate (Mignot et al 2004;Tian et al 2010).…”

“…The prevalent pathophysiological hypothesis regarding AxD is based on the occurrence of a toxic gain-of-function of mutated GFAP, which causes intracytoplasmic aggregates in astrocytes (Rosenthal fibers), containing GFAP, aB-Crystallin, the heat shock protein 27, and ubiquitin (Mignot et al 2004;Li et al 2005), and on the occurrence of excitotoxicity related to impairment of the buffering capacity of dystrophic astrocytes and of their ability to metabolize extracellular glutamate (Mignot et al 2004;Tian et al 2010). Therefore, in AxD, lowering the production of GFAP and promoting its degradation and/or the enhancement of the astroglial glutamate uptake from the extracellular fluid may have potential therapeutic effects.…”