This report describes Alexander disease (ALXDRD); Alexander disease exhibits autosomal dominant inheritance. The human gene implicated in this disease is GFAP, which encodes glial fibrillary acidic protein, an intermediate filament protein. No fly ortholog of GFAP has been identified.
Multiple UAS constructs of the human Hsap\GFAP gene have been introduced into flies, including wild-type GFAP and genes carrying mutational lesions implicated in Alexander disease. Pathogenic variants expressed in fly glial cells result in protein aggregation (producing inclusions similar to Rosenthal fibers) and oxidative stress, which contribute to activation of an autophagic response in the cells.
Variant(s) implicated in human disease tested (as transgenic human gene, GFAP): the R79H, R239H, R239C, L352P, and A364P variant forms of the human gene have been introduced into flies.
[updated Aug. 2019 by FlyBase; FBrf0222196]
[ALEXANDER DISEASE; ALXDRD](https://omim.org/entry/203450)
[GLIAL FIBRILLARY ACIDIC PROTEIN; GFAP](https://omim.org/entry/137780)
Alexander disease is a progressive disorder of cerebral white matter that predominantly affects infants and children and has variable life expectancy. The later-onset forms present with a slower clinical course. The infantile form comprises about 42% of affected individuals, the juvenile form about 22%, and the adult form about 33%. A neonatal form is also recognized. The neonatal form leads to severe disability or death within two years. Characteristics include seizures, hydrocephalus, severe motor and intellectual disability, and elevated CSF protein concentration. MRI shows severe white matter abnormalities with involvement of the basal ganglia and cerebellum. The infantile form presents in the first two years of life, typically with progressive psychomotor retardation with loss of developmental milestones, megalencephaly, frontal bossing, and seizures. Other findings include hyperreflexia and pyramidal signs, ataxia, and occasional hydrocephalus secondary to aqueductal stenosis. Affected children survive weeks to several years. The juvenile form usually presents between ages four and ten years, occasionally in the mid-teens. Findings can include bulbar/pseudobulbar signs, ataxia, gradual loss of intellectual function, seizures, normocephaly or megalencephaly, and breathing problems. Survival ranges from the early teens to the 20s-30s. The adult form is the most variable. [from GeneReviews, Alexander Disease, pubmed:20301351 2015.12.18]
In decreasing order of frequency, 3 forms of Alexander disease are recognized, based on age of onset: infantile, juvenile, and adult. Younger patients typically present with seizures, megalencephaly, developmental delay, and spasticity. In older patients, bulbar or pseudobulbar symptoms predominate, frequently accompanied by spasticity. The disease is progressive, with most patients dying within 10 years of onset. Imaging studies of the brain typically show cerebral white matter abnormalities, preferentially affecting the frontal region (Gorospe et al., 2002, pubmed:12034785). All 3 forms have been shown to be caused by mutations in the GFAP gene. [From MIM:203450, 2015.12.18]
Alexander disease (ALXDRD) is caused by heterozygous mutation in the gene encoding glial fibrillary acidic protein (GFAP). [From MIM:203450, 2015.12.18]
The pathologic hallmark of all forms of Alexander disease is the presence of Rosenthal fibers, cytoplasmic inclusions in astrocytes that contain the intermediate filament protein GFAP in association with small heat-shock proteins. Sequence analysis of DNA from patients representing different Alexander disease phenotypes showed that most cases were associated with nonconservative mutations in the coding region of the GFAP gene. Alexander disease, therefore, represents the first example of a primary genetic disorder of astrocytes, one of the major cell types in the vertebrate CNS (Brenner et al., 2001, pubmed:11139011). [From MIM:137780, 2015.12.18]
Glial fibrillary acidic protein is an intermediate-filament (IF) protein that is highly specific for cells of astroglial lineage. The predicted amino acid sequence indicated that GFAP shares structural similarities--particularly in the central rod domain and to a lesser degree in the carboxyl-terminal domain--with other IF proteins found in nonepithelial cell types. Considerable sequence divergence in the amino-terminal region of GFAP suggested that the tissue-specific functions of this IF protein may be mediated through this region of the molecule. GFAP is a useful marker of astroglia in the brain (Reeves et al., 1989, pubmed:2740350). A splice variant of GFAP, GFAP-epsilon contains 42 amino acids encoded by exon 7a at its C terminus in place of the 43-amino acid C terminus encoded by exons 8 and 9 of GFAP-alpha, the originally identified GFAP transcript (Nielsen et al., 2002, pubmed:12058025). [From MIM:137780, 2015.12.18]
No gene orthologous to human GFAP in Drosophila (DIOPT).
