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GENATLAS PHENOTYPE
last update : 11-03-2020
Symbol ALXD1
Location 17q21.31
Name Alexander disease 1
Corresponding gene GFAP
Main clinical features
  • progressive white-matter degeneration, with astrocytes containing cytoplasmic aggregates, called Rosenthal fibers
  • infantile form : megalencephaly, seizures, progressive dementia, leukoencephalopathy, spastic tetraparesis, bulbar or pseudobulbar palsy, palatal myoclonus symptomatologically, early death ( <10years)
  • juvenile form : ataxia, spasticity, dysphagia and dysphonia, bulbar or pseudobulbar symptoms
  • adult form : bulbar or pseudobulbar symptoms predominate, frequently accompanied by spasticity, ataxia, myoclonia of the soft palate
  • on magnetic resonance imaging, Rosenthal fiber ( abundant presence in astrocytes of protein aggregates) in central nervous system and prominent atrophy of the medulla oblongata and upper spinal cord, abnormal signal in the grey nuclei, and thalamus
  • male predominance for the juvenile form
    • Genetic determination autosomal dominant
    autosomal recessive
    Function/system disorder neurology
    Type disease
    Gene product
    Name glial fibrillary acidic protein (GFAP)
    Mechanism(s)
    Gene mutationChromosome rearrangementEffectComments
    missense   abnormal protein/gain of function mostly affecting arginine residues in the rod domain of the molecule
    missense   abnormal protein/loss of function R416W inducing the formation of GFAP-containing cytoplasmic aggregates including the association of HSPB1 and CRYAB in a wide range of different cell types, including astrocytes, in form adult, juvenile or infantile
    Remark(s)
  • presence of abnormal astrocytes that contain GFAP protein aggregates, termed Rosenthal fibers (RFs), due to mutant GFAP accumulation that stimulates autophagy, in a manner regulated by MAPK14 and FRAP1 signaling pathways ; CRYAB regulates GFAP assembly and could play a critical role in tempering ALXD pathology
  • accumulation of the intermediate filament protein, glial fibrillary acidic protein (GFAP), in astrocytes of Alexander disease (AxD) impairs proteasome function in astrocytes (Tang 2010)
  • most of the disease-causing mutations described to date have been found in the conserved alpha-helical rod domain, some mutations are found in the C-terminal non-alpha-helical tail domain (PMID: 21756903))
  • ALXD1-causing mutations in GFAP disrupt intracellular vesicle regulation and impair astrocyte secretion, resulting in astrocyte dysfunction and ALXD1 pathogenesis (PMID: 30355500))
    • Genotype/Phenotype correlations
  • common R79H mutation in infantile-juvenile form
  • possibility that the C/C genotype at rs2070935 of the GFAP promoter in late-onset ALXD1 was associated with an earlier onset and a more rapid progression of ambulatory disability compared with the other genotypes.(PMID: 23903069))