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A rare neurodegenerative disorder of the astrocytes comprised of two clinical forms: Alexander disease (AxD) type I and type II manifesting with various degrees of macrocephaly, spasticity, ataxia and seizures and leading to psychomotor regression and death.
ORPHA:58Classification level: Disorder
The prevalence is unknown. One population based study in Japan estimated an annual incidence of 1/ 2.7 million.
The clinical presentation depends on the subtype. Previously, AxD was classified either as infantile, juvenile or adult, based simply on age of onset. The currently used classification system is based on a constellation of clinical and radiologic features and includes AxD type I and AxD type II (see these terms). AxD type I is more likely to be of early onset (mean 1.74 years) and shorter survival (median 14 years) whereas type II exhibits onset throughout the lifespan (mean 21.64 years, but can occur in early childhood) and has longer survival (median 25 years). The two types also differ in their clinical symptoms. AxD type I manifests with symptoms of encephalopathy, epilepsy and failure to thrive and has an infantile presentation, while patients with AxD type II manifest with bulbar, autonomic and motor signs such as dysarthria, dysphonia, dysphagia, ataxia, spastic paraparesis and palatal myoclonus. AxD type II also has a slower progression and cognitive impairment can be completely absent.
In the vast majority (95%) of patients, AxD is caused by gain-of-function de novo mutations in the glial fibrillary acidic protein (GFAP) gene. Several familial cases have also been reported with autosomal dominant transmission. This gene encodes GFAP, the major intermediate filament protein found in astrocytes. The over-expression and accumulation of this mutant protein leads to the formation of astrocytic inclusion bodies (Rosenthal fibers) throughout the central nervous system (CNS). It is currently unknown how Rosenthal fibers are involved in disease pathogenesis.