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Alexander Disease

  • GFAP (glial fibrillary acidic protein)
Alexander disease (AD) is a progressive disorder of the white matter of the central nervous system (CNS). The three types of AD are categorized by age of onset: infantile, juvenile, and adult. Affected infants develop a megalencephalic leukodystrophy, seizures, spasticity, ataxia, and psychomotor retardation. Infantile AD frequently leads to death within a decade after the diagnosis. Juvenile and adult forms of AD have a more slowly progressive course and are characterized by ataxia, bulbar signs and spasticity. Rosenthal fibers, observed in the astrocytes of affected individuals upon autopsy, are a hallmark feature of AD. These cytoplasmic inclusions are made up of glial acidic fibrillary protein (GFAP) and small heat-shock proteins. MRI has proven to be a useful tool for diagnosing AD, and often shows high signal intensity of white matter in the frontal area and basal ganglia. Alexander disease is usually sporadic and is most often caused by de novo heterozygous mutations in the GFAP gene.

Using genomic DNA obtained from buccal (cheek) swabs or blood (1-5cc in EDTA), all 9 exons of the GFAP gene are tested using bi-directional sequence analysis. All of the mutations identified in AD have been heterozygous missense mutations that are suspected to cause a gain in GFAP function. Many of these point mutations affect an arginine residue. There are mutation hot spots in exons 1 and 4, although mutations have been identified in other regions of the gene. Mutations found in infantile AD have also been seen in juvenile and adult forms of AD, suggesting that other factors contribute to the expression of the disease. A number of studies have found that 90-95% of individuals diagnosed with Alexander disease have GFAP mutations.

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Alexander Disease, Alexander's Disease, Leukodystrophy, Megalencephaly, Rosenthal fibers

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