This is the first report of a novel deletion mutation in the glial fibrillary acidic protein gene with a frame shift associated with Alexander disease.
Functional studies on this complex allele revealed less severe aggregation patterns compared to those observed with p.R239C GFAP mutant, associated with a severe Alexander disease phenotype.
Pathogenic, dominant, de novo missense mutations in the glial fibrillary acidic protein (GFAP) have been found in the three subtypes of infantile, juvenile and adult Alexander disease.
These findings suggest that the functional abnormalities of astrocytes might be induced prior to aggregation of GFAP in Alexander disease and that the functional alteration depends on the location of the domain.
In a 6-year-old patient with a relatively mild form of Alexander disease, we detected a common R79H mutation in GFAP, previously only described in the infantile form.
Heterozygous, missense GFAP mutations that usually arise spontaneously during spermatogenesis have recently been found in the majority of patients with Alexander disease.
Assay of CSF-GFAP may prove to be a rapid and cost-effective screening test in clinical variants of Alexander disease and an indicator of GFAP gene mutations.
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.
This mtDNA polymorphism, which has been associated with limb-girdle type mitochondrial myopathy, may modify the clinical symptoms of this juvenile form of Alexander disease with GFAP mutation.
This is the first report of identification of the causative mutation of the GFAP gene for neuropathologically proven hereditary adult-onset Alexander's disease, suggesting a common molecular mechanism underlies the three Alexander's disease subtypes.
These results confirm that GFAP mutations are a reliable molecular marker for the diagnosis of infantile Alexander disease, and they also form a basis for the recommendation of GFAP analysis for prenatal diagnosis to detect potential cases of germinal mosaicism.
We sequenced the GFAP gene of a Japanese girl who presented with typical symptoms of Alexander disease but in whom the diagnosis was not proven by histopathology.