Diagnosis of Alexander disease in a Japanese patient by molecular genetic analysis

Abstract

Alexander disease is a leukodystrophy that is neuropathologically characterized by the presence of numerous Rosenthal fibers in astrocytes. Recently, mutations in the gene encoding glial fibrillary acidic protein (GFAP) were identified in patients with Alexander disease. 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. We identified a missense mutation, R239C, which is identical to the mutation previously reported to be most frequent. As was the case in previously described patients, our patient was also heterozygous for the de novo mutation. Interestingly, despite the fact that this is a de novo mutation, R239C was found to be common in different ethnic groups, implying that the site is a "hot spot" for mutagenesis. Molecular genetic analysis now makes the antemortem diagnosis of Alexander disease possible.

Relationship between plasma homocysteine levels and brain atrophy in healthy elderly individuals

“…The first report on GFAP gene mutation associated with Alexander disease included 12 patients-11 with early-onset (infantile form) and one with onset at age 10 (probable juvenile form)-although limited clinical information was provided. 3 Subsequently, reports of 16 patients with early-onset (infantile) Alexander disease 4,6,7 showed the restricted localization of the mutations to exon 1 (coding for 1A rod region) and exon 4 (coding for 2A rod region) with only one in exon 8 (coding for tail region). R79 and R239 were two hot spots each including nine patients (32%) and 11 patients (39%) of the previously reported 28 patients with GFAP gene mutation.…”

“…We examined 36 healthy community volunteer subjects (mean age, 71.6 years; range, 59 -85 years; 18 men and 18 women), with a mean education of 12.0 years and a mean score of 113.1 on the National Adult Reading Test-Revised. 6 The subjects had no history of neurologic or psychiatric disorder. No subject had a history of cerebrovascular disease, but the presence of cardiovascular disease was not exclusionary.…”

Molecular findings in symptomatic and pre-symptomatic Alexander disease patients

“…[6][7][8][9] In a study of 11 autopsy-or biopsy-proven patients with Alexander disease, all but 1 patient were confirmed to harbor heterozygous mutations in the gene for glial fibrillary acidic protein (GFAP) that resulted in single amino acid changes. [6][7][8][9] In a study of 11 autopsy-or biopsy-proven patients with Alexander disease, all but 1 patient were confirmed to harbor heterozygous mutations in the gene for glial fibrillary acidic protein (GFAP) that resulted in single amino acid changes.…”

Alexander-disease mutation ofGFAPcauses filament disorganization and decreased solubility of GFAP

“…Many patients with Alexander disease have been found to have one of a series of mutations in the GFAP gene (Aoki et al, 2001;Brenner et al, 2001;Gorospe et al, 2002;Okamoto et al, 2002;Rodriguez et al, 2001;Sawaishi et al, 2002;Shiihara et al, 2002;Shiroma et al, 2001) (for a review, see Li et al, 2002). The predicted amino acid changes are scattered throughout the protein, but occur principally in the rod domains, which are crucial for polymerization of GFAP into filaments.…”