Effects of a polymorphism in the GFAP promoter on the age of onset and ambulatory disability in late-onset Alexander disease

Alexander disease (AxD) is a rare neurodegenerative disorder. Most patients with AxD have a de novo dominant missense mutation in the glial fibrillary acidic protein (GFAP) gene. Patients with late-onset AxD exhibit a more variable onset and severity than patients with early-onset AxD, suggesting the existence of factors that modify the clinical phenotype of late-onset AxD. A −250-bp C/A single-nucleotide polymorphism (SNP) of the GFAP promoter (rs2070935) in the activator protein-1 binding site is a candidate factor for modification of the clinical phenotype. We analyzed the SNP in 10 patients with late-onset AxD and evaluated the effects of the SNP on the clinical course of late-onset AxD. Three of four cases with the C/C genotype lost the ability to walk in their 30s or 40s, whereas all six cases with the other genotypes retained the ability to walk throughout their 30s. The age of onset in patients with the C/C genotype was significantly earlier than in patients with the other genotypes (P<0.05). A more severe phenotype was observed in the patient in whom the C allele of rs2070935 was in cis with the GFAP mutation compared with the patient in whom the C allele of rs2070935 was in trans with the GFAP mutation. Our investigation revealed the possibility that the C/C genotype at rs2070935 of the GFAP promoter in late-onset AxD was associated with an earlier onset and a more rapid progression of ambulatory disability compared with the other genotypes.