Two novel GFAP mutations and genotype-phenotype associations in Alexander disease

Abstract

Abstract Background Alexander disease (AxD) is a rare genetic disorder caused by mutations in the GFAP gene, which encodes glial fibrillary acidic protein and leads to astrocyte dysfunction. This study aims to report two novel GFAP mutations in Chinese AxD patients and summarize genotype-phenotype associations of AxD patients reported in the literature. Methods and Results A 65-year-old male presented with gradual weakness in both lower limbs and global mild brain atrophy as well as subtle white matter changes. No lesion was found in the lower brainstem or upper cervical cord. A novel frameshift mutation was identified in the GFAP gene, which is expected to result in the production of a premature truncated protein (p.R11Qfs*16). Another pathogenic mutation, c.1085A > G (p.E362G), was identified as the genetic cause of unsteady gait in an 18-year-old female who presented at age 22. Most of the pathogenic mutations described in literatures were in exons 1, 4 and 6. Mutations causing infantile form were mostly identified in Coil 1A and Coil 2B domain, but some mutations leading to adult form were found in Coil 1B and C-terminal tail domain. Conclusions This study further expands the clinical and genetic spectrum of juvenile and adult-onset AxD as well as the knowledge on genotype-phenotype associations.