Activation of a Cryptic Splice Site of GFAP in a Patient With Adult-Onset Alexander Disease

Background and Objective Alexander disease (ALXDRD) is an autosomal dominant neurologic disorder caused by mutations in the glial fibrillary acidic protein (GFAP) gene and is pathologically defined by Rosenthal fiber accumulation. Most mutations are exonic missense mutations, and splice site mutations are rare. We report a very-late-onset autopsied case of adult-onset ALXDRD with a novel splice site mutation. Methods Genetic testing of GFAP was performed by Sanger sequencing. Using autopsied brain tissues, GFAP transcript analysis was performed. Results The patient presented mild upper motor neuron symptoms in contrast to the severe atrophy of spinal cord and medulla oblongata. The patient had c.619-1G>A mutation, which is located in the canonical splice acceptor site of intron 3. The brain RNA analysis identified the r.619_621de1 (p.Glu207del) mutation, which is explained by the activation of the cryptic splice acceptor site in the second and third nucleotides from the 5' end of the exon 4. Discussion GFAP gene expression analysis is necessary to clarify the effects of intronic mutations on splicing, even if they are in canonical splice sites. This case showed a much milder phenotype than those in previous cases with missense mutations at Glu207, thereby expanding the clinical spectrum of ALXDRD with Glu207 mutation.

Automated summary

This case report describes an autopsied case of adult-onset Alexander disease with a novel splice site mutation. The patient presented mild upper motor neuron symptoms despite severe spinal cord and medulla oblongata atrophy. Genetic testing revealed a mutation in the canonical splice acceptor site, leading to activation of a cryptic splice acceptor site and expanding the clinical spectrum of ALXDRD.