Adult-Onset Alexander Disease: New Causal Sequence Variant in the GFAP Gene. (20th June 2022)

• Record Type: Journal Article
• Authors: Goerttler, Tsepo; Zanetti, Letizia; Regoni, Maria; Egger, Karl; Kellner, Elias; Deuschl, Cornelius; Kleinschnitz, Christoph; Sassone, Jenny; Klebe, Stephan
• Is Part Of: Neurology. Volume 8:Number 3(2022)
• Publication Date: 2022-06-20
• Subjects: Neurogenetics -- Periodicals; 616.80442
• DOI: 10.1212/NXG.0000000000000681
• Languages: English
• ISSNs: 2376-7839

Abstract

Abstract : Objectives: Alexander disease (AD) is a rare disorder of the CNS. Diagnosis is based on clinical symptoms, typical MRI findings, and mutations in the glial fibrillary acid protein (GFAP) gene. In this case study, we describe a new mutation (p.L58P) in GFAP that caused a phenotype of adult-onset AD (AOAD). Methods: In our outpatient clinic, a patient presented with cerebellar and bulbar symptoms after brain concussion. We used MRI and performed next-generation exome sequencing (NGS) to find mutations in GFAP to diagnose AD. The mutation was then transfected into HeLa cell lines to prove its pathogenicity. Results: The brain MRI finding showed typical AD alterations. The NGS found a heterozygous variant of unknown significance in GFAP (c.173T>C; p.L58P). After transfecting HeLa cell lines with this mutation, we showed that GFAP-L58P formed pathogenic clusters of cytoplasmic aggregates. Discussion: We have found a new mutation that causes AOAD. We recommend that AOAD is included in the diagnostic workup in adult patients with gait ataxia and cerebellar and bulbar symptoms in association with a traumatic head injury.