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Adult-Onset Alexander Disease: New Causal Sequence Variant in the GFAP Gene
Tsepo Goerttler1, Letizia Zanetti1, Maria Regoni1
1Department of Neurology (T.G., C.K., S.K.), Essen University Hospital, Germany; Division of Neuroscience (L.Z., M.R., J.S.), San Raffaele Scientific Institute; Vita-Salute San Raffaele University (L.Z., M.R., J.S.), Milan, Italy; Department of Radiology (K.E.), Tauernklinikum Zell am See, Academic Teaching Hospital of the Paracelsus University Salzburg, and Medical University of Vienna, Austria; Department of MR Physics (E.K.), Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Germany; and Institute of Diagnostic and Interventional Radiology and Neuroradiology (C.D.), University Hospital Essen, Germany.
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.
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