Objective: In the present study we describe a new mutation (p.L58P) in the GFAP gene and its functional consequences causing a phenotype with adult-onset Alexander’s disease (AOAD) which is associated with cerebellar ataxia and bulbar symptoms.

Background: Alexander’s disease (AD) is a rare disorder of the central nervous system. In AD patients, diagnosis is based on clinical symptoms, typical MRI findings and mutations in the GFAP gene. An autosomal-dominant transmission has been described, but many patients with AD have de novo mutations. Disease progression, clinical phenotype, and imaging findings in AD differ enormously according to the age at onset.

Method: In a patient in our outpatient clinic with cerebellar and bulbar symptoms we used MR-Imaging and automated brain-volumetry analysis using the software VEOmorph (VEObrain GmbH, Freiburg, Germany) to verify AD-diagnosing. We performed next generation exome sequencing to find mutations in the GFAP gene. The found mutations was transfected into HeLa-celllines to prove its pathogenicity.

Results: In MRI progressive T2-hyperintensities surrounding the 4th ventricle, symmetrical in the dentate nucleus and in the putamina together with the “tadpole” sign were seen. The automated brain-volumetry analysis supports the visual findings of atrophic changes in the medulla oblongata.
In the next generation exome sequencing a heterozygous variant of unknown significance in the GFAP gene (c.173T>C; p.L58P) was found. By transfecting HeLa-cellines with this mutations we showed that wild-type GFAP assembled into bundled filaments that extended throughout the cytoplasm, whereas GFAP-L58P failed to assemble into filaments; instead, this variant formed clusters of cytoplasmic aggregates.

Conclusion: Concluding, we found a new mutation in the GFAP gene which is causal for Adult-Onset Alexander’s disease. AOAD should be included in the diagnostic work-up in adult patient with gait ataxia, cerebellar and bulbar symptoms and signs of atrophy in the medulla oblongata in MRI.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/adult-onset-alexanders-disease-new-causal-mutation-in-gfap-gene/