PT - JOURNAL ARTICLE AU - Carlos Casasnovas AU - Edgard Verdura AU - Valentina Vélez AU - Agatha Schlüter AU - Albert Pons-Escoda AU - Christian Homedes AU - Montserrat Ruiz AU - Stéphane Fourcade AU - Nathalie Launay AU - Aurora Pujol TI - A novel mutation in the <em>GFAP</em> gene expands the phenotype of Alexander disease AID - 10.1136/jmedgenet-2018-105959 DP - 2019 Apr 19 TA - Journal of Medical Genetics PG - jmedgenet-2018-105959 4099 - http://jmg.bmj.com/content/early/2019/04/18/jmedgenet-2018-105959.short 4100 - http://jmg.bmj.com/content/early/2019/04/18/jmedgenet-2018-105959.full AB - Background Alexander disease, an autosomal dominant leukodystrophy, is caused by missense mutations in GFAP. Although mostly diagnosed in children, associated with severe leukoencephalopathy, milder adult forms also exist.Methods A family affected by adult-onset spastic paraplegia underwent neurological examination and cerebral MRI. Two patients were sequenced by whole exome sequencing (WES). A candidate variant was functionally tested in an astrocytoma cell line.Results The novel variant in GFAP (Glial Fibrillary Acidic Protein) N-terminal head domain (p.Gly18Val) cosegregated in multiple relatives (LOD score: 2.7). All patients, even those with the mildest forms, showed characteristic signal changes or atrophy in the brainstem and spinal cord MRIs, and abnormal MRS. In vitro, this variant did not cause significant protein aggregation, in contrast to most Alexander disease mutations characterised so far. However, cell area analysis showed larger size, a feature previously described in patients and mouse models.Conclusion We suggest that this variant causes variable expressivity and an attenuated phenotype of Alexander disease type II, probably associated with alternative pathogenic mechanisms, that is, astrocyte enlargement. GFAP analysis should be considered in adult-onset neurological presentations with pyramidal and bulbar symptoms, in particular when characteristic findings, such as the tadpole sign, are present in MRI. WES is a powerful tool to diagnose atypical cases.