We used exome sequencing to diagnose a family presenting with adult-onset spastic paraplegia. We identified a novel variant in GFAP (p.Gly18Val) cosegregating in multiple relatives, reaching a LOD score of 2.7. All patients showed characteristic signal changes in MRI and abnormal MRS. In vitro, this variant did not cause significant protein aggregation, but enlarged size of astrocytes instead, consistent with neuropathological findings in patients brain and mouse models. This suggests that alternative pathogenetic mechanisms may occur, leading to an attenuated phenotype of Alexander Disease type II in this family. We posit WES as first-tier test in adult-onset spastic paraplegias. (By Dr. Edgard Verdura, https://jmg.bmj.com/content/early/2019/04/18/jmedgenet-2018-105959 )