A novel mutation in the GFAP gene expands the phenotype of Alexander disease

Abstract

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 WES. A candidate variant was functionally tested in an astrocytoma cell line. Results: The novel variant in GFAP 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 characterized 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, i.e. astrocyte enlargement. GFAP analysis should be considered in adult-onset neurologic 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.