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.
- alexander disease
- astrocyte hypertrophy
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CC and EV contributed equally.
Contributors CC, EV, SF and AP designed and conceptualised the study. CC, EV, VV, AS, AP-E, CH, MR and NL analysed and interpreted the data. CC, EV, VV and AP drafted the manuscript. All authors critically revised the manuscript.
Funding This study was supported by the Centre for Biomedical Research on Rare Diseases (CIBERER) (ACCI14-759), Hesperia Foundation, and the Secretariat for Universities and Research of the Ministry of Business and Knowledge of the Government of Catalonia (2017SGR1206) to AP, and Instituto de Salud Carlos III (PI14/00581) (cofunded by the European Regional Development Fund. ERDF, a way to build Europe) and la Marató de TV3 (345/C/2014) to CC and AP. EV was funded by a grant from Ministerio de Economia, Industria y Competitividad (Juan de la Cierva Programme FJCI-2016-28811). SF was funded by Instituto de Salud Carlos III (Miguel Servet Programme CPII16/00016), and MR and NL were funded by CIBERER.
Competing interests None declared.
Patient consent for publication Obtained.
Ethics approval The research project was approved by the Clinical Research Ethics Committee of the Bellvitge University Hospital (PR076/14).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data are in the submitted paper.
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