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

Authors:
Carlos Casasnovas
Carlos Casasnovas
Hospital Universitari de Bellvitge
Spain
Edgard Verdura
Edgard Verdura
Hospital de la Santa Creu i Sant Pau and CIBERER
Spain
Albert Pons-Escoda
Albert Pons-Escoda
Hospital Universitari de Bellvitge
Christian Homedes
Christian Homedes
Bellvitge University Hospital- Biomedical Research Institute of Bellvitge (IDIBELL)
Montserrat Ruiz
Montserrat Ruiz
Hospital General Universitario de Elche
Spain
Stephane Fourcade
Stephane Fourcade
University of Burgundy 21000 Dijon
France

J Med Genet 2019 Apr 19. Epub 2019 Apr 19.

Neurometabolic Diseases Laboratory, Institut d'Investigacio Biomedica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat (Barcelona), Catalonia, Spain

Background: Alexander disease, an autosomal dominant leukodystrophy, is caused by missense mutations in . 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 (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. 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.

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Source
http://jmg.bmj.com/lookup/doi/10.1136/jmedgenet-2018-105959
Publisher Site
http://dx.doi.org/10.1136/jmedgenet-2018-105959DOI Listing
April 2019
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