Neuropediatrics 2018; 49(02): 118-122
DOI: 10.1055/s-0037-1608921
Original Article
Georg Thieme Verlag KG Stuttgart · New York

Whole Exon Deletion in the GFAP Gene Is a Novel Molecular Mechanism Causing Alexander Disease

Lydia Green
1   Department of Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
,
Ian R. Berry
2   Leeds Genetics Laboratory, St. James's University Hospital, Leeds, United Kingdom
,
Anne-Marie Childs
1   Department of Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
,
Helen McCullagh
1   Department of Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
,
Sandhya Jose
3   Hull Royal Infirmary, Hull, United Kingdom
,
Dan Warren
4   Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
,
Ian Craven
4   Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
,
Nick Camm
2   Leeds Genetics Laboratory, St. James's University Hospital, Leeds, United Kingdom
,
Katrina Prescott
5   Department of Clinical Genetics, Leeds, United Kingdom
,
Marjo S. van der Knaap
6   Department of Child Neurology, VU University Medical Center, Amsterdam, The Netherlands
,
Eamonn Sheridan
7   School of Medicine, University of Leeds, St. James's University Hospital, Leeds, United Kingdom
,
John H. Livingston
1   Department of Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
› Author Affiliations
Further Information

Publication History

06 July 2017

28 August 2017

Publication Date:
18 December 2017 (online)

Abstract

Alexander disease (AD) is a leukodystrophy caused by heterozygous mutations in the gene encoding the glial fibrillary acidic protein (GFAP). Currently, de novo heterozygous missense mutations in the GFAP gene are identified in over 95% of patients with AD. However, patients with biopsy-proven AD have been reported in whom no GFAP mutation has been identified. We report identical twin boys presenting in infancy with seizures and developmental delay in whom MR appearances were suggestive of AD with the exception of an unusual, bilateral, arc of calcification at the frontal white–gray junction. Initial mutation screening of the GFAP gene did not identify a mutation. Whole exome sequencing in both brothers revealed a de novo heterozygous in-frame deletion of the whole of exon 5 of the GFAP gene. Mutations in the GFAP gene are thought to result in a toxic effect of mutant GFAP disrupting the formation of the normal intermediate filament network and resulting in Rosenthal fiber formation, which has hitherto not been linked to exonic scale copy number variants in GFAP. Further studies on mutation negative AD patients are warranted to determine whether a similar mechanism underlies their disease.

 
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