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Title: Severe infantile onset developmental and epileptic encephalopathy caused by mutations in autophagy gene WDR45.
Austin Authors: Carvill, Gemma L;Liu, Aijie;Mandelstam, Simone;Schneider, Amy;Lacroix, Amy;Zemel, Matthew;McMahon, Jacinta M;Bello-Espinosa, Luis;Mackay, Mark;Wallace, Geoffrey;Waak, Michaela;Zhang, Jing;Yang, Xiaoling;Malone, Stephen;Zhang, Yue-Hua;Mefford, Heather C;Scheffer, Ingrid E 
Affiliation: Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia
Department of Neurology, Lady Cilento Children's Hospital, Brisbane, Queensland, Australia
Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
Departments of Paediatrics and Radiology, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA
Department of Paediatrics, University of Calgary, Alberta Children's Hospital, Calgary, Alberta, Canada
Department of Pediatrics, Peking University First Hospital, Beijing, China
Issue Date: Jan-2018 2017-11-24
Publication information: Epilepsia 2018; 59(1): e5-e13
Abstract: Heterozygous de novo variants in the autophagy gene, WDR45, are found in beta-propeller protein-associated neurodegeneration (BPAN). BPAN is characterized by adolescent onset dementia and dystonia; 66% patients have seizures. We asked whether WDR45 was associated with developmental and epileptic encephalopathy (DEE). We performed next generation sequencing of WDR45 in 655 patients with developmental and epileptic encephalopathies. We identified 3/655 patients with DEE plus 4 additional patients with de novo WDR45 pathogenic variants (6 truncations, 1 missense); all were female. Six presented with DEE and 1 with early onset focal seizures and profound regression. Median seizure onset was 12 months, 6 had multiple seizure types, and 5/7 had focal seizures. Three patients had magnetic resonance susceptibility-weighted imaging; blooming was noted in the globus pallidi and substantia nigra in the 2 older children aged 4 and 9 years, consistent with iron accumulation. We show that de novo pathogenic variants are associated with a range of developmental and epileptic encephalopathies with profound developmental consequences.
DOI: 10.1111/epi.13957
ORCID: 0000-0002-8317-3331
PubMed URL: 29171013
Type: Journal Article
Subjects: DEE
de novo variant
Magnetic Resonance Imaging
Appears in Collections:Journal articles

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