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Severe infantile onset developmental and epileptic encephalopathy caused by mutations in autophagy gene WDR 45
Author(s) -
Carvill Gemma L.,
Liu Aijie,
Mandelstam Simone,
Schneider Amy,
Lacroix Amy,
Zemel Matthew,
McMahon Jacinta M.,
BelloEspinosa Luis,
Mackay Mark,
Wallace Geoffrey,
Waak Michaela,
Zhang Jing,
Yang Xiaoling,
Malone Stephen,
Zhang YueHua,
Mefford Heather C.,
Scheffer Ingrid E.
Publication year - 2018
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.13957
Subject(s) - epilepsy , dystonia , missense mutation , age of onset , neurodegeneration , west syndrome , pediatrics , global developmental delay , encephalopathy , medicine , pathology , biology , genetics , disease , phenotype , gene , psychiatry
Summary Heterozygous de novo variants in the autophagy gene, WDR 45 , 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 WDR 45 was associated with developmental and epileptic encephalopathy ( DEE ). We performed next generation sequencing of WDR 45 in 655 patients with developmental and epileptic encephalopathies. We identified 3/655 patients with DEE plus 4 additional patients with de novo WDR 45 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.