Severe infantile onset developmental and epileptic encephalopathy caused by mutations in autophagy gene WDR45.

2018-01

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

DEE

de novo variant

genetics

Magnetic Resonance Imaging

Journal Article

0000-0002-8317-3331

0000-0002-2311-2174

10.1111/epi.13957

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.

link

Epilepsia 2018; 59(1): e5-e13

Epilepsia