JOURNAL ARTICLE

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

Gemma L Carvill, Aijie Liu, Simone Mandelstam, Amy Schneider, Amy Lacroix, Matthew Zemel, Jacinta M McMahon, Luis Bello-Espinosa, Mark Mackay, Geoffrey Wallace, Michaela Waak, Jing Zhang, Xiaoling Yang, Stephen Malone, Yue-Hua Zhang, Heather C Mefford, Ingrid E Scheffer
Epilepsia 2018, 59 (1): e5-e13
29171013
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.

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