Severe infantile onset developmental and epileptic encephalopathy caused by mutations in autophagy gene WDR 45 WDR WDR 45

摘要

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.