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SummaryHeterozygous de novo variants in the autophagy gene, WDR45, are found in betapropeller 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. K E Y W O R D Sde novo variant, genetics, magnetic resonance imaging, DEE Aijie Liu, Simone Mandelsta, and Amy Schneider are equal second authors. Yue-Hua Zhang, Heather C. Mefford, and Ingrid E. Scheffer are equal coauthors.

Background:Acute hemorrhagic leukoencephalopathy is a rare encephalopathy of unknown etiology, causing fulminant, hemorrhagic CNS demyelination with high mortality. It is unclear whether AHLE is an entirely distinct entity from ADEM. Patients and methods:We report two patients with rapidly progressive neurological illness resulting in raised ICP and coma, with biopsy proven AHLE (perivascular haemorrhages/demyelination, predominantly neutrophil infiltrates). Results:Acute CSF showed pronounced T cell associated cytokine elevation (IL-6, IL-8, IL17A) and CCL2 / CCL3, higher than in ADEM patients, but no B cell associated cytokine elevation. Conclusion:Improved understanding of the immune process may provide rationale for use of anti-cytokine biologic agents.

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