These findings suggest that autonomic dysfunction is associated with SUDEP risk in patients with epilepsy due to sodium channel mutations. The relationship of HRV to SUDEP merits further study; HRV may eventually have potential as a biomarker of SUDEP risk, which would allow for more informed counseling of patients and families, and also serve as a useful outcome measure for research aimed at developing therapies and interventions to reduce SUDEP risk.

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Objective Developmental epileptic encephalopathies (DEEs) are genetically heterogeneous severe childhood‐onset epilepsies with developmental delay or cognitive deficits. In this study, we explored the pathogenic mechanisms of DEE‐associated de novo mutations in the CACNA1A gene. Methods We studied the functional impact of four de novo DEE‐associated CACNA1A mutations, including the previously described p.A713T variant and three novel variants (p.V1396M, p.G230V, and p.I1357S). Mutant cDNAs were expressed in HEK293 cells, and whole‐cell voltage‐clamp recordings were conducted to test the impacts on CaV2.1 channel function. Channel localization and structure were assessed with immunofluorescence microscopy and three‐dimensional (3D) modeling. Results We find that the G230V and I1357S mutations result in loss‐of‐function effects with reduced whole‐cell current densities and decreased channel expression at the cell membrane. By contrast, the A713T and V1396M variants resulted in gain‐of‐function effects with increased whole‐cell currents and facilitated current activation (hyperpolarized shift). The A713T variant also resulted in slower current decay. 3D modeling predicts conformational changes favoring channel opening for A713T and V1396M. Significance Our findings suggest that both gain‐of‐function and loss‐of‐function CACNA1A mutations are associated with similarly severe DEEs and that functional validation is required to clarify the underlying molecular mechanisms and to guide therapies.

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.