Highlights d Discovery of 107 mutations in the RNA helicase DDX3X causing cortical malformations d Clinical severity is linked to reduced helicase activity and RNA-protein granules d Ddx3x is required in neural progenitors to produce cortical neurons during development d Severe missense mutations cause polymicrogyria and impair translation of targets

Objectives: To examine the role of viruses in febrile seizures (FS) by comparing the relative risk (RR) of developing FS with common viral infections and subsequent risk of recurrence. Methods: We matched the medical records of all children admitted with FS over 5 years and the contemporary records for all admissions for febrile illnesses associated with influenza, adenovirus, parainfluenza, respiratory syncytial virus (RSV) and rotavirus to calculate the RR of FS following these viral infections. For patients admitted for a first FS, we carried multivariate analysis for type of viral infection, age of onset, family history, complex FS features and maximum temperature during the episode, to identify the risk factors for recurrence. Results: There were 923 admissions for FS, of which 565 were for first seizures. The five most common viruses in FS were influenza (163/923, 17.6%), adenovirus (63/923, 6.8%), parainfluenza (55/923, 6%), RSV (25/923, 2.7%) and rotavirus (12/923, 1.3%). Incidences of FS in febrile illnesses due to these viruses were 20.8% (163/785) for influenza, 20.6% (55/267) for parainfluenza, 18.4% (63/343) for adenovirus, 5.3% (25/468) for RSV and 4.3% (12/280) for rotavirus. Complex FS occurred in 20.6% (n = 191) and the risk of developing complex FS was similar for the five viruses. Overall recurrence rate was 20.5% and was not predicted by type of viral infection. Conclusion: The risk of developing FS is similar with influenza, adenovirus or parainfluenza and is higher than with RSV or rotavirus. Type of viral infection is not important in predicting complex features or future recurrences.

Defects of the V-type proton (H) ATPase (V-ATPase) impair acidification and intracellular trafficking of membrane-enclosed compartments, including secretory granules, endosomes, and lysosomes. Whole-exome sequencing in five families affected by mild to severe cutis laxa, dysmorphic facial features, and cardiopulmonary involvement identified biallelic missense mutations in ATP6V1E1 and ATP6V1A, which encode the E1 and A subunits, respectively, of the V domain of the heteromultimeric V-ATPase complex. Structural modeling indicated that all substitutions affect critical residues and inter- or intrasubunit interactions. Furthermore, complexome profiling, a method combining blue-native gel electrophoresis and liquid chromatography tandem mass spectrometry, showed that they disturb either the assembly or the stability of the V-ATPase complex. Protein glycosylation was variably affected. Abnormal vesicular trafficking was evidenced by delayed retrograde transport after brefeldin A treatment and abnormal swelling and fragmentation of the Golgi apparatus. In addition to showing reduced and fragmented elastic fibers, the histopathological hallmark of cutis laxa, transmission electron microscopy of the dermis also showed pronounced changes in the structure and organization of the collagen fibers. Our findings expand the clinical and molecular spectrum of metabolic cutis laxa syndromes and further link defective extracellular matrix assembly to faulty protein processing and cellular trafficking caused by genetic defects in the V-ATPase complex.