Polymicrogyria is a relatively common but poorly understood defect of cortical development characterized by numerous small gyri and a thick disorganized cortical plate lacking normal lamination. Here we report de novo mutations in a beta-tubulin gene, TUBB2B, in four individuals and a 27-gestational-week fetus with bilateral asymmetrical polymicrogyria. Neuropathological examination of the fetus revealed an absence of cortical lamination associated with the presence of ectopic neuronal cells in the white matter and in the leptomeningeal spaces due to breaches in the pial basement membrane. In utero RNAi-based inactivation demonstrates that TUBB2B is required for neuronal migration. We also show that two disease-associated mutations lead to impaired formation of tubulin heterodimers. These observations, together with previous data, show that disruption of microtubule-based processes underlies a large spectrum of neuronal migration disorders that includes not only lissencephaly and pachygyria, but also polymicrogyria malformations.
Objective Severe complications of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) include arterial ischemic stroke (AIS) in adults and multisystem inflammatory syndrome in children. Whether stroke is a frequent complication of pediatric SARS‐CoV‐2 is unknown. This study aimed to determine the proportion of pediatric SARS‐CoV‐2 cases with ischemic stroke and the proportion of incident pediatric strokes with SARS‐CoV‐2 in the first 3 months of the pandemic in an international cohort. Methods We surveyed 61 international sites with pediatric stroke expertise. Survey questions included: numbers of hospitalized pediatric (≤ 18 years) patients with SARS‐CoV‐2; numbers of incident neonatal and childhood ischemic strokes; frequency of SARS‐CoV‐2 testing for pediatric patients with stroke; and numbers of stroke cases positive for SARS‐CoV‐2 from March 1 to May 31, 2020. Results Of 42 centers with SARS‐CoV‐2 hospitalization numbers, 8 of 971 (0.82%) pediatric patients with SARS‐CoV‐2 had ischemic strokes. Proportions of stroke cases positive for SARS‐CoV‐2 from March to May 2020 were: 1 of 108 with neonatal AIS (0.9%), 0 of 33 with neonatal cerebral sinovenous thrombosis (CSVT; 0%), 6 of 166 with childhood AIS (3.6%), and 1 of 54 with childhood CSVT (1.9%). However, only 30.5% of neonates and 60% of children with strokes were tested for SARS‐CoV‐2. Therefore, these proportions represent 2.9, 0, 6.1, and 3.0% of stroke cases tested for SARS‐CoV‐2. Seven of 8 patients with SARS‐CoV‐2 had additional established stroke risk factors. Interpretation As in adults, pediatric stroke is an infrequent complication of SARS‐CoV‐2, and SARS‐CoV‐2 was detected in only 4.6% of pediatric patients with ischemic stroke tested for the virus. However, < 50% of strokes were tested. To understand the role of SARS‐CoV‐2 in pediatric stroke better, SARS‐CoV‐2 testing should be considered in pediatric patients with stroke as the pandemic continues. ANN NEUROL 2021;89:657–665
Moyamoya angiopathy (MMA) is a cerebral angiopathy affecting the terminal part of internal carotid arteries. Its prevalence is 10 times higher in Japan and Korea than in Europe. In East Asian countries, moyamoya is strongly associated to the R4810K variant in the RNF213 gene that encodes for a protein containing a RING-finger and two AAA+ domains. This variant has never been detected in Caucasian MMA patients, but several rare RNF213 variants have been reported in Caucasian cases. Using a collapsing test based on exome data from 68 European MMA probands and 573 ethnically matched controls, we showed a significant association between rare missense RNF213 variants and MMA in European patients (odds ratio (OR)=2.24, 95% confidence interval (CI)=(1.19-4.11), P=0.01). Variants specific to cases had higher pathogenicity predictive scores (median of 24.2 in cases versus 9.4 in controls, P=0.029) and preferentially clustered in a C-terminal hotspot encompassing the RING-finger domain of RNF213 (P<10). This association was even stronger when restricting the analysis to childhood-onset and familial cases (OR=4.54, 95% CI=(1.80-11.34), P=1.1 × 10). All clinically affected relatives who were genotyped were carriers. However, the need for additional factors to develop MMA is strongly suggested by the fact that only 25% of mutation carrier relatives were clinically affected.
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