De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects.

Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function

De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects

Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function

Endoscopic ultrasound-guided gastro-enteric anastomosis: A systematic review and meta-analysis

BACKGROUND AND AIMS: Endoscopic ultrasound-guided gastro-enteric anastomosis (EUS-GEA) using lumen-apposing metal stents (LAMS) is emerging as a minimally invasive alternative to surgery across several indications. Literature on this subject is heterogeneous, with variable reporting of techniques and outcomes. Our aim was to perform a meta-analysis of published data on EUS-GEA, providing a pooled estimate of technical and clinical outcomes. METHODS: The protocol was registered in PROSPERO (Reg. no. CRD42018111110). PubMed, Embase, Scopus, and Web of Science databases were searched until February 2019 for studies describing patients undergoing EUS guided enteric anastomosis. PRISMA methodology was used. Pooled technical and clinical success rates as well as pooled adverse events rates were calculated. Study quality, publication bias, and heterogeneity were explored. RESULTS: Twelve studies including 290 patients were included, published between 2016 and 2019. All studies but one were retrospective. Main procedure indication was gastric outlet obstruction (62.4%), followed by ERCP access (27.9%) in patients with gastric bypass surgery. Direct puncture technique was the most frequently adopted (68.2%). Pooled technical success rate (12 studies, 290 patients) was 93.5% [95% confidence interval (CI) 89.7-6.0%; I(2):0%], while clinical success rate (11 studies, 260 patients) was 90.1% [95%CI 85.5-93.4%; I(2):0%]. Pooled total adverse events rate (11 cohorts, 261 patients) was 11.7% [95%CI 8.2-16.6%; I(2):0%], mainly mild/moderate: 10.6% [95%CI 7 - 15.6%]. No publication bias or significant heterogeneity was found. CONCLUSIONS: EUS-GEA has a high rate of technical and clinical success when performed in expert centers. The procedure appears to be relatively safe, and might represent a non-inferior minimally invasive alternative to surgery. The paucity of long-term clinical outcomes suggests prudency and need for further research, especially regarding non-malignant indications

Impact of the COVID-19 pandemic on gastrointestinal endoscopy in Africa

Background and study aims  As with all other fields of medical practice, gastrointestinal endoscopy has been impacted by the COVID-19 pandemic. However, data on the impact of the pandemic in Africa, especially sub-Saharan Africa are lacking. Methods  A web-based survey was conducted by the International Working Group of the European Society for Gastrointestinal Endoscopy and the World Endoscopy Organization to determine the impact and effects the COVID-19 pandemic has had on endoscopists in African countries. Results  Thirty-one gastroenterologists from 14 countries in north, central, and sub-Saharan Africa responded to the survey. The majority of respondents reduced their endoscopy volume considerably. Personal protective equipment including FFP-2 masks were available in almost all participating centers. Pre-endoscopy screening was performed as well. Conclusion  The COVID-19 pandemic has had a substantial impact on gastrointestinal endoscopy in most African countries; however, the impact may not have been as devastating as expected