Biallelic variants in KARS1 are associated with neurodevelopmental disorders and hearing loss recapitulated by the knockout zebrafish

Purpose: Pathogenic variants in Lysyl-tRNA synthetase 1 (KARS1) have increasingly been recognized as a cause of early-onset complex neurological phenotypes. To advance the timely diagnosis of KARS1-related disorders, we sought to delineate its phenotype and generate a disease model to understand its function in vivo. Methods: Through international collaboration, we identified 22 affected individuals from 16 unrelated families harboring biallelic likely pathogenic or pathogenic in KARS1 variants. Sequencing approaches ranged from disease-specific panels to genome sequencing. We generated loss-of-function alleles in zebrafish. Results: We identify ten new and four known biallelic missense variants in KARS1 presenting with a moderate-to-severe developmental delay, progressive neurological and neurosensory abnormalities, and variable white matter involvement. We describe novel KARS1-associated signs such as autism, hyperactive behavior, pontine hypoplasia, and cerebellar atrophy with prevalent vermian involvement. Loss of kars1 leads to upregulation of p53, tissue-specific apoptosis, and downregulation of neurodevelopmental related genes, recapitulating key tissue-specific disease phenotypes of patients. Inhibition of p53 rescued several defects of kars1−/− knockouts. Conclusion: Our work delineates the clinical spectrum associated with KARS1 defects and provides a novel animal model for KARS1-related human diseases revealing p53 signaling components as potential therapeutic targets

Fisioterapia respiratória associada à pressão positiva nas vias aéreas na evolução pós-operatória da cirurgia bariátrica Respiratory physiotherapy associated with airway positive pressure in the postoperative bariatric surgery evolution

Analisar volume corrente (VC), volume minuto (VM) e frequência respiratória (FR) de obesas mórbidas no pós-operatório de cirurgia bariátrica (CB), após a fisioterapia respiratória convencional (FRC) associada ou não à pressão positiva contínua nas vias aéreas (CPAP) no pré-operatório. Foram estudadas 36 mulheres, com idade de 40,1±8,41 anos, que seriam submetidas à CB por laparotomia e que realizaram FRC (exercícios respiratórios diafragmáticos, de inspirações profundas, fracionadas e associados a movimentos de membros superiores, 1 série de 10 repetições de cada exercício) por 30 dias antes da cirurgia. Após internação, 18 delas foram submetidas a 20 minutos de CPAP, 1 hora antes da indução anestésica e compuseram o grupo FRC+CPAP. As outras 18 não receberam o CPAP e compuseram o grupo FRC. Foram avaliados VM, VC e FR por meio do ventilômetro, no momento da internação e 24 horas após a realização da cirurgia. Constatou-se que as medidas de VC, VM e FR não apresentaram significância estatística quando comparados os resultados do pré e pós-operatório em ambos os grupos, bem como quando comparados os dois grupos entre si tanto no pré como no pós-operatório. Os resultados sugerem que a tanto a aplicação da FRC como a aplicação da FRC+CPAP no período pré-operatório contribui para a manutenção das variáveis respiratórias no pós-operatório. A aplicação do CPAP antes da indução anestésica não promoveu benefícios adicionais no pós-operatório de CB no que se refere aos volumes pulmonares.<br>To assess the tidal volume (VT), minute volume (MV) and respiratory rate (RR) of morbidly obese women in postoperative bariatric surgery (BS), after the conventional respiratory physiotherapy (CRP) with or without preoperatively continuous positive airway pressure (CPAP). Thirty-six women, aged 40.1±8.41 years, that would be submitted to BS by laparotomy were studied. All of them underwent preoperative outpatient conventional respiratory physiotherapy (CRP) (diaphragmatic breathing exercises, deep breathing, fractionated breathing and breathing associated to movements of the upper limbs, a series of 10 repetitions of each exercise) by 30 days. Once admitted, 18 were subjected to 20 minutes of CPAP, an hour before induction of anesthesia and composed group CRP+CPAP. The other 18 did not receive CPAP and composed group CRP. VT, MV, and RR were performed through the ventilometer, at admission and 24 hours after surgery. It was found that measures of TV, VM and RR were not statistically significant when comparing pre and postoperative in both groups and as well as when the two groups were compared between them in both pre and postoperative. The results suggest that both the application and the implementation of FRC and FRC+CPAP in the preoperative period contribute to the maintenance of respiratory variables in the postoperative period. The use of CPAP before induction of anesthesia, did not provide additional benefits in the post-bariatric surgery with regard to the volumes