Departments of Neurology, Neurological Surgery, Translational Neuroscience, Barrow Neurological Institute, and St. Joseph's Hospital and Medical Center, Phoenix, Arizona.
Department of Anesthesiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Shock. 2024 Nov 1;62(5):688-697. doi: 10.1097/SHK.0000000000002457. Epub 2024 Sep 3.
Background: Sepsis-associated brain injury is associated with deterioration of mental status, persistent cognitive impairment, and morbidity. The SUR1/TRPM4 channel is a nonselective cation channel that is transcriptionally upregulated in the central nervous system with injury, allowing sodium influx, depolarization, cellular swelling, and secondary injury. We hypothesized that genetic variation in ABCC8 (SUR1 gene) and TRPM4 would associate with central nervous system dysfunction in severe pediatric sepsis. Methods: 326 children with severe sepsis underwent whole exome sequencing in an observational cohort. We compared children with and without central nervous system dysfunction (Glasgow Coma Scale <12) to assess for associations with clinical characteristics and pooled rare variants in ABCC8 and TRPM4. Sites of variation were mapped onto protein structure and assessed for phenotypic impact. Results: Pooled rare variants in either ABCC8 or TRPM4 associated with decreased odds of central nervous system dysfunction in severe pediatric sepsis (OR 0.14, 95% CI 0.003-0.87), P = 0.025). This association persisted following adjustment for race, organ failure, viral infection, and continuous renal replacement therapy (aOR 0.11, 95% CI 0.01-0.59, P = 0.038). Structural mapping showed that rare variants concentrated in the nucleotide-binding domains of ABCC8 and N-terminal melastatin homology region of TRPM4 . Conclusion : This study suggests a role for the ABCC8/TRPM4 channel in central nervous system dysfunction in severe pediatric sepsis. Although exploratory, the lack of therapies to prevent or mitigate central nervous system dysfunction in pediatric sepsis warrants further studies to clarify the mechanism and confirm the potential protective effect of these rare ABCC8/TRPM4 variants.
脓毒症相关性脑损伤与精神状态恶化、持续认知障碍和发病率有关。SUR1/TRPM4 通道是一种非选择性阳离子通道，在中枢神经系统损伤时转录上调，允许钠离子内流、去极化、细胞肿胀和继发损伤。我们假设 ABCC8（SUR1 基因）和 TRPM4 的遗传变异与严重儿科脓毒症的中枢神经系统功能障碍有关。
326 名严重脓毒症患儿在观察队列中进行了全外显子组测序。我们比较了有和无中枢神经系统功能障碍（格拉斯哥昏迷量表<12）的患儿，以评估与临床特征的关联，并对 ABCC8 和 TRPM4 的罕见变异进行了汇总。变异部位被映射到蛋白质结构上，并评估其表型影响。
ABCC8 或 TRPM4 中的罕见变异汇总与严重儿科脓毒症患者中枢神经系统功能障碍的几率降低相关（OR 0.14，95%CI 0.003-0.87，P=0.025）。在调整种族、器官衰竭、病毒感染和持续肾脏替代治疗后，这种关联仍然存在（aOR 0.11，95%CI 0.01-0.59，P=0.038）。结构映射显示，ABCC8 的核苷酸结合域和 TRPM4 的 N 端 melastatin 同源区的罕见变异集中。
本研究表明 ABCC8/TRPM4 通道在严重儿科脓毒症的中枢神经系统功能障碍中起作用。尽管这是一项探索性研究，但儿科脓毒症中缺乏预防或减轻中枢神经系统功能障碍的治疗方法，这需要进一步的研究来阐明机制，并确认这些罕见的 ABCC8/TRPM4 变异的潜在保护作用。
