Fang Chuchu, Zhou Wenhao
Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
Guangzhou Women and Children's Medical Center, National Children's Medical Center for South Central Region, Guangzhou Medical University, 9 Jinsui Road, Guangzhou, China.
Pediatr Nephrol. 2025 Feb;40(2):301-317. doi: 10.1007/s00467-024-06492-5. Epub 2024 Sep 16.
Neonatal hypokalemia (defined as a serum potassium level <3.5 mEq/L) is the most common electrolyte disorder encountered in clinical practice. In addition to common secondary causes, primary genetic etiologies are also closely associated with hypokalemia. Currently, a systematic characterization of these genetic disorders is lacking, making early recognition challenging and clinical management uncertain. This review will aid clinicians by summarizing the genetic background of neonatal hypokalemia from two aspects: (1) increased excretion of K, whereby genetic factors primarily lead to increased renal Na influx, decreased H efflux, or reduced Cl influx, ultimately resulting in increased K efflux; and (2) decreased extracellular distribution of K, whereby genetic factors result in abnormalities in transmembrane ion channels, reducing outward potassium currents or generating inward cation leak currents. We describe over ten genetic diseases associated with neonatal hypokalemia, which involve pathogenic variants in dozens of genes and affect multiple target organs, including the kidneys, intestines, and skeletal muscle. For example, in the renal tubules, pathogenic variants in the SLC12A1 gene encoding the Na-K-2Cl cotransporter lead to renal K loss, causing Bartter syndrome type I; in intestinal epithelial cells, pathogenic variants in the SLC26A3 gene result in a defective Cl⁻-HCO₃⁻ exchanger, causing congenital chloride diarrhea; and in skeletal muscle, pathogenic variants in the CACNA1S gene impact membrane calcium ion channels resulting in hypokalemic periodic paralysis. Given the wide variety of organs and genetic alterations that can contribute to neonatal hypokalemia, we believe this review will provide valuable insights for clinical diagnosis and treatment.
新生儿低钾血症（定义为血清钾水平<3.5 mEq/L）是临床实践中最常见的电解质紊乱。除常见的继发性病因外，原发性遗传病因也与低钾血症密切相关。目前，缺乏对这些遗传疾病的系统特征描述，这使得早期识别具有挑战性，临床管理也不确定。本综述将从两个方面总结新生儿低钾血症的遗传背景，以帮助临床医生：（1）钾排泄增加，即遗传因素主要导致肾钠内流增加、氢外流减少或氯内流减少，最终导致钾外流增加；（2）细胞外钾分布减少，即遗传因素导致跨膜离子通道异常，减少外向钾电流或产生内向阳离子泄漏电流。我们描述了十多种与新生儿低钾血症相关的遗传疾病，这些疾病涉及数十个基因的致病变异，并影响多个靶器官，包括肾脏、肠道和骨骼肌。例如，在肾小管中，编码钠-钾-2氯共转运体的SLC12A1基因的致病变异导致肾钾流失，引起I型巴特综合征；在肠上皮细胞中，SLC26A3基因的致病变异导致氯离子-碳酸氢根交换体缺陷，引起先天性氯腹泻；在骨骼肌中，CACNA1S基因的致病变异影响膜钙离子通道，导致低钾性周期性麻痹。鉴于可导致新生儿低钾血症的器官和遗传改变多种多样，我们相信本综述将为临床诊断和治疗提供有价值的见解。
