Hypokalemic periodic paralysis is an autosomal dominant, rare disorder caused by variants in the genes for voltage-gated calcium channel CaV1.1 (CACNA1S) and NaV1.4 (SCN4A). Patients with hypokalemic periodic paralysis may suffer from periodic paralysis alone, periodic paralysis co-existing with permanent weakness or permanent weakness alone. Hypokalemic periodic paralysis has been known to be associated with vacuolar myopathy for decades, and that vacuoles are a universal feature regardless of phenotype. Hence, we wanted to investigate the nature and cause of the vacuoles. Fourteen patients with the p.R528H variation in the CACNA1S gene was included in the study. Histology, immunohistochemistry and transmission electron microscopy was used to assess general histopathology, ultrastructure and pattern of expression of proteins related to muscle fibres and autophagy. Western blotting and real-time PCR was used to determine the expression levels of proteins and mRNA of the proteins investigated in immunohistochemistry. Histology and transmission electron microscopy revealed heterogenous vacuoles containing glycogen, fibrils and autophagosomes. Immunohistochemistry demonstrated autophagosomes and endosomes arrested at the pre-lysosome fusion stage. Expression analysis showed a significant decrease in levels of proteins an mRNA involved in autophagy in patients, suggesting a systemic effect. However, activation level of the master regulator of autophagy gene transcription, TFEB, did not differ between patients and controls, suggesting competing control over autophagy gene transcription by nutritional status and calcium concentration, both controlling TFEB activity. The findings suggest that patients with hypokalemic periodic paralysis have disrupted autophagic processing that contribute to the vacuoles seen in these patients.

中文翻译：

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低钾性周期性麻痹患者的自噬受到影响：与空泡性肌病有关？

低钾性周期性麻痹是一种常染色体显性遗传的罕见疾病，由电压门控钙通道 CaV1.1 (CACNA1S) 和 NaV1.4 (SCN4A) 的基因变异引起。低钾性周期性麻痹患者可能单独患有周期性麻痹，周期性麻痹与永久性虚弱共存或单独存在永久性虚弱。几十年来，已知低钾性周期性麻痹与液泡性肌病有关，无论表型如何，液泡都是普遍特征。因此，我们想调查液泡的性质和原因。该研究包括了 14 名在 CACNA1S 基因中具有 p.R528H 变异的患者。组织学、免疫组织化学和透射电子显微镜用于评估一般组织病理学，与肌纤维和自噬相关的蛋白质的超微结构和表达模式。使用蛋白质印迹和实时 PCR 来确定蛋白质的表达水平和免疫组织化学中研究的蛋白质的 mRNA。组织学和透射电子显微镜显示含有糖原、原纤维和自噬体的异质空泡。免疫组织化学证明自噬体和内体在溶酶体融合前阶段被捕。表达分析显示参与患者自噬的 mRNA 蛋白水平显着降低，表明存在全身效应。然而，自噬基因转录的主要调节因子 TFEB 的激活水平在患者和对照组之间没有差异，表明营养状态和钙浓度对自噬基因转录的竞争控制，两者都控制着 TFEB 活性。研究结果表明，低钾性周期性麻痹患者破坏了导致这些患者出现液泡的自噬过程。