Triggers for episodes of HypoPP are primarily associated with intense exercise and high carbohydrate intake, and less frequently related to viral infections, stress, cold, salt consumption, and medications (such as glucocorticoids and insulin) [1, 2]. Familial HypoPP is associated with variants in the skeletal muscle sodium channel gene SCN4A in 20% of patients or the L-type calcium channel gene CACNA1S in 60% of patients [1, 2]. The majority of reported pathogenic variants involve arginine residues in S4 transmembrane segments, with notable hotspots at codons R528 and R1239 [3]. The pathogenic variant observed in this case, c.1583 G > A (p. R528H) in CACNA1S, has been documented previously [1, 2]. Mutations associated with this condition trigger a gating pore current and reduce the overall calcium channel current in the cell, but the reduction is too minor to significantly impact the cell’s membrane potential. However, when potassium levels drop, the membrane behavior changes significantly, leading to depolarization of the resting membrane potential and unusual muscle membrane depolarization, which would normally only occur at much lower potassium levels. As a result, conditions that cause mild changes in potassium levels, such as elevated insulin levels after consuming carbohydrate-rich meals or thyrotoxicosis (which induces an intracellular shift of potassium due to thyroid hormone’s effect on Na+/K+–ATPase), can trigger episodes of paralysis [4]. Generally, the existence of hyperthyroidism is more strongly associated with a diagnosis of thyrotoxic periodic paralysis (TPP), with most cases occurring in Asian males without a family history of the condition. The role of genetics in TPP has gained increasing attention in recent years. Genetic predisposition plays a crucial role in the susceptibility to TPP. One of the most significant is the presence of certain polymorphisms in genes related to ion channels, particularly those encoding for potassium channels such as KCNJ2 and KCNJ18 [1, 5]. KCNJ2 and KCNJ18 encode Kir 2.1 and Kir2.6 respectively, inwardly rectifying potassium channels expressed in skeletal muscle and transcriptionally regulated by thyroid hormone [1]. Therefore, these genetic variants can influence the function of these channels, contributing to the development of TPP. The likelihood of TPP in this case is reduced, given that the patient is not of Asian descent, has a family history of HypoPP, and lacks identifiable variants in KCNJ2 and KCNJ18. Nevertheless, Graves’ disease and a high-salt diet are factors that likely triggered the HypoPP episode in this patient.
Management of acute paralytic episodes involves maintaining proper control of serum potassium levels, necessitating vigilant monitoring for post-treatment hyperkalemia. Lifestyle and dietary modifications to avoid triggering factors are integral to treatment. Although the precise mechanism is not fully elucidated, carbonic anhydrase inhibitors have demonstrated efficacy in reducing the frequency of familiar HypoPP episodes [6]. There is variability in the response to carbonic anhydrase inhibitors based on genotype; individuals with CACNA1S variants tend to exhibit a more favorable response compared to SCN4A variants [6]. Additionally, the incorporation of a potassium-sparing diuretic, either in conjunction with carbonic anhydrase inhibitors or as a standalone treatment, may offer advantages for specific patients.
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