Novel CACNA1S Mutation c.3491 A>C in Hypokalemic Periodic Paralysis: First Report with Functional Validation

Hypokalemic periodic paralysis (HypoPP) is a muscle disease caused by abnormal ion channels and is characterized by recurrent skeletal muscle relaxation paralysis and hypokalemia. There are obvious triggers before disease onset, such as cold, excessive exercise, excessive consumption of sugary and high-energy foods, and overeating. The aim of this study was to elucidate the pathogenic mechanism of novel mutations in the voltage-dependent L-type calcium channel subunit alpha-1 S (CACNA1S) gene associated with HypoPP. Method: Whole-exome sequencing and American College of Medical Genetics and Genomics (ACMG) compliance analysis were performed, supplemented by serum potassium and blood biochemistry tests for bioinformatics analysis. We report a 13-year-old adolescent male patient with hypokalemic periodic paralysis, who complained of limb muscle weakness accompanied by pain for 10 h. Whole-exome sequencing revealed a mutation in the CACNA1S gene (NM_000069.3: exon27: c.3491 A>C [p. Glu1164Ala]), which was classified as an uncertain mutation. The clinical presentation and protein structure prediction of the gene mutation confirmed its pathogenic role and mechanism. The mutation caused a conformational change in the calcium ion channel. This study revealed a new mutation site in the HypoPP gene and proposed the possibility of a new pathogenesis. Moreover, obesity and low magnesium are two factors that induce HypoPP, which may increase the risk of disease.