Hypokalemic Periodic Paralysis in a Young Woman With Mast Cell Activation Syndrome: A Case Report of an Atypical Presentation Associated With an Ultra-Rare CACNA1S Variant.

Hypokalemic periodic paralysis (hKPP) is a rare neuromuscular channelopathy characterized by transient episodes of muscle weakness or paralysis associated with low serum potassium levels. It has been most commonly linked to autosomal dominant mutations in ion channel genes, specifically CACNA1S and SCN4A, which impair skeletal muscle excitability. Although hKPP typically presents in adolescent males with a positive family history, atypical cases in women may be underrecognized due to milder or less frequent attacks and non-specific symptoms between episodes. We present the case of a 31-year-old female with a history of confirmed mast cell activation syndrome (MCAS) and no family history of similar symptoms, who presented with episodes of weakness, muscle cramps, and presyncope, typically triggered by high-carbohydrate meals or exercise. During one of these attacks, she was found to have severe hypokalemia. Although mast cell activation syndrome can also cause weakness and hypokalemia with certain triggers, this patient did not experience flushing or urticaria during the episodes. Given her atypical presentation, including weakness rather than flaccid paralysis commonly seen in hKPP, and the absence of typical symptoms of MCAS, genetic testing was performed. This revealed an ultra-rare heterozygous variant in the CACNA1S gene (NM_000069.3: c.3844G > T; p.A1282S), classified as a variant of uncertain significance (VUS). When aligning protein sequences, Alanine at amino acid position 1282 is evolutionary conserved among species (human, mouse, bovine, whale); however, no functional studies on A1282S exist. In conclusion, maintaining a high index of suspicion for hKPP in patients presenting with nonspecific fatigue or weakness associated with hypokalemia and identifiable triggers is important. Although genetic testing is not always required, in cases with autosomal dominant inheritance, it can be useful in patients without family history, nonspecific symptoms or when the differential diagnosis remains challenging.