Hypokalemic Periodic Paralysis Associated With a Rare CACNA1S Variant (p.Leu1243Val): Expanding the Mutational Spectrum.

BACKGROUND: Hypokalemic periodic paralysis (HypoPP) is a rare skeletal muscle channelopathy, most often caused by mutations in CACNA1S or SCN4A. Most pathogenic CACNA1S mutations affect arginine residues in S4 voltage-sensor domains, but other variants remain poorly understood.

CASE PRESENTATION: I describe a 30-year-old Caucasian woman with recurrent paralytic episodes and hypokalemia (2.1-2.3 mmol/L), triggered by stress and carbohydrate-rich meals. Genetic testing revealed heterozygosity for CACNA1S c.3727C  >  G (p.Leu1243Val), a variant of uncertain significance not previously associated with pathogenicity. Her phenotype was consistent with HypoPP. Treatment with spironolactone and acetazolamide reduced episode frequency, although the latter caused intolerable side effects, particularly tachypnea; she was later approved for dichlorphenamide. During one hospitalization, she also developed transient hypophosphatemia and hypokalemia, consistent with her HypoPP picture. Kidney function and imaging were normal. Family history revealed electrolyte disturbances in her grandfather.

CONCLUSIONS: This case highlights a possible genotype-phenotype link involving CACNA1S p.Leu1243Val. Continued reporting of such cases is essential for variant reclassification and for improving recognition of metabolic shifts during HypoPP attacks.