A novel CACNA1S variant associated with diltiazem-related worsening of hypokalemic periodic paralysis: a case report.

BACKGROUND AND OBJECTIVES: Hypokalemic periodic paralysis (HypoPP) is a skeletal muscle channelopathy characterized by recurrent episodes of transient paralysis associated with hypokalemia. Most cases are caused by heterozygous missense variants in CACNA1S, which encodes the α1 subunit of the skeletal muscle L-type calcium channel (CaV1.1). Known triggers include excessive carbohydrate intake, rest after strenuous exercise, and emotional stress; however, worsening potentially associated with the use of L-type calcium channel blockers (LTCCBs) has not been well documented. CASE PRESENTATION: A 68-year-old man with HypoPP and a five-generation family history of the disease developed increased frequency of paralytic attacks and progressive muscle weakness after initiation of LTCCBs (nifedipine and diltiazem) for vasospastic angina. Exome sequencing and segregation analysis identified a novel heterozygous CACNA1S variant (NM_000069.3:c.4097T > G, p.(Met1366Arg)), which co-segregated with disease among genotyped affected family members and was classified as likely pathogenic. Despite continued nifedipine therapy, paralytic episodes ceased following discontinuation of diltiazem, and muscle strength improved. DISCUSSION: The p.(Met1366Arg) variant is located in the S6 segment of CaV1.1, outside the canonical S4 arginine residues implicated in most cases of CACNA1S-related HypoPP; nevertheless, strong intrafamilial segregation evidence supports its pathogenicity. Furthermore, its proximity to the diltiazem-binding site raises the possibility of altered drug-channel interactions. The observed diltiazem-associated worsening of HypoPP may be variant-specific rather than a class effect of LTCCBs. Nevertheless, careful monitoring may be warranted when prescribing these agents to patients with HypoPP.