VOLTAGE SENSOR CHARGE LOSS ACCOUNTS FOR MOST CASES OF HYPOKALEMIC PERIODIC PARALYSIS

To the Editor:

Matthews et al.¹ highlight the importance of mutations in the arginine residues in S4 voltage sensors of skeletal muscle Ca²⁺ and Na⁺ channels in the genesis of hypokalemic periodic paralysis (HypoKPP) types 1 and 2.

Previous studies have demonstrated that loss of charged arginine residues produces a leak current pathway through portions of the ion channel that support voltage-induced movements of the S4 segments.² Current flowing through the alternative ion pathway created by the S4 mutations could account for the anomalous cation depolarizing current that occurs in type 2 HypoKPP and is likely present in type 1 HypoKPP.

Current passage via an alternative pathway would also explain why the anomalous depolarizing current is not blocked by traditional Na⁺ or Ca²⁺ channel blockers.³ The highly selective association of the arginine gating pore mutations with the HypoKPP phenotype suggests that this type of mutation is likely key to the genesis of this phenotype.

The authors also consider whether other ion channel alterations associated with HypoKPP are important for creation of the phenotype.¹ Type 1 HypoKPP is associated with reduction in the outward current component of the inward rectifier K⁺ channel (Kir).³ While reduced Kir may be an epiphenomena, a role for reduced Kir in the HypoKPP phenotype has been suggested. Reduced Kir is the ion channel defect responsible for Andersen syndrome, which includes a periodic paralysis phenotype. Increasing K⁺ current may be the mechanism of action of acetazolamide-induced improvement in HypoKPP symptoms.⁴

In type 2 HypoKPP, the Na⁺ channel mutations …