Hypokalemic Periodic Paralysis: Genetic Basis, Triggers, and Management

Hypokalemic periodic paralysis (HypoPP) is a rare autosomal dominant channelopathy (CACNA1S, SCN4A mutations) causing episodic flaccid weakness with hypokalemia.

Genetics

• CACNA1S (Caᵥ1.1) — ~60%: Voltage-gated calcium channel α1-subunit (DHP receptor).
• SCN4A (Naᵥ1.4) — ~20%: Voltage-gated sodium channel α-subunit.
• Others/unknown: ~20%.
• Penetrance: Higher in males; females often milder/asymptomatic.

Pathophysiology

Mutant channels → aberrant gating pore current at rest → depolarization → Na⁺ channel inactivation → inexcitability. Low K⁺ exacerbates by reducing K⁺ equilibrium potential → further depolarization block.

Triggers

• High-carbohydrate meal (insulin → K⁺ shift intracellular)
• Rest after strenuous exercise
• Stress, cold, corticosteroids, alcohol, saline infusion

Clinical Features

• Onset: Childhood/teens.
• Episodes: Hours to days; proximal > distal; legs > arms; spares respiratory/bulbar usually.
• Ictal K⁺: 2.0–3.0 mEq/L (can be lower).
• Interictal: Normal strength, normal K⁺.
• Fixed weakness (myopathy) may develop late (>50% by 60s).

Diagnosis

• Genetic testing (confirmatory).
• Provocative testing (glucose/insulin, exercise) — specialized centers only.
• EMG: Reduced CMAP amplitude during attack; normal between.

Treatment

• Acute: Oral K⁺ (KCl 20–40 mEq) — IV if severe/swallowing impaired.
• Prophylaxis:
  • Carbonic anhydrase inhibitors: Acetazolamide 125–250 mg BID (first-line) or dichlorphenamide (FDA-approved).
  • Low-carb, low-Na⁺ diet; avoid triggers.
  • K⁺-sparing diuretic (spironolactone, eplerenone) if acetazolamide intolerant.
• Genetic counseling for family.

Differential

• Thyrotoxic periodic paralysis (Asian males, low TSH, high T4).
• Hyperkalemic PP (SCN4A, K⁺ high during attacks).
• Andersen-Tawil (KCNJ2, dysmorphic features, arrhythmia).

HypoPP is manageable with trigger avoidance and carbonic anhydrase inhibitors. Quality of life can be excellent.