What are the causes of hypokalemic periodic paralysis?

Causes of Hypokalemic Periodic Paralysis

Primary Genetic Causes (Channelopathies)

Hypokalemic periodic paralysis is primarily caused by mutations in genes encoding skeletal muscle ion channels, with the vast majority of cases resulting from defects in calcium or sodium channel genes. 1

Calcium Channel Mutations (HypoPP-1)

• Mutations in the CACNA1S gene (encoding the Cav1.1 calcium channel) account for approximately 76% of familial hypokalemic periodic paralysis cases, with the most common mutations being p.R528H and p.R1239G/H. 1
• CACNA1S mutations follow an autosomal dominant inheritance pattern, though sporadic cases without family history can occur. 2, 1

Sodium Channel Mutations (HypoPP-2)

• Mutations in the SCN4A gene (encoding the Nav1.4 sodium channel) cause approximately 24% of familial cases, with hotspot mutations including p.R669H, p.R672C/H, p.R1132G/Q, and p.R1135H. 2, 1
• The R669His mutation in SCN4A has been confirmed through next-generation sequencing in patients presenting with hypokalemic paralytic attacks triggered by high carbohydrate intake and exercise. 2

Potassium Channel Mutations (Rare)

• Mutations in the KCNE3 potassium channel gene (specifically the R83H mutation) have been identified as a rare genetic cause, with this mutation decreasing outward potassium flux and resulting in a more positive resting membrane potential. 3
• The R83H mutation was first identified in a sporadic case who remained asymptomatic until developing thyrotoxicosis, and was subsequently confirmed in 2 of 3 descendants, demonstrating genetic susceptibility that requires a trigger for clinical manifestation. 3

Secondary (Acquired) Causes

Thyrotoxic Hypokalemic Periodic Paralysis (THypoKPP)

• Thyrotoxicosis (most commonly from Graves' disease) can trigger hypokalemic periodic paralysis in genetically susceptible individuals, representing a genetically conditioned complication of thyrotoxicosis rather than a purely acquired disorder. 3
• THypoKPP shares the same genetic mutations as familial hypokalemic periodic paralysis (particularly KCNE3 mutations), with paralysis symptoms remaining dormant until thyroid hormone excess unmasks the underlying channelopathy. 3
• The incidence of hypokalemic periodic paralysis is 1 in 100,000, making it an exceedingly rare presentation even among thyrotoxic patients. 4

Other Endocrine Disorders

• Hyperaldosteronism can precipitate hypokalemic paralysis through excessive renal potassium wasting. 5
• Hypercortisolism (Cushing's syndrome) may trigger episodes through cortisol-mediated potassium depletion. 5

Pathophysiologic Mechanism

The fundamental defect in hypokalemic periodic paralysis involves dysfunction of skeletal muscle ion channels that disrupts normal membrane excitability. 4, 2

• Mutant calcium or sodium channels cause abnormal sarcolemmal depolarization, leading to inexcitability of muscle fibers despite normal nerve conduction. 1
• The KCNE3 R83H mutation specifically decreases outward potassium flux, resulting in a more positive resting membrane potential that renders muscle fibers refractory to normal excitation. 3
• During attacks, potassium shifts intracellularly (transcellular shift), causing severe hypokalemia (often <2.0 mEq/L) that correlates with the degree of muscle weakness. 2, 5

Common Triggers (Not Causes)

While not etiologic causes, the following precipitants unmask the underlying channelopathy:

• High carbohydrate meals trigger insulin-mediated intracellular potassium shifts in susceptible individuals. 2, 5
• Intense exercise followed by rest precipitates attacks through catecholamine-driven potassium flux. 4, 2
• Fasting or prolonged periods without food can trigger episodes. 4
• Thyroid hormone excess (in THypoKPP) amplifies the underlying channel dysfunction. 3

Diagnostic Confirmation

• Next-generation sequencing (NGS) of CACNA1S, SCN4A, and KCNE3 genes is the most cost-effective and definitive diagnostic method, particularly when targeted to hotspot regions. 2, 1
• Extension of genetic analysis beyond hotspot regions to complete gene sequencing does not significantly increase diagnostic yield in typical cases, as 85% of mutations cluster in well-defined hotspot regions. 1
• Thyroid function testing is mandatory to exclude thyrotoxic hypokalemic periodic paralysis, as this represents a treatable secondary cause. 2

Critical Clinical Pearls

• Cardiac manifestations are exceedingly rare despite the temporal association with severe hypokalemia, but when present (ventricular fibrillation, severe dysrhythmias), they require electrophysiology evaluation and possible implantable defibrillator to prevent sudden cardiac death. 4
• The paralysis pattern is typically ascending and proximal > distal, though rare cases of descending flaccid paralysis have been reported. 5
• Refractory hypokalemia requiring aggressive and continuous potassium supplementation is characteristic, with some patients needing potassium-sparing diuretics and carbonic anhydrase inhibitors for long-term management. 4
• Patients may remain asymptomatic for years until a trigger (thyrotoxicosis, dietary indiscretion, exercise) unmasks the underlying genetic defect. 3, 2