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Hypokalemic periodic paralysis
A rare genetic, muscle channelopathy characterized by recurrent episodic attacks of generalized muscle weakness associated with a decrease in blood potassium levels.
ORPHA:681Classification level: Disorder
Prevalence is estimated at around 1/100,000 in Europe.
Attacks of muscle weakness generally begin during childhood/adolescence (second decade). They vary in frequency, duration (hours to days) and severity (focal paresis to total paralysis). They generally involve the limbs muscles and spare the facial and respiratory musculature. Episodes are triggered by rest after strenuous exercise, meals rich in carbohydrates and prolonged immobility. Other factors may include stress, infection, glucocorticoids, anesthesia and pregnancy. In an undefined number of cases, hypokalemic periodic paralysis (hypoPP) may be associated with a vacuolar myopathy resulting in a permanent and progressive muscle weakness predominantly in proximal lower limb muscles. The myopathy may occur independent of paralytic symptoms.
Around 70% of cases are associated with mutations in the muscle calcium channel gene CACNA1S (1q32.1) and 10% of cases are linked to mutations in the muscle sodium channel gene SCN4A (17q23.3).
Diagnosis is based on clinical history, electromyographic and genetic tests. Hypokalemia during attacks can be very low. Serum creatinine kinase (CK) levels can be softly elevated. EMG reveals muscle excitability anomalies after a prolonged exercise test (decrement > 30% of the compound muscle action potential). Muscle biopsy may show non-specific results (muscle fibers atrophy with vacuoles). Molecular diagnosis is feasible through analysis of the causative genes identified so far.
Differential diagnoses should include hyper/normokalemic periodic paralysis, Andersen-Tawil syndrome and secondary hypoPP caused by renal or endocrine diseases such as thyrotoxicosis (thyrotoxic periodic paralysis).
Once the pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible but rarely performed because of the non life-threatening prognosis.
HypoPP is transmitted as an autosomal dominant disease with a possible incomplete penetrance, especially in females. Genetic counseling should be offered to affected families. Sporadic cases and de novo mutations have been reported. Offspring of a proband are at a 50% risk of inheriting the pathogenic variant.
Management and treatment
Management of patients consists in medical therapy and avoidance of triggering factors. Gentle physical activity, and ingestion of oral potassium salts at the onset of attacks may abort them. Severe attacks require more intensive medical management with intravenous potassium infusion. Daily potassium supplementation or intake of carbonic anhydrase inhibitors (acetazolamide, dichlorphenamide) or potassium-sparing diuretics help in preventing attacks. Dietary advice includes a diet low in carbohydrates and rich in potassium. There is no known curative treatment for hypoPP-related myopathy; physiotherapy may help to maintain strength and motor skills.
With age, the frequency of the episodes decline but some patients may develop a chronic myopathy of variable severity that may cause a permanent muscle weakness.
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