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Hyperkalemic periodic paralysis
A rare muscle disorder characterized by episodic attacks of muscle weakness associated with an increase in serum potassium concentration.
ORPHA:682Classification level: Disorder
- Adynamia episodica hereditaria
- Familial hyperPP
- Familial hyperkalemic periodic paralysis
- Gamstorp disease
- Gamstorp episodic adynamy
- Hyperkalemic PP
- Primary hyperPP
- Primary hyperkalemic periodic paralysis
- Prevalence: 1-9 / 1 000 000
- Inheritance: Autosomal dominant
- Age of onset: Childhood
- ICD-10: G72.3
- OMIM: 170500
- UMLS: C0238357 C2930895
- MeSH: C535409 D020513
- GARD: 195
- MedDRA: -
The prevalence is estimated at around 1/200,000.
Attacks of muscle weakness generally begin during childhood (first decade). They vary in frequency, duration (a few minutes to hours) and severity (focal paresis to total paralysis). They generally involve the limb muscles and spare the facial and respiratory musculature. Episodes are triggered by rest after exercise, fasting and cold exposure. Other factors may include ingestion of potassium-rich food, stress, infection, glucocorticoids, anesthesia and pregnancy. Maintaining exercise alleviates symptoms. 12.5% of patients present with clinical moderate and permanent myotonia that frequently involves facial muscles (lid-lag sign, eye closure myotonia) while electrical myotonia can be demonstrated in at least 50% of patients on electromyography (EMG). When clinical and electrical myotonia are a feature of the disease, the condition is called hyperkalemic periodic paralysis with myotonia (see this term). Another particular form of the disease, periodica paramyotonia, shares features with paramyotonia congenita (see this term) i.e. weakness is preceded by muscle stiffness provoked by cold and exercise.
HyperPP is a sodium muscle channelopathy due to point mutations (Thr704Met and Met1592Val mutations in 80% of cases) in the SCN4A gene encoding the alpha subunit of the skeletal muscle voltage-gated sodium channel Nav1.4. These mutations lead to defective inactivation of the channel.
Diagnosis is based on clinical history, EMG and genetic tests. Hyperkalemia during attacks can be very mild and fugitive. Serum creatinine kinase (CK) levels can be slightly elevated. Classical EMG may record myotonic discharges and/or myopathic features. The prolonged exercise test is positive in 80% of cases (decrease of over 30% of the compound muscle actionpotential after exercise). Muscle biopsy may show non-specific results (muscle fibers atrophy with vacuoles).
Differential diagnoses include secondary hyperPP caused by renal or endocrine diseases, other familial periodic paralyses such as hypokalemic or normokalemic PP (see these terms) and non dystrophic myotonias such as paramyotonia congenita (see this term).
Prenatal diagnosis is theoretically possible if the disease-causing mutation in the family has been identified but is rarely performed because of the non life-threatening prognosis.
Transmission is autosomal dominant with almost complete penetrance but variable expression in severity within and between families. Genetic counseling should be offered to affected families informing them of the 50% risk the child of an affected parent has of inheriting the disease-causing mutation.
Management and treatment
Management of patients consists in medical therapy and avoidance of triggering factors. Gentle physical activity, ingestion of carbohydrate-rich drinks/snacks or inhaled salbutamol at the onset of attacks may abort them. Daily use of carbonic anhydrase inhibitors or thiazide diuretics helps in preventing attacks. Dietary advice includes regular meals (to prevent fasting) and avoidance of potassium-rich foods.
With age (generally after 40 years of age), the frequency of the episodes declines but some patients may develop chronic myopathy of variable severity that may cause permanent muscle weakness.
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