Clinical characteristics: Hyperkalemic periodic paralysis (hyperPP) is characterized by attacks of flaccid limb weakness (which may also include weakness of the muscles of the eyes, throat, breathing muscles, and trunk), hyperkalemia (serum potassium concentration >5 mmol/L) or an increase of serum potassium concentration of at least 1.5 mmol/L during an attack of weakness and/or provoking/worsening of an attack by oral potassium intake, normal serum potassium between attacks, and onset before age 20 years. In approximately half of affected individuals, attacks of flaccid muscle weakness begin in the first decade of life, with 25% reporting their first attack at age ten years or older. Initially infrequent, the attacks then increase in frequency and severity over time until approximately age 50 years, after which the frequency of attacks declines considerably. The major attack trigger is eating potassium-rich foods; other triggers include: cold environment; rest after exercise, stress, or fatigue; alcohol; hunger; and changes in activity level. A spontaneous attack commonly starts in the morning before breakfast, lasts for 15 minutes to one hour, and then passes. Individuals with hyperPP frequently have myotonia (muscle stiffness), especially around the time of an episode of weakness. Paramyotonia (muscle stiffness aggravated by cold and exercise) is present in about 45% of affected individuals. More than 80% of individuals with hyperPP older than age 40 years report permanent muscle weakness and about one third develop a chronic progressive myopathy.
Diagnosis/testing: The diagnosis of hyperPP is established in a proband with suggestive findings and a heterozygous pathogenic variant in SCN4A identified by molecular genetic testing. In case of diagnostic uncertainty, a provocative test can be employed, although the availability of genetic testing and electrophysiologic studies largely obviates the need for such dangerous tests.
Management: Treatment of manifestations: At the onset of weakness, attacks may be prevented or aborted with mild exercise and/or oral ingestion of carbohydrates, intravenously injected glucocorticoids, inhalation of salbutamol, or intravenous calcium gluconate.
Prevention of primary manifestations: Hyperkalemic attacks of weakness can be prevented by frequent meals rich in carbohydrates; continuous use of a thiazide diuretic or a carbonic anhydrase inhibitor; and avoidance of potassium-rich medications and foods, fasting, strenuous work, and exposure to cold.
Surveillance: Yearly neurologic examination with focus on muscle strength in the legs in order to detect permanent weakness; in those with permanent muscle weakness, MRI of leg muscles every one to three years; during prophylactic treatment, determination of serum potassium concentration twice per year to avoid severe diuretic-induced hypokalemia; annual monitoring of thyroid function.
Agents/circumstances to avoid: Potassium-rich medications and foods, fasting, strenuous work, exposure to cold, and use of depolarizing anesthetic agents during general anesthesia or ACE-inhibitor medications.
Evaluation of relatives at risk: It is appropriate to test asymptomatic at-risk family members for the pathogenic variant identified in an affected relative in order to institute preventive measures, particularly those that would decrease the risk of unexpected acute paralysis or anesthetic events.
Genetic counseling: HyperPP is inherited in an autosomal dominant manner. Most individuals with hyperPP have an affected parent; the proportion of individuals with hyperPP caused by a de novo pathogenic variant is unknown. Each child of an individual with hyperPP has a 50% chance of inheriting the pathogenic variant. Once the SCN4A pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for hyperPP are possible.
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