Familial periodic paralysis is a rare autosomal dominant condition with considerable variation in penetrance characterized by episodes of flaccid paralysis with loss of deep tendon reflexes and failure of muscle to respond to electrical stimulation. There are 4 forms: hypokalemic, hyperkalemic, thyrotoxic, and Andersen-Tawil syndrome. Diagnosis is indicated by history and used to be confirmed by provoking an episode (eg, by giving dextrose and insulin to cause hypokalemia or potassium chloride to cause hyperkalemia). These provocative tests have been replaced by an exercise test, which is safer, and by genetic testing. Treatment depends on the form.
Each form of familial periodic paralysis involves a different gene and electrolyte channel.
In the hypokalemic form, 70% of affected people have a mutation in the alpha-subunit of the voltage-sensitive muscle calcium channel gene on chromosome 1q (HypoPP type I). In some families, the mutation is in the alpha-subunit of the sodium channel gene on chromosome 17 (HypoPP type II). Although the hypokalemic form is the most common form of familial periodic paralysis, it is nonetheless quite rare, with a prevalence of 1/100,000.
The hyperkalemic form is due to mutations in the gene that encodes the alpha-subunit of the skeletal muscle sodium channel (SCN4A).
In the thyrotoxic form, the mutations and affected electrolyte channels are unknown, but this form usually involves hypokalemia and is associated with symptoms of thyrotoxicosis. Prevalence of the thyrotoxic form is highest in Asian men.
Andersen-Tawil syndrome is a rare, autosomal dominant disorder usually caused by mutations to the KCNJ2 gene located on chromosome 17q24.3 or, rarely, to the KCNJ5 gene. Patients can have a high, low, or normal serum potassium level.
Symptoms and Signs of Familial Periodic Paralysis
Гіпокаліємічний періодичний параліч
Episodes usually begin before age 16. The day after vigorous exercise, the patient often awakens with weakness, which may be mild and limited to certain muscle groups or may affect all four limbs. Episodes are also precipitated by carbohydrate-rich meals, emotional or physical stress, alcohol ingestion, and cold exposure. Ocular, bulbar, and respiratory muscles are spared. Consciousness is not altered. Serum and urine potassium are decreased. Weakness may last up to 24 hours. (See also Hypokalemia.)
Гіперкаліємічний періодичний параліч
Episodes often begin at an earlier age and usually are shorter, more frequent, and less severe. Episodes are precipitated by rest after exercise, exercise after meals, or fasting. Myotonia (delayed relaxation after muscle contraction) is common. Eyelid myotonia may be the only symptom. (See also Hyperkalemia.)
Тиреотоксичний періодичний параліч
Episodes last hours to days and are usually precipitated by exercise, stress, or a carbohydrate load, similar to the hypokalemic form. Symptoms of thyrotoxicosis (eg, anxiety, emotional lability, weakness, tremor, palpitations, heat intolerance, increased perspiration, weight loss) are typically present. Clinical features of hyperthyroidism often precede the onset of periodic paralysis by months or years; however, features have been noted to occur at the same time as (in up to 60% of patients) or after the development of (in up to 17% of patients) periodic paralysis.
Синдром Андерсена-Тавіла
Episodes usually begin before age 20 with all or some of the clinical triad:
Periodic paralysis
Prolonged QT interval and ventricular arrhythmias
Dysmorphic physical features
Dysmorphic physical features include short stature, high-arched palate, low-set ears, broad nose, micrognathia, hypertelorism, clinodactyly of the fingers, short index fingers, and syndactyly of the toes.
Episodes are precipitated by rest after exercise, may last for days, and occur monthly.
Diagnosis of Familial Periodic Paralysis
History of typical episodes
Serum potassium level during symptoms
Exercise test
Genetic testing
The best diagnostic indicator is a history of typical episodes. If measured during an episode, serum potassium may be abnormal. Previously, for diagnosis, an attempt was made to provoke episodes by giving dextrose and insulin (to cause the hypokalemic form) or potassium chloride (to cause the hyperkalemic form), but because these tests may cause respiratory paralysis or cardiac conduction abnormalities and are not needed to make the diagnosis, they have been replaced by a safer exercise test. In the exercise test, the patient vigorously exercises a single muscle for 2 to 5 minutes in an attempt to cause focal muscle weakness. Weakness is assessed by an electrophysiologic study called the compound muscle action potential (CMAP), which is done before and after exercise. A ≥ 40% decrease postexercise is abnormal and consistent with periodic paralysis.
Diagnosis of the hyperkalemic form is based on clinical findings and/or the identification of a heterozygous pathogenic variant in the alpha-subunit of the skeletal muscle sodium channel.
Treatment of Familial Periodic Paralysis
Varies with type and severity
Гіпокаліємічний періодичний параліч
Episodes of paralysis are managed by giving potassium chloride 2 to 10 g in an unsweetened oral solution or giving potassium chloride IV. Following a low-carbohydrate, low-sodium diet, avoiding strenuous activity, avoiding alcohol after periods of rest, and taking acetazolamide 250 mg orally 2 times a day may help prevent hypokalemic episodes.
Гіперкаліємічний періодичний параліч
Episodes of paralysis, if mild, can be aborted at onset by light exercise and a 2-g/kg oral carbohydrate load. Established episodes require thiazides, acetazolamide, or inhaled beta-agonists. Severe episodes require calcium gluconate and insulin and dextrose IV (see also treatment of severe hyperkalemia). Regularly ingesting carbohydrate-rich, low-potassium meals and avoiding fasting, strenuous activity after meals, and cold exposure help prevent hyperkalemic episodes.
Тиреотоксичний періодичний параліч
Acute episodes are treated with potassium chloride, and serum potassium levels are closely monitored. Episodes are prevented by maintaining a euthyroid state (see treatment of hyperthyroidism) and giving beta-blockers (eg, propranolol).
Синдром Андерсена-Тавіла
In addition to lifestyle changes, including tightly controlled levels of exercise or activity, episodes may be prevented by giving a carbonic anhydrase inhibitor (eg, acetazolamide). The major complication of Andersen-Tawil syndrome is sudden death resulting from cardiac arrhythmias, and a cardiac pacemaker or implantable cardioverter-defibrillator may be required to control cardiac symptoms.
Ключові моменти
There are 4 types of familial periodic paralysis, which are caused by rare mutations of membrane electrolyte channels.
Serum potassium is usually but not always abnormal but may be low or high.
Patients have intermittent episodes of weakness, typically precipitated by exercise and sometimes meals (particularly containing carbohydrates) or alcohol.
Diagnose by typical symptoms and measuring serum potassium during symptoms; sometimes an exercise test is done.
Treat episodes by correcting serum potassium and prevent episodes by recommending lifestyle changes.
