Familial Periodic Paralysis
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 is confirmed by provoking an episode (eg, by giving dextrose and insulin to cause hypokalemia or potassium chloride to cause hyperkalemia). Treatment depends on the form.
Each form of familial periodic paralysis involves a different gene and electrolyte channel. In 70% of affected people, the hypokalemic form is due to 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).
The mutations and affected electrolyte channels in the thyrotoxic form are unknown, but this form usually involves hypokalemia and is associated with symptoms of thyrotoxicosis. Incidence of the thyrotoxic form is highest in Asian men.
Andersen-Tawil syndrome is due to an autosomal dominant defect of the inward-rectifying potassium channel; patients can have a high, low, or normal serum potassium level.
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 h.
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.
Episodes usually begin before age 20 with all or some of the clinical triad:
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.
The best diagnostic indicator is a history of typical episodes. If measured during an episode, serum potassium may be abnormal. Episodes can sometimes be provoked by giving dextrose and insulin (to cause the hypokalemic form) or potassium chloride (to cause the hyperkalemic form), but only experienced physicians should attempt provocative testing, because respiratory paralysis or cardiac conduction abnormalities may occur with provoked episodes.
Diagnosis of the hyperkalemic form is based on clinical findings and/or the identification of a heterozygous pathogenic variant in SNC4A.
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 po bid may help prevent hypokalemic episodes.
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.
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).
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 from cardiac arrhythmias, and a cardiac pacemaker or implantable cardioverter-defibrillator may be required to control cardiac symptoms.
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.
Treat episodes by correcting serum potassium and prevent episodes by recommending lifestyle changes.