Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Hypokalemic Periodic Paralysis (HypoPP) [G72.3]

OMIM numbers: 170400 (HypoPP Typ 1),  114208 (CACNA1S), 601887 (malignant hyperthermia susceptibility)

Dr. rer. biol. hum. Soheyla Chahrokh-Zadeh, M.Sc. Anna Munzig

Scientific Background

Primary periodic paralysis is an autosomal dominant inherited disorder characterized by reversible, episodic, muscle weakness and intermittent myotonia. Sudden attacks of paralysis, in which the respiratory musculature is affected to a lesser extent and consciousness and speech are never affected, resolve within hours or a few days. The symptoms are caused by malfunctions in muscular iron channels (sodium, calcium and potassium channels) which control the activity of myocytes. The muscle weakness may be accompanied by changes in the serum potassium levels and differentiated into hyper or hypokalemic periodic paralysis. However, clinical differentiation by means of serum potassium which must be measured during the appearance of symptoms, is not always possible.

The most common form is hypokalemic periodic paralysis (prevalence 1:100,000); continuous paralysis of all extremities lasting from one hour to days accompanied by a fall in serum potassium levels below 3 mmol/L (reference value: 3.5-5 mmol/L). The extent of paralysis can be very variable, from slight weakness to complete paralysis of the extremities. The first symptoms usually appear before the age of 20, although the highest incidence is between 15 and 35 years. Triggers for the attacks include a high carbohydrate diet, stress, alcohol consumption or physical exertion. In severe cases, continuing weakness of the limb-girdle musculature may develop during later stages of the disease.

Mutations in the CACNA1S gene can be documented in approximately 60% of patients with hypokalemic periodic paralysis. The gene codes for the alpha-1 subunit of the muscular voltage controlled calcium channel CaV1.1, which is expressed predominately in skeletal muscle and the retina. Mutations in this gene are also associated with a predisposition to malignant hyperthermia (see pharmacogenetics). Mutations in the SCN4A gene are found in approximately 10% of hypokalemic periodic paralysis cases and approximately 3% of patients have mutations in the KCNJ18 gene.