SCIENTIFIC BACKGROUND

CACNA1S, KCNJ2, SCN4A

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Scientific Background

Autosomal dominant inherited primary periodic paralyses are characterized by reversible episodic muscle weakness and intermittent myotonia. Seizure-like paralyses regress within a few hours to a few days, with respiratory muscles less affected and consciousness and speech always unaffected. Dysfunction in muscular ion channels (sodium, calcium, potassium channels) that control myocyte activity are causative. Muscle weakness may be associated with changes in serum potassium levels and differentiated into hyperkalemic or hypokalemic periodic paralysis. However, a clinical differentiation based on serum potassium, which must be determined during the onset of symptoms, is not always possible.

 

The most common form is hypokalemic periodic paralysis (prevalence: 1:100,000). The paralysis of all extremities, lasting from one hour to days, is accompanied by a drop in serum potassium level below 3mmol/L (reference value: 3.5-5mmol/L). The severity of the paralysis can be highly variable – from mild weakness to complete paralysis of the extremities. The first symptoms usually appear before the age of 20, with a peak in seizure frequency between the ages of 15 and 35. Triggers for the seizures include high-carbohydrate meals, stress, alcohol consumption, or physical exertion. In very severe cases, persistent weakness of the limb-girdle muscles may develop later during the course of the disease.

 

Pathogenic variants in the CACNA1S gene can be detected in approximately 60% of patients with HypoPP. This gene encodes the alpha-1 subunit of the muscular voltage-gated calcium channel CaV1.1, which is predominantly expressed in skeletal muscle and retina. Variants in this gene are also associated with a predisposition to malignant hyperthermia. Pathogenic variants in the SCN4A gene are found in approximately 10% of HypoPP cases.

 

References

Fialho et al. 2018, Handb Clin Neurol 148:505 / Statland et al. 2018 Muscle Nerve 57:522 / Statland et al. 2013, Continuum (Minneap Minn) 19 (6 Muscle Disease):1598 / Matthews et al. 2010, J Physiol 588:1879 / Striessnig et al. 2010, Pflugers Arch 460:361 / Rayan & Hanna 2010, Curr Op in Neur 23:466

GENES

CACNA1S, KCNJ2, SCN4A

ASSOCIATED TESTS

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