Genotype-Phenotype Correlation and Therapeutic Rationale in Hyperkalemic Periodic Paralysis

Abstract

Summary:Familial hyperkalemic periodic paralysis (PP) is a dominantly inherited muscle disease characterized by attacks of flaccid weakness and intermittent myotonia. Some patients experience muscle stiffness that is aggravated by cold and exercise, bordering on the diagnosis of paramyotonia congenita. Hyperkalemic PP and paramyotonia congenita are allelic diseases caused by gain-of-function mutations of the skeletal muscle sodium channel, Nav1.4, which is essential for the generation of skeletal muscle action potentials. In this review, the functional and clinical consequences of the mutations and therapeutic strategies are reported and the differential diagnoses discussed. Also, the question is addressed of whether hyperkalemic PP is truly a different entity than normokalemic PP. Additionally, the differential diagnosis of Andersen-Tawil syndrome in which hyperkalemic PP attacks may occur will be briefly introduced. Last, because hyperkalemic PP has been described to be associated with an R83H mutation of a MiRP2 potassium channel subunit, evidence refuting disease-causality in this case will be discussed.

Hypokalemic periodic paralysis: an unusual presentation

“…Primary periodic paralysis is a hereditary disorder associated with decreased potassium levels during attacks and sometimes presents with myotonia whereas secondary paralysis is less common that occurs due to mutations in CACNA1S and SCNA4 as it is a rare, autosomal dominant channelopathy. 5 Weakness ranges from slight weakness of an isolated muscle group to severe weakness. Frequently attacks begin in the early morning, followed with strenuous exercise or a high carbohydrate meal.…”

Sodium Channel Blockers for the Treatment of Neuropathic Pain

“…[72][73][74] Na v 1.5 is predominantly expressed on cardiac myocytes and is essential to cardiac action potential initiation and conduction. 75 Pharmacological inhibition or genetic mutations of Na v 1.5 interfere with channel function, resulting in disruption of cardiac excitability leading to arrhythmias.…”

Synthesis of Skeletal Analogues of Saxitoxin Derivatives and Evaluation of Their Inhibitory Activity on Sodium Ion Channels NaV1.4 and NaV1.5

“…Indeed, mutation studies have thrown some light on the functions of these channels. For example, mutation of Na V 1.4 is associated with primary periodic paralysis, [6] whereas mutation of Na V 1.5 leads to cardiovascular syndromes. [7] Consequently, these channels are considered to be good candidates for new drug targets.…”