Hypokalemic Periodic Paralysis, Type 2

A number sign (#) is used with this entry because hypokalemic periodic paralysis type 2 (HOKPP2) is caused by heterozygous mutation in the SCN4A gene (603967).

Mutations in the SCN4A gene can also cause hyperkalemic periodic paralysis (HYPP; 170500).

For a general phenotypic description and a discussion of genetic heterogeneity of HOKPP, see HOKPP1 (170400), which is caused by mutation in the CACNL1A3 gene (CACNA1S; 114208).

Clinical Features

Bulman et al. (1999) reported 2 cousins with HOKPP. The proband experienced a first paralytic attack at age 14 on awakening in the morning, and was found to have a serum potassium of 2.2 mmol/L. Myotonia was not present. Similar paralytic episodes involving either his legs or all 4 limbs recurred with variable frequency, ranging from 1 to 2 times per week to once every 2 months. Potassium supplementation was effective. His cousin had a similar phenotype.

Sugiura et al. (2000) reported an unusual HOKPP phenotype in a Japanese family. Affected members showed heat-induced myotonia and cold-induced paralysis with hypokalemia. Myotonia lessened with exercise and was alleviated by cold, which distinguished the disorder from paramyotonia congenita (PMC; 168300). Treatment with acetazolamide alleviated the myotonia, but slightly worsened the paralysis. Patients showed seasonal swings with myotonia in the summer and paralysis in the winter, with hypokalemia during the paralytic attacks.

Venance et al. (2004) reported a sporadic patient with HOKPP2, confirmed by mutation in the SCN4A gene (603967.0020), who responded well to acetazolamide. The authors noted the variability in response to the drug in HOKPP, and suggested that carbonic anhydrase inhibitors should be considered in patients with SCN4A-associated HOKPP.

In a review of 71 patients from 56 kindreds with HOKPP, Miller et al. (2004) found that 64% of kindreds had mutations in either the CACNA1S or SCN4A genes. The arg1239-to-his (R1239H; 114208.0001) and arg528-to-his (R528H; 114208.0003) mutations of the CACNA1S gene were the most common mutations, each found in 42% of kindreds. Five kindreds had SCN4A mutations. No mutations were identified in 20 kindreds. HOKPP patients with mutations had a significantly earlier age at disease onset (10 years) compared to those without mutations (22 years); however, 2 patients with mutations presented at ages 23 and 26 years, respectively. Among those with mutations, the disease was most severe during the teenage years, and 72% of patients had residual muscle weakness. Muscle biopsies showed vacuolar changes in 80% of patients with CACNA1S mutations; these changes were not seen in any patients without mutations. Treatment with acetazolamide was beneficial in 85% of those with mutations and 100% of those without mutations. In a diagnostic flow chart for the periodic paralyses, Miller et al. (2004) indicated that HOKPP shows onset in childhood to adolescence and is characterized by infrequent but severe attacks, often lasting up to 24 hours, and decreased serum potassium. Myotonia is not a feature.

Molecular Genetics

Studying families in which linkage to the CACNL1A3 gene had been excluded, Bulman et al. (1999) identified a mutation in the SCN4A gene (603967.0015), and Jurkat-Rott et al. (2000) identified other mutations (603967.0016 and 603967.0017) in the same gene. The clinical picture did not differ from that of HOKPP caused by mutations in the CACNL1A3 gene.

In a Japanese family with an unusual temperature-dependent HOKPP phenotype, Sugiura et al. (2000) identified a mutation in the SCN4A gene (P1158S; 603967.0021).

Davies et al. (2001) found that 11 of 36 families with HOKPP harbored mutations in the CACNA1S gene (114208.0001 and 114208.0003), whereas only 1 family had a mutation in the SCN4A gene (603967.0020), suggesting that SCN4A mutations are an uncommon cause of HOKPP in the U.K. Among 58 independent index cases of HOKPP, Sternberg et al. (2001) found that 40 were linked to the CACNA1S gene and 5 to the SCN4A gene, all of which were in the same codon (see, e.g., 603967.0016). Thirteen families remained without known mutations, indicating genetic heterogeneity.

Matthews et al. (2009) identified mutations in the CACNA1S or SCN4A gene in 74 (almost 90%) of 83 patients with HOKPP. All of the mutations, including 3 novel mutations, affected arginine residues in the S4 voltage sensing region in 1 of the transmembrane domains of each gene. The most common mutations affected residues arg528 (25 cases) and arg1239 (39 cases) in CACNA1S (see, e.g., R1239H; 114208.0001 and R528H; 114208.0003). The most common mutations in SCN4A affected residues arg672 (see, e.g., 603967.0016) and arg1132. The findings supported the hypothesis that loss of positive charge in S4 voltage sensors is important to the pathogenesis of this disorder. (Sokolov et al., 2007).

Pathogenesis

In muscle fibers of patients with HOKPP, Rudel et al. (1984) determined that the basic defects were a reduced excitability and an increased sodium conductance, and that these defects were aggravated by reduction of the extracellular potassium concentration.

In a commentary, Ruff (2000) reviewed the evidence that HOKPP is caused by membrane depolarization triggering sodium channel inactivation, which renders the muscle membrane inexcitable. In addition, SCN4A mutations may also result in decreased density of membrane sodium channels, also decreasing overall current. HOKPP resulting from calcium channel mutations (CACNA1S) represent an 'indirect channelopathy': membrane depolarization results from hypokalemia activating a pathologic depolarizing current and from decreased inward rectifier potassium channel conductance.

By in vitro studies, Kuzmenkin et al. (2002) showed that 2 mutations in the voltage sensor region of the SCN4A gene (R669H 603967.0015 and R672H; 603967.0016) showed enhanced inactivation. The inactivation defects could be alleviated by decreased pH, which may explain why some patients have relief by some physical exercise.

Sokolov et al. (2007) showed that 3 mutations in gating charge-carrying arginine residues in an S4 segment that cause HOKPP induced a hyperpolarization-activated cationic leak through the voltage sensor of the skeletal muscle Nav1.4 channel (SCN4A). This cation leak would substantially increase resting membrane conductance and sodium influx into HOKPP skeletal muscle fibers, resulting in a gain of function effect that contributes to the dominant inheritance, depolarization, reduced rate of rise and amplitude of the action potential, cytopathology, and episodic paralysis correlated with decreased serum potassium. The mutant channels showed similar permeability to sodium, potassium, and cesium ions, but the organic monovalent cations tetraethylammonium and N-methyl-D-glucamine were much less permeant. Sokolov et al. (2007) concluded that their results revealed gating pore current in naturally occurring disease mutations of an ion channel and showed a clear correlation between mutations that cause gating pore current and HOKPP. In addition, the findings contrasted with the well-established paradigm in which alterations in control of ion conductance through the central pore of ion channels impair cell function. Sokolov et al. (2007) postulated that their observations might be generalizable to other ion channelopathies.

Francis et al. (2011) demonstrated that an R1132Q mutation (603967.0030) in the domain III voltage sensor domain of SCN4A found in a family with HOKPP created an anomalous gating pore current similar to that observed by Sokolov et al. (2007). This current is sufficient to depolarize and render the muscle fiber inexcitable particularly during low external potassium. The findings suggested a mechanism for loss of sarcolemmal excitability during attacks of weakness in HOKPP. In contrast, the R1148C mutation (603967.0003) causing PMC (168300) did not result in gating pore abnormalities.