Primary Periodic Paralysis Panel

Primary periodic paralysis is a group of rare genetic disorders characterized by episodes of flaccid weakness or paralysis of skeletal muscles (Finsterer 2008). There are at least three types of primary periodic paralysis: Hyperkalemic Periodic Paralysis (HyperPP), Hypokalemic Periodic Paralysis (HypoPP) and Andersen-Tawil Syndrome (ATS).

HyperPP is characterized by episodes of flaccid limb weakness and paralysis with normal or elevated serum potassium concentrations (>5.0 mmol/L). The attacks of hyperPP usually begin in the first or second decade of life. Initially infrequent, the attacks tend to increase in frequency and severity until approximately age 50 years, after which they occur less frequently (Weber et al. 2003). Conditions that trigger hyperPP include rest after exercise, low temperature, high potassium in food or beverage, and stress or fatigue (Charles et al. 2013). An attack usually starts in the morning, lasts for about one hour and then disappears. Most affected individuals with hyperPP also have mild myotonia (muscle stiffness) or paramyotonia (muscle stiffness worsened by low temperature and exercise) (Miller et al. 2004).

HypoPP is the most common periodic paralysis with an estimated prevalence of 1:100,000 (Finsterer 2008). Patients with hypoPP have episodic attacks of muscle weakness, which are associated with hypokalemia (<2.5mmol/L). Onset of the attack is usually in the first two decade of life (Vicart et al. 2002). The triggering factors include carbohydrate-rich meals and rest after strenuous exercise. Contrary to hyperPP, hypoPP is usually not accompanied with myotonia (Vicart et al. 2002). Approximately 25% of hypoPP patients may develop permanent proximal weakness, typically in the lower limbs (Buruma et al. 1978; Jurkat-Rott et al. 2000). Patients with hypoPP may be at an increased risk for malignant hyperthermia (Lambert et al. 1994; Marchant et al. 2004).

ATS is characterized by a triad of clinical features: episodic flaccid muscle weakness, ventricular arrhythmias and long QT interval, and multiple dysmorphic features including widely spaced eyes, low-set ears, small mandible and short stature (Statland et al. 2004). About 80% of affected individuals manifest two of the cardinal features and 60% express the complete triad of features (Tristani-Firouzi et al. 2002; Haruna et al. 2007). The symptoms are highly variable (Statland et al. 2004). Mild cognitive dysfunctions have also been described previously (Davies et al. 2005).

HyperPP, HypoPP and ATS are inherited in an autosomal dominant manner with variable penetrance and expressivity (Vicart et al. 2002; Weber et al. 2003; Statland et al. 2004).

Pathogenic variants in the SCN4A gene are the most common genetic cause for hyperPP (Fontaine et al. 1990; Jurkat-Rott et al. 2007). SCN4A encodes the skeletal muscle voltage-gated sodium channel protein type 4 subunit alpha. The sodium channel of skeletal muscle is important for generating “action potential”, which spreads over the muscle fiber to initiate a contraction response (Lehmann-Horn & Jurkat-Rott et al. 1999). HyperPP pathogenic variants in the SCN4A gene cause incomplete or slowed fast inactivation of the sodium channel, resulting in increased sodium current and increased tendency of muscle fibers to depolarize (Finsterer 2008). The penetrance of the pathogenic variants is >90%.

Pathogenic variants in CACNA1S and SCN4A account for approximately 60% and 20% of all the patients affected with HypoPP, respectively (Vicart et al. 2002). CACNA1S codes for the alpha-1S subunit of voltage-gated calcium channel (Hogan et al. 1994). The HypoPP-causing variants in CACNA1S and SCN4A genes are almost exclusively missense substitutions that change a positively charged Arginine of voltage sensor S4 segment into a lesser-charged amino acid (Human Gene Mutation Database). In general, the penetrance is lower in women (50%) than in men (90%) (Finsterer 2008).

Pathogenic variants in KCNJ2 have been identified in approximately 60% of patients with ATS (Statland et al. 2004). KCNJ2 encodes the inward rectifier potassium channel 2 protein (Kir2.1), which is primarily expressed in skeletal muscle, heart and brain. Kir2.1 has important roles regulating the membrane potential in skeletal and cardiac muscle (Plaster et al. 2001; Tristani-Firouzi et al. 2002). KCNJ2 pathogenic variants impair the channel's binding to PIP2 (phosphatidylinositol 4,5-bisphosphate), a major component in the modulation of the Kir family (Bendahhou et al. 2005). Reduced penetrance is evident in 6-20% of affected individuals carrying a KCNJ2 pathogenic variant (Finsterer 2008).

It is difficult to estimate the clinical sensitivity of this test due to the lack of large cohort studies. Analytical sensitivity is expected be high because nearly all of the pathogenic variants reported are detectable by this test.

For SCN4A and CACNA1S, no gross deletions or duplications have been documented to cause disease. Only three gross deletions have been identified in KCNJ2 so far (Human Gene Mutation Database).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).