Type IV Voltage-Gated Sodium Channel (Alpha Subunit)-Related Disorders via the SCN4A Gene

Disorders related to the skeletal muscle type 4 voltage-gated sodium channel alpha subunit gene (SCN4A, OMIM 603967) generally share the common feature of flaccid muscle weakness but differ from one another in key clinical findings.  Hyperkalemic periodic paralyisis (HYPP, OMIM 170500) is characterized by elevated serum potassium during attacks of limb weakness and normal potassium levels between attacks.  Average age of onset is two years old (Miller et al. Neurology 63:1647-1655, 2004).   Symptoms can be provoked with oral intake of potassium and alleviated by calcium intake (Jurkat-Rott and Lehmann-Horn, GeneReviews 2011).  Hypokalemic periodic paralysis, type 2 (HOKKP2, OMIM 613345) is characterized by infrequent but severe attacks which may include paralysis, low serum potassium levels, and onset in childhood to adolescence.  Acute symptoms are treated with administration of potassium and long term management is accomplished with diet (low sodium and carbohydrate/high potassium), oral doses of potassium salts, and in some cases with cholinesterase inhibitors (Sternberg et al. GeneReviews, 2009).  Potassium-aggravated myotonia congenita (OMIM 608390) includes three clinical entities: mild myotonia fluctuans (Ricker et al. Arch Neurol 51:1095-1102, 1994), severe myotonia permanens (Colding-Jorgensen et al. Neurology 67:153-155, 2006), and acetazolamide-responsive myotonia (Ptacek et al. Neurology 42:431-433, 1992, Trudell et al. Neurology 37:488-491, 1987).  Clinical symptoms include painful stiffness and cramping induced by exercise, cold temperature, fever, or potassium-rich diet.  Paramyotonia congenita (PMC, OMIM 168300) is characterized by frequent episodes lasting <24 hours, cold-induced myotonia, persistent weakness, increased serum creatine kinase, and normal serum potassium levels (Miller et al. 2004).  Congenital myasthenic syndrome associated with fatigable weakness and recurrent attacks of respiratory and bulbar paralysis (OMIM 614198) has been described in one patient (Tsujino et al. Proc Nat Acad Sci 100:7377-7382, 2003).  The condition resembled infantile CHAT-associated CMS, and affected muscle groups included ocular, facial, limb, and truncal.  The patient was successfully treated with a cholinesterase inhibitor.  Other SCN4A-related conditions include severe congenital episodic laryngospasms (Lion-Francois et al. Neurology 75: 641-645, 2010) and severe painful generalized myotonia with muscle hypertrophy, which was found in French-Canadians (Dupre et al. et al. Neuromusc Disord 19:330-334, 2009).

All disorders related to the SCN4A gene are inherited in an autosomal dominant pattern.  Hypokalemic periodic paralysis type 1 is caused by variants in the CACNA1S gene and myotonia congenita type 1 is caused by variants in the CLCN1 gene.  The SCN4A p.Thr704Met and p.Met1592Val variants are common among HYPP patients.

Among 56 families with HOKKP2 and 47 with HYPP, five and thirty families, respectively, were found to have SCN4A variants (Miller et al. 2004). Among 56 patients with PMC, 49 were found to have SCN4A variants (Miller et al. 2004). The other SCN4A disorders are too rare to estimate clinical sensitivity.

This test provides full coverage of all coding exons of the SCN4A gene 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 full 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).