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SCN4A (chromosomal locus 17q23-q25, sodium channel gene)

NDC Entry
NCBI #168300
Pub Med Search for Paramyotonia Congenita

Cannon (2002), reports that PMC shares significant clinical features with HyperKPP. These two disorders are both associated with mutations in the same gene (SCN4A sodium channel). PMC often results in episodic attacks of weakness with duration, severity, and serum potassium fluctuations similar to those seen in patients with HyperKPP. The hallmark symptoms in PMC are muscle stiffness that worsens with continued activity (paradoxical myotonia, or paramyotonia), severe worsening of myotonia when exposed to cold, and in most cases weakness will result from longer exposure to cold (Mitrovic and Lerche, 2000).

According to Jurkat-Rott and Lehmann-Horn, Another clinical characteristic is the inability to reopen the eyes after several forceful closures in rapid succession. Paramyotonia is usually not induced or aggravated by potassium. In most families, the stiffness gives way to flaccid weakness or even to paralysis on intensive exercise and cooling. Some families also have attacks of generalized hyperkalemic periodic paralysis provoked by rest or ingestion of potassium lasting for an hour or less. In contrast, the cold-induced weakness usually lasts several hours even when the muscles are immediately rewarmed. The mutation M1370V [Okuda et al 2001] is associated with this phenotype.

The classical form of Paramyotonia Congenita was first described by Eulenburg and independently by Rich. Several mutations in the Na+ channel gene result in the classical clinical picture.

PMC is characterized by:autosomal dominant inheritance, with 100% penetrance. Onset begins as early as birth.

Clinical Signs include:muscle stiffness increasing with exercise (paradoxical myotonia). In many families paramyotonia is dramatically increased when the muscles are exercised in the cold. Caveat: Some families present consistently cold- and exercise-induced stiffness without weakness. These cases are often misdiagnosed as having myotonia congenita.

Variability of signs:
There are families where affected members present with the classical symptoms of paramyotonia congenita and also often experience attacks of hyperkalemic paralysis.

The presentation of both sets of symptoms in severe form was termed paralysis periodica paramyotonica (PPP) by P.E. Becker; however, a continuum seems to exist, with PPP families and families having the classical form of paramyotonia congenita presenting the two extremes.

  • The severity of stiffness is not the same in all paramyotonia families.

  • Weakness may be precipitated by hypokalemia


  • For Myotonia: Antiarrhythmic drugs, Mexiletine 100 to 1,000 mg/day; Tocainide

  • For Weakness: (K+-sensitive) Hydrochlorothiazide (250 to 1,000 mg/day) supplemental K+, Acetazolamide (125 to 1,000 mg/d), Dichlorphenamide (50 to 150 mg/day)

  • Weakness with Paramyotonia: Mexiletine 100 to 1,000 mg/day, Tocainide, and potassium supplementation if needed.

    The following abstracts may also be of help:

    A Novel Mutation in the Gene for the Adult Skeletal Muscle Sodium Channel -Subunit (SCN4A) That Causes Paramyotonia Congenita of von Eulenburg: Arch Neurol. 1999;56:692-696, Ryogen Sasaki, MD; Hiroki Takano, MD, PhD; Keiko Kamakura, MD; Kenichi Kaida, MD; Akira Hirata, MD; Masaaki Saito, MD; Hajime Tanaka, MD; Shigeki Kuzuhara, MD; Shoji Tsuji, MD, PhD

    Background: Paramyotonia congenita (PMC) of von Eulenburg is an autosomal dominant muscular disease characterized by exercise- and cold-induced myotonia and weakness. To date, 18 missense mutations in the adult skeletal muscle sodium channel -subunit (SCN4A) gene have been identified to cause a spectrum of muscular diseases, including PMC of von Eulenburg, PMC without cold paralysis, potassium-aggravating myotonia, and hyperkalemic periodic paralysis. However, no obvious correlations can be made between the location or nature of amino acid substitutions in SCN4A and its clinical phenotypes. Objective: To describe clinical and genetic features of a family with PMC of von Eulenburg. Results: A Japanese family with cold-induced myotonia and weakness was diagnosed as having PMC of von Eulenburg. This phenotype was identified to be caused by a novel mutation that substituted a glutamic acid residue for a highly conserved glycine residue in the fourth transmembrane segment (S4) of domain IV. This predicted a decrease in positive charge specific for the S4.

    Conclusion: 4 mutations that cause a decrease in positive charge in the S4/D4 are associated with the phenotype of PMC of von Eulenburg. This provides an important genotype-phenotype correlation in sodium channelopathies.

    Paramyotonia Congenita of Von Eulenburg; PMC

    A defect in skeletal muscle sodium channel deactivation exacerbates hyperexcitability in human paramyotonia congenita.

    Also See:
    Bendahhou S, Cummins TR, Kwiecinski H, Waxman SG, Ptacek LJ., 1999

    Section Last Modified:
    12/29/2009 07:38 PT