Medline ® Abstracts for References 5,7,8
of 'Hyperkalemic periodic paralysis'
Genotype-phenotype correlation and therapeutic rationale in hyperkalemic periodic paralysis.
Jurkat-Rott K, Lehmann-Horn F
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.
Department of Applied Physiology, Ulm University, Ulm, Germany.
Hyperkalemic periodic paralysis and the adult muscle sodium channel alpha-subunit gene.
Fontaine B, Khurana TS, Hoffman EP, Bruns GA, Haines JL, Trofatter JA, Hanson MP, Rich J, McFarlane H, Yasek DM
Hyperkalemic periodic paralysis (HYPP) is an autosomal dominant disorder characterized by episodes of muscle weakness due to depolarization of the muscle cell membrane associated with elevated serum potassium. Electrophysiological studies have implicated the adult muscle sodium channel. Here, portions of the adult muscle sodium channel alpha-subunit gene were cloned and mapped near the human growth hormone locus (GH1) on chromosome 17. In a large pedigree displaying HYPP with myotonia, these two loci showed tight linkage to the genetic defect with no recombinants detected. Thus, it is likely that the sodium channel alpha-subunit gene contains the HYPP mutation.
Molecular Neurogenetics Laboratory, Massachusetts General Hospital, Charlestown, MA 02129.
Altered fast and slow inactivation of the N440K Nav1.4 mutant in a periodic paralysis syndrome.
Lossin C, Nam TS, Shahangian S, Rogawski MA, Choi SY, Kim MK, Sunwoo IN
Neurology. 2012 Sep;79(10):1033-40. Epub 2012 Aug 22.
OBJECTIVE: To electrophysiologically characterize the Na(v)1.4 mutant N440K found in a Korean family with a syndrome combining symptoms of paramyotonia congenita, hyperkalemic periodic paralysis, and potassium-aggravated myotonia.
METHODS: We characterized transiently expressed wild-type and mutant Na(v)1.4 using whole-cell voltage-clamp analysis.
RESULTS: N440K produced a significant depolarizing shift in the voltage dependence of fast inactivation and increased persistent current and acceleration in fast inactivation recovery, which gave rise to a 2-fold elevation in the dynamic availability of the mutant channels. In addition, the mutant channels required substantially longer and stronger depolarization to enter the slow-inactivated state.
CONCLUSIONS: N440K causes a gain of function consistent with skeletal muscle hyperexcitability as observed in individuals with the mutation. How the same mutation results in distinct phenotypes in the 2 kindreds remains to bedetermined.
Department of Neurology, University of California, Davis, School of Medicine, USA.