Paramyotonia congenita and hyperkalemic periodic paralysis associated with a Met 1592 Val substitution in the skeletal muscle sodium channel α subunit — a large kindred with a novel phenotype

Kelly, PA; Yang, Wei-Shun; Costigan, Donal; Farrell, Molly; Murphy, S. Salisbury; Hardiman, Orla

doi:10.1016/s0960-8966(96)00429-4

Cited by 25 publications

(19 citation statements)

References 23 publications

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“…The original "normokalemic" periodic paralysis family described by Poskanzer and Kerr (43) and subsequently shown to harbor the Met1592Val mutation in the Na V 1.4 gene (42), showed a sensitivity to oral ingestion of K + even though the plasma [K + ] remained in the normal range during attacks. The phenotype associated with the Met1592Val mutation can be heterogeneous, though, with other reports indicating attacks of weakness associated with mild hyperkalemia or with cold sensitivity (44,45). We observed that raising [K + ] o from 4 to 8 mM produced only transient weakness in isolated mutant EDL muscle.…”

Section: Elevated [K + ] O Produced Sustained Weakness Of Isolated Mumentioning

confidence: 41%

Targeted mutation of mouse skeletal muscle sodium channel produces myotonia and potassium-sensitive weakness

Hayward¹,

Kim²,

Lee³

et al. 2008

J. Clin. Invest.

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Hyperkalemic periodic paralysis (HyperKPP) produces myotonia and attacks of muscle weakness triggered by rest after exercise or by K + ingestion. We introduced a missense substitution corresponding to a human familial HyperKPP mutation (Met1592Val) into the mouse gene encoding the skeletal muscle voltage-gated Na + channel Na V 1.4. Mice heterozygous for this mutation exhibited prominent myotonia at rest and muscle fibertype switching to a more oxidative phenotype compared with controls. Isolated mutant extensor digitorum longus muscles were abnormally sensitive to the Na + /K + pump inhibitor ouabain and exhibited age-dependent changes, including delayed relaxation and altered generation of tetanic force. Moreover, rapid and sustained weakness of isolated mutant muscles was induced when the extracellular K + concentration was increased from 4 mM to 10 mM, a level observed in the muscle interstitium of humans during exercise. Mutant muscle recovered from stimulation-induced fatigue more slowly than did control muscle, and the extent of recovery was decreased in the presence of high extracellular K + levels. These findings demonstrate that expression of the Met1592Val Na + channel in mouse muscle is sufficient to produce important features of HyperKPP, including myotonia, K + -sensitive paralysis, and susceptibility to delayed weakness during recovery from fatigue.

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Section: Elevated [K + ] O Produced Sustained Weakness Of Isolated Mumentioning

confidence: 41%

Targeted mutation of mouse skeletal muscle sodium channel produces myotonia and potassium-sensitive weakness

Hayward¹,

Kim²,

Lee³

et al. 2008

J. Clin. Invest.

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“…This mutation causes both myotonia and paralysis in humans (Rojas et al, 1991;Kelly et al, 1997) and was demonstrated to produce the same symptoms in the mouse indicating the validity of the model. At a few months of age the heterozygous mice displayed subtle myopathic changes.…”

Section: Mechanisms Of Muscle Degenerationmentioning

confidence: 96%

The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment

Matthews

Fialho

Tan

et al. 2009

Brain

196

229

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The non-dystrophic myotonias are an important group of skeletal muscle channelopathies electrophysiologically characterized by altered membrane excitability. Many distinct clinical phenotypes are now recognized and range in severity from severe neonatal myotonia with respiratory compromise through to milder late-onset myotonic muscle stiffness. Specific genetic mutations in the major skeletal muscle voltage gated chloride channel gene and in the voltage gated sodium channel gene are causative in most patients. Recent work has allowed more precise correlations between the genotype and the electrophysiological and clinical phenotype. The majority of patients with myotonia have either a primary or secondary loss of membrane chloride conductance predicted to result in reduction of the resting membrane potential. Causative mutations in the sodium channel gene result in an abnormal gain of sodium channel function that may show marked temperature dependence. Despite significant advances in the clinical, genetic and molecular pathophysiological understanding of these disorders, which we review here, there are important unresolved issues we address: (i) recent work suggests that specialized clinical neurophysiology can identify channel specific patterns and aid genetic diagnosis in many cases however, it is not yet clear if such techniques can be refined to predict the causative gene in all cases or even predict the precise genotype; (ii) although clinical experience indicates these patients can have significant progressive morbidity, the detailed natural history and determinants of morbidity have not been specifically studied in a prospective fashion; (iii) some patients develop myopathy, but its frequency, severity and possible response to treatment remains undetermined, furthermore, the pathophysiogical link between ion channel dysfunction and muscle degeneration is unknown; (iv) there is currently insufficient clinical trial evidence to recommend a standard treatment. Limited data suggest that sodium channel blocking agents have some efficacy. However, establishing the effectiveness of a therapy requires completion of multi-centre randomized controlled trials employing accurate outcome measures including reliable quantitation of myotonia. More specific pharmacological approaches are required and could include those which might preferentially reduce persistent muscle sodium currents or enhance the conductance of mutant chloride channels. Alternative strategies may be directed at preventing premature mutant channel degradation or correcting the mis-targeting of the mutant channels.

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“…20 In typical hyperkalemic PP mutations such as T704M and M1592V, paramyotonic signs have been reported in single families. [31][32][33] The reason for the clinical variability is unknown.…”

Section: Hyperkalemic Pp and Pc: Phenotypic Overlapmentioning

confidence: 99%

Genotype-Phenotype Correlation and Therapeutic Rationale in Hyperkalemic Periodic Paralysis

Jurkat‐Rott¹,

Lehmann‐Horn²

2007

Neurotherapeutics

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Summary: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.

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Paramyotonia congenita and hyperkalemic periodic paralysis associated with a Met 1592 Val substitution in the skeletal muscle sodium channel α subunit — a large kindred with a novel phenotype

Cited by 25 publications

References 23 publications

Targeted mutation of mouse skeletal muscle sodium channel produces myotonia and potassium-sensitive weakness

Targeted mutation of mouse skeletal muscle sodium channel produces myotonia and potassium-sensitive weakness

The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment

Genotype-Phenotype Correlation and Therapeutic Rationale in Hyperkalemic Periodic Paralysis

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