Correlating phenotype and genotype in the periodic paralyses

Miller, Timothy M.; Silva, Magnus R. Dias da; Miller, Hannah A.; Kwieciński, Hubert; Mendell, Jerry R.; Tawil, Rabi; McManis, Philip G.; Griggs, Robert C.; Angelini, Corrado; Servidei, Serenella; Petajan, Jack H.; Dalakas, Marinos C.; Ranum, Laura P.W.; Fu, Ying Hui; Ptáček, Louis J.

doi:10.1212/01.wnl.0000143383.91137.00

Cited by 229 publications

(283 citation statements)

References 36 publications

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“…Interictally, HyperKPP muscle may exhibit abnormal repetitive firing of muscle action potentials (myotonia) that produces muscle stiffness (6). Weakness can be provoked by immobility after strenuous exercise, ingestion of K + salts, fasting, cold exposure, emotional stress, or glucocorticoids (1,(7)(8)(9)(10), although the triggers can be highly variable even among members of a single affected family. Attacks can be prevented by carbohydrate ingestion, mild exercise, thiazide diuretics, or carbonic anhydrase inhibitors (1,11).…”

Section: Introductionmentioning

confidence: 99%

“…The latter agents, and inhaled β-adrenergic agonists (9,12) or intravenous calcium gluconate (5,6), may also ameliorate symptoms during an attack. Despite treatment, however, individuals with HyperKPP frequently develop a slowly progressive vacuolar myopathy that affects proximal muscles by the third decade (10,13,14).…”

Section: Introductionmentioning

confidence: 99%

“…Na V 1.4 comprises a pore-forming 260-kDa protein, the α-subunit ( Figure 1A), which associates with a 38-kDa β 1 subunit (19). The two most common mutations identified in HyperKPP include Thr704Met and Met1592Val, which have each been observed in approximately 30% of kindreds (10). Both of these substitutions are located in regions near the cytoplasmic face of the channel α-subunit.…”

Section: Introductionmentioning

confidence: 99%

“…While all individuals with HyperKPP share a K + -sensitive phenotype (1,26), considerable variability exists with respect to the triggers and severity of attacks in vivo (10,14). Furthermore, inducible attacks of human HyperKPP occur with quite unpredictable success, and the relationship of factors such as muscle cooling to symptoms is not well defined.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, inducible attacks of human HyperKPP occur with quite unpredictable success, and the relationship of factors such as muscle cooling to symptoms is not well defined. For example, exercise and cold are reported as triggers of weakness by patients with the Met1592Val mutation, but only with probabilities of 0.73 and 0.38, respectively (10). While improved electrodiagnostic tests show promise in discriminating among different subgroups of muscle channelopathies (27,28), an in vitro muscle preparation could allow further dissection of the complex physiological interactions that contribute to episodic paralysis.…”

Section: Introductionmentioning

confidence: 99%

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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: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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Ion Channels and Human Disorders

Rayan¹,

Hanna²

2010

Encyclopedia of Life Sciences

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The human channelopathies are a rapidly expanding group of primarily genetic conditions. They are characterised by dysfunction of membrane‐bound glycoproteins (ion channels). Several neurological and general medical disorders have been shown to be due to underlying ion channel dysfunction and genetic analysis is now often routine clinical practice. These disorders exhibit extensive phenotypic and genetic heterogeneity with many distinct diseases caused by dysfunction of the same channel by differing mechanisms. Our understanding of the mechanisms behind these diseases continues to extend as more mutations are identified and functional analysis is performed. In the future this will lead to the identification of better targeted treatments for these diseases. Key Concepts: Ion channels are transmembrane glycoproteins important in intra‐ and intercellular processes. Channelopathies are commonly due to mutations in functionally important regions of either pore‐forming or auxillary channel subunits. Mutations often cause disease by altering channel gating, voltage dependence and channel assembly. Channelopathies may manifest with intermittent symptoms which may completely recover or have a secondary progression. Channleopathies, like myotonia congenita, have extensive phenotypic variability even within a single pedigree. Genetic heterogeneity occurs in many channelopathies like the episodic ataxias and periodic paralyses. In the calcium channel, CACNA1A , different mutations cause distinct central nervous diseases. Mutations in a number of channel genes can increase the predisposition to epilepsy.

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Ion Channels and Human Disorders

Rayan¹,

Hanna²

2018

Encyclopedia of Life Sciences

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The human channelopathies are a rapidly expanding group of primarily genetic conditions. They are characterised by dysfunction of membrane‐bound glycoproteins (ion channels). Several neurological and general medical disorders have been shown to be owing to underlying ion‐channel dysfunction and genetic analysis is now often a routine clinical practice. These disorders exhibit extensive phenotypic and genetic heterogeneity with many distinct diseases caused by dysfunction of the same channel by differing mechanisms. With the advent of the next‐generation sequencing, we are discovering even greater genetic heterogeneity and our understanding of the mechanisms behind these diseases continues to extend as more functional analysis is performed and new techniques are developed. In the future, this will lead to the identification of better targeted treatments for these diseases. Key Concepts Channelopathies are commonly owing to mutations in functionally important regions of either pore‐forming or auxiliary channel subunits resulting in episodic disorders. Mutations often cause disease by altering channel gating, voltage dependence or channel assembly and now there is also evidence for effects in posttranslational modification. Channelopathies are now understood to present either with intermittent symptoms which may completely recover, have a secondary progression or may be a severe primary progressive disease. The location and type of the mutation often influence this. Genetic heterogeneity is very common amongst the channelopathies and is likely to increase with the use of modern genetic analysis. Channelopathies, such as myotonia congenita, have extensive phenotypic variability even within a single pedigree, making it difficult to predict and give accurate genetic counselling.

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Correlating phenotype and genotype in the periodic paralyses

Cited by 229 publications

References 36 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

Ion Channels and Human Disorders

Ion Channels and Human Disorders

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