Channelopathies: The nondystrophic myotonias and periodic paralyses

Lehmann‐Horn, Frank; Rüdel, Reinhardt

doi:10.1016/s1071-9091(96)80041-6

Cited by 69 publications

(112 citation statements)

References 93 publications

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“…Hyperkalemic periodic paralysis (HyperKPP) is one of several familial disorders of muscle excitability caused by missense mutations in the skeletal muscle Na + channel Na V 1.4 (1,2). Na V 1.4 normally allows rapid propagation of the muscle action potential along the surface membrane and radially into the myofiber via the transverse (t) tubules, where depolarization triggers Ca 2+ release from the sarcoplasmic reticulum.…”

Section: Introductionmentioning

confidence: 99%

“…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%

“…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). The latter agents, and inhaled β-adrenergic agonists (9,12) or intravenous calcium gluconate (5,6), may also ameliorate symptoms during an attack.…”

Section: Introductionmentioning

confidence: 99%

“…Subsequent studies identified more than 30 missense mutations in SCN4A among individuals with overlapping phenotypes of Hyper-KPP and related disorders (1,2,18). 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).…”

Section: Introductionmentioning

confidence: 99%

“…Electrophysiological studies of mutant Na + channels in heterologous expression systems have demonstrated functional abnormalities that may contribute to the phenotypic heterogeneity observed among different families with HyperKPP and related myotonic disorders (1,2). For instance, HyperKPP mutant Na + channels can exhibit enhanced activation, impaired slow inactivation, and a persistent noninactivating inward current (20)(21)(22).…”

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%

See 3 more Smart Citations

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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Channelopathies of Skeletal Muscle Excitability

Cannon

2015

Comprehensive Physiology

173

176

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Familial disorders of skeletal muscle excitability were initially described early in the last century and are now known to be caused by mutations of voltage-gated ion channels. The clinical manifestations are often striking, with an inability to relax after voluntary contraction (myotonia) or transient attacks of severe weakness (periodic paralysis). An essential feature of these disorders is fluctuation of symptoms that are strongly impacted by environmental triggers such as exercise, temperature, or serum K+ levels. These phenomena have intrigued physiologists for decades, and in the past 25 years the molecular lesions underlying these disorders have been identified and mechanistic studies are providing insights for therapeutic strategies of disease modification. These familial disorders of muscle fiber excitability are “channelopathies” caused by mutations of a chloride channel (ClC-1), sodium channel (NaV1.4), calcium channel (CaV1.1) and several potassium channels (Kir2.1, Kir2.6, Kir3.4). This review provides a synthesis of the mechanistic connections between functional defects of mutant ion channels, their impact on muscle excitability, how these changes cause clinical phenotypes, and approaches toward therapeutics.

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Molecular diagnosis of inheritable neuromuscular disorders. Part II: Application of genetic testing in neuromuscular disease

Greenberg

Walsh

2005

Muscle and Nerve

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Molecular genetic advances have led to refinements in the classification of inherited neuromuscular disease, and to methods of molecular testing useful for diagnosis and management of selected patients. Testing should be performed as targeted studies, sometimes sequentially, but not as wasteful panels of multiple genetic tests performed simultaneously. Accurate diagnosis through molecular testing is available for the vast majority of patients with inherited neuropathies, resulting from mutations in three genes (PMP22, MPZ, and GJB1); the most common types of muscular dystrophies (Duchenne and Becker, facioscapulohumeral, and myotonic dystrophies); the inherited motor neuron disorders (spinal muscular atrophy, Kennedy's disease, and SOD1 related amyotrophic lateral sclerosis); and many other neuromuscular disorders. The role of potential multiple genetic influences on the development of acquired neuromuscular diseases is an increasingly active area of research.

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Channelopathies: The nondystrophic myotonias and periodic paralyses

Cited by 69 publications

References 93 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

Channelopathies of Skeletal Muscle Excitability

Molecular diagnosis of inheritable neuromuscular disorders. Part II: Application of genetic testing in neuromuscular disease

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