Periodic muscle weakness, normokalemia, and tubular aggregates

Meyers, Karl R.; Gilden, Donald H.; Rinaldi, Charles F.; Hansen, James L.

doi:10.1212/wnl.22.3.269

Cited by 47 publications

(11 citation statements)

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“…The disorder resembled hyperkalemic PP in many aspects; the only real differences were the lack of increase in the concentration of serum potassium even during serious attacks, and the lack of a beneficial effect of glucose administration. 11,12 The existence of normokalemic PP as a nosologic entity was questioned, because of the potassium sensitivity of the patients and the identification of the most frequent hyperkalemic PP mutations T704M or M1592V in such families, including the original family. 4,13 Recently, a potassium-sensitive type of PP with normokalemia and episodes of weakness reminiscent of those in both hyperkalemic and hypokalemic PP was reported.…”

Section: Normokalemic Periodic Paralysis: a Separate Entity?mentioning

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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Section: Normokalemic Periodic Paralysis: a Separate Entity?mentioning

confidence: 99%

Genotype-Phenotype Correlation and Therapeutic Rationale in Hyperkalemic Periodic Paralysis

Jurkat‐Rott¹,

Lehmann‐Horn²

2007

Neurotherapeutics

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“…Some patients with periodic paralysis have serum potassium in the normal physiological range during attacks of weakness (3.0-5.5 mM) (15)(16)(17), suggesting an intermediate category of normokalemic periodic paralysis (NormoPP). However, studies of patients with the T704M mutation revealed increased blood potassium levels during attacks in 50% of cases (18), and some of families diagnosed as NormoPP were subsequently found to have the HyperPP mutations T704M or M1592V, leading to the suggestion that NormoPP may be a phenotypic variant of HyperPP (19).…”

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confidence: 99%

Depolarization-activated gating pore current conducted by mutant sodium channels in potassium-sensitive normokalemic periodic paralysis

Sokolov

Scheuer

Catterall

2008

Proc. Natl. Acad. Sci. U.S.A.

125

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Some inherited periodic paralyses are caused by mutations in skeletal muscle Na V1.4 sodium channels that alter channel gating and impair action potential generation. In the case of hypokalemic periodic paralysis, mutations of one of the outermost two gating charges in the S4 voltage sensor in domain II of the Na V1.4 ␣ subunit induce gating pore current, resulting in a leak of sodium or protons through the voltage sensor that causes depolarization, sodium overload, and contractile failure correlated with low serum potassium. Potassium-sensitive normokalemic periodic paralysis (NormoPP) is caused by mutations in the third gating charge in domain II of the Na V1.4 channel. Here, we report that these mutations in rat Na V1.4 (R669Q/G/W) cause gating pore current that is activated by depolarization and therefore is conducted in the activated state of the voltage sensor. In addition, we find that this gating pore current is retained in the slow-inactivated state and is deactivated only at hyperpolarized membrane potentials. Gating pore current through the mutant voltage sensor of slowinactivated NormoPP channels would cause increased sodium influx at the resting membrane potential and during trains of action potentials, depolarize muscle fibers, and lead to contractile failure and cellular pathology in NormoPP.skeletal muscle ͉ Nav 1.4 ͉ gating charge ͉ voltage sensor V oltage-gated sodium channels in skeletal muscle (Na V 1.4) generate action potentials that initiate muscle contraction in response to nerve stimulation. They are complexes of a large pore-forming ␣-subunit and a small, auxiliary ␤1-subunit (1-4). The ␣-subunits are organized in 4 repeated domains with 6 transmembrane segments (S1-S6) and a reentrant P loop between S5 and S6 (4, 5). The voltage sensitivity of sodium channels arises from the force of the transmembrane electric field exerted on arginine residues in 3-residue repeat motifs in the S4 transmembrane segments, which move outward upon depolarization and initiate a conformational change that opens the central pore (4, 6).The periodic paralyses are rare, dominantly inherited muscle disorders characterized by episodic attacks of muscle weakness (7). Hyperkalemic periodic paralysis (HyperPP) and paramyotonia congenita are caused by mutations in the ␣ subunit of skeletal muscle Na V 1.4 channels that are widely spread through the protein and usually cause a gain-of-function by impairing fast and/or slow inactivation (8). Increased sodium channel activity leads to depolarization, hyperexcitability, and either repetitive firing or depolarization block. In contrast, hypokalemic periodic paralysis (HypoPP) is caused by mutations in both the ␣-subunit of the Na V 1.4 channel and the homologous ␣1-subunit of the skeletal muscle Ca V 1.1 channel, which initiates excitationcontraction coupling (8). In HypoPP, mutations in both of these large channel proteins specifically target the outermost two gating-charge-carrying arginine residues in their S4 voltage sensors in domains II, III, or IV. The convergence...

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“…36,37 In two individuals with normokalemic PP neither potassium nor glucose precipitated attacks. 38 Both had vacuoles and collections of tubular aggregates on muscle biopsy, and the clinical features were similar to those of a cohort of patients who were later identified as having a sodium channel mutation associated with FIG. 5.…”

Section: Provocative Challenges In the Diagnosis Of Muscle Channelopamentioning

confidence: 53%

Clinical Evaluation of Membrane Excitability in Muscle Channel Disorders: Potential Applications in Clinical Trials

Cleland

Logigian

2007

Neurotherapeutics

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Summary:Muscle channelopathies are inherited disorders that cause paralysis and myotonia. Molecular technology has contributed immeasurably to diagnostic testing, to correlation of genotype with phenotype, and to insight into the pathophysiology of these disorders. In most cases, the diagnosis of muscle channelopathy is still made on clinical grounds, but is supported by ancillary laboratory and electrodiagnostic testing such as serum potassium measurement, exercise testing, repetitive nerve stimulation, needle electromyography, calculation of muscle fiber conduction velocity, or electromyography power spectra. Although provocative glucose or potassium challenges are now infrequently performed, they have contributed greatly to our understanding of the pathophysiology of these disorders, and to our ability to differentiate between periodic paralysis types. Despite considerable progress, ample opportunity remains for future clinical research, particularly in expanding genotype-phenotype correlations and in optimizing electrodiagnostic methods. With respect to diagnostic testing, there is a need for accurate, efficient, and cost-effective bedside testing, given the substantial proportion (as high as 20%) of genetically undefined cases. Even in genetically defined cases, minimal clinical expressivity due to incomplete penetrance poses a significant challenge to currently available nonmolecular testing.

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Periodic muscle weakness, normokalemia, and tubular aggregates

Cited by 47 publications

References 0 publications

Genotype-Phenotype Correlation and Therapeutic Rationale in Hyperkalemic Periodic Paralysis

Genotype-Phenotype Correlation and Therapeutic Rationale in Hyperkalemic Periodic Paralysis

Depolarization-activated gating pore current conducted by mutant sodium channels in potassium-sensitive normokalemic periodic paralysis

Clinical Evaluation of Membrane Excitability in Muscle Channel Disorders: Potential Applications in Clinical Trials

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