Clinical and ultrastructural observations in a kindred with normo-hyperkalaemic periodic paralysis.

Danowski, T. S.; Fisher, E R; Vidalon, C.; Vester, John W.; Thompson, Robert E.; Nolan, Sean; Stephan, T; Sunder, J. H.

doi:10.1136/jmg.12.1.20

Cited by 7 publications

(2 citation statements)

References 33 publications

(37 reference statements)

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“…Three point mutations in the skeletal muscle dihydropyridine sensitive calcium channel (CACLN1A3) are responsible for most cases of hypoKPP, and mutations in the muscle‐specific sodium channel gene ( SCN4A ) have been identified in a spectrum of disorders that includes hyperKPP, paramyotonia congenita, and potassium aggravated myotonia 1. Despite its prominence in standard texts, normoKPP has been reported only in a few families 2–4. Clinical and molecular reanalysis of some of the original cases of normoKPP confirmed earlier suspicions that these families actually had a variant of hyperKPP due to a SCN4A gene mutation 1, 5.…”

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confidence: 63%

Normokalemic periodic paralysis revisited: Does it exist?

Chinnery

Walls

Hanna³

et al. 2002

Annals of Neurology

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Normokalemic periodic paralysis (normoKPP) is well established in the literature, but there are doubts as to whether it exists as a discrete entity. Retrospective clinical and molecular analysis has confirmed suspicions that most normoKPP families actually have a variant of hyperkalemic periodic paralysis (hyperKPP) due to a mutation of the muscle-specific sodium channel gene (SCN4A). However, the original normoKPP family described by Poskanzer and Kerr (Poskanzer DC, Kerr DNS. A third type of periodic paralysis, with normokalemia and favourable response to sodium chloride. Am J Med 1961;31:328-342) has remained unchallenged. We identified the Met1592Val mutation of SCN4A in an affected descendent of this original normoKPP family. This is the final piece in the puzzle: normoKPP is actually a variant of hyperKPP and is not a distinct disorder.

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confidence: 63%

Normokalemic periodic paralysis revisited: Does it exist?

Chinnery

Walls

Hanna³

et al. 2002

Annals of Neurology

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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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AAEE minimonograph #27: Differential diagnosis of myotonic syndromes

Streib

1987

Muscle and Nerve

127

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Recent advances in neuromuscular diseases have also widened the diagnostic spectrum of myotonic disorders. Treatment, prognosis, and genetic aspects are different in the various syndromes and mandate a correct diagnosis. The combination of neurologic examination, standard EMG, exercise test, cold exposure, potassium loading, eye examination, and pedigree analysis allows correct classification of nearly all patients with myotonic disorders. In this review emphasis is placed on clinical features and electrophysiologic evaluation.

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Clinical and ultrastructural observations in a kindred with normo-hyperkalaemic periodic paralysis.

Cited by 7 publications

References 33 publications

Normokalemic periodic paralysis revisited: Does it exist?

Normokalemic periodic paralysis revisited: Does it exist?

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

AAEE minimonograph #27: Differential diagnosis of myotonic syndromes

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