Sodium channel mutations in acetazolamide‐responsive myotonia congenita, paramyotonia congenita, and hyperkalemic periodic paralysis

  title={Sodium channel mutations in acetazolamide‐responsive myotonia congenita, paramyotonia congenita, and hyperkalemic periodic paralysis},
  author={Louis J. Pt{\'a}{\vc}ek and Rabi Tawil and Robert C. Griggs and Giovanni Meola and Philip G. McManis and Richard J. Barohn and Jerry R. Mendell and Chris M. Harris and Robert M. Spitzer and F. Santiago and M. Leppert},
  pages={1500 - 1500}
Hyperkalemic periodic paralysis (hyperKPP) and paramyotonia congenita (PC) are genetic muscle disorders sharing the common features of myotonia and episodic weakness. In hyperKPP, patient symptoms and signs are worsened by elevated serum potassium, whereas in PC, muscle cooling exacerbates the condition. There are patients in whom features of both hyperKPP and PC are present. These diseases result from molecular alterations in the adult skeletal muscle sodium channel. This report summarizes our… 

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Mutation in the S4 segment of the adult skeletal sodium channel gene in an Italian Paramyotonia Congenita (PC) family

A mutation in an S4 segment of the adult skeletal muscle sodium channel in a clinically-defined Italian family is described that leads to the paramyotonia congenita (PC) phenotype with dominant autosomal inheritance and temperature-related symptoms (regional weakness following cooling and exercise), present since childhood in all of the affected family members.

From mutation to myotonia in sodium channel disorders

Muscle channelopathies and electrophysiological approach

Five electromyographic patterns (I-V) that may be used in clinical practice as guides for molecular diagnosis are discussed and can be used as a functional test in electromyography to improve the diagnosis of these muscle disorders.

Lack of sodium channel mutation in an Italian family with paramyotonia congenita.

The existence of a second gene different from SCN4A that can give rise to a clinical PC phenotype can be speculated upon.

Skeletal muscle channelopathies: nondystrophic myotonias and periodic paralysis.

Recent discoveries in the skeletal muscle channelopathies have increased understanding of the genetics and pathophysiology of these diseases, and studies reporting imaging techniques raise the possibility of improved disease monitoring and better outcome measures for clinical trials.

Hypokalemic periodic paralysis and the dihydropyridine receptor (CACNL1A3): genotype/phenotype correlations for two predominant mutations and evidence for the absence of a founder effect in 16 caucasian families.

It is shown that a founder effect is unlikely to account for the two predominant mutations in hypoPP, and analysis of the clinical characteristics of both groups of families demonstrated that incomplete penetrance is a distinctive feature of the Arg528His mutation.

Hypokalaemic periodic paralysis type 2 caused by mutations at codon 672 in the muscle sodium channel gene SCN4A.

A complete penetrance in men and women, an early age at onset, postcritic myalgias and an increased number and severity of attacks induced by acetazolamide are observed in a large hypoPP family carrying an SCN4A mutation.

Correlating phenotype and genotype in the periodic paralyses

This series of 226 patients (127 kindreds) confirms some clinical features of this disorder with notable exceptions: in this series, patients without mutations had a less typical clinical presentation including an older age at onset, no changes in diet as a precipitant, and absence of vacuolar myopathy on muscle biopsy.



Paramyotonia congenita and hyperkalemic periodic paralysis are linked to the adult muscle sodium channel gene

The hypothesis that hyperkalemic periodic paralysis (without myotonia) and paramyotonia congenita are tightly linked to the tetrodotoxin‐sensitive adult skeletal muscle sodium channel gene on chromosome 17q23‐25 in two large pedigrees is tested.

Sodium channel mutations in paramyotonia congenita and hyperkalemic periodic paralysis

Five other HYPP and PC families have been ascertained, and previously reported sodium channel mutations have been identified in each, and an additional mutation is reported, a leucine ‐ arginine substirution in the ss segment of domain 4 (L1433R), that results in the PC phenotype.

Paramyotonia congenita and hyperkalemic periodic paralysis map to the same sodium-channel gene locus.

Linkage results implicate a sodium-channel gene as an important candidate for the site of mutation responsible for PC, and provide strong evidence for the hypothesis that PC and HYPP are allelic disorders.

Hyperkalemic periodic paralysis

A novel procedure is described, using ligase chain reaction (LCR), to simultaneously identify two different point mutations and one rare, apparently benign polymorphism that results in a nonconservative amino acid substitution in hyperkalemic periodic paralysis.

Novel mutations in families with unusual and variable disorders of the skeletal muscle sodium channel

Two mutations in SCN4A which affect regions of the sodium channel not previously associated with a disease phenotype are found, causing affected family members to display an unusual mixture of clinical features reminiscent of PMC, HPP and of a third disorder, myotonia congenita (MC).

Linkage of atypical myotonia congenita to a sodium channel locus

The molecular alteration causing acetazolamide-responsive myotonia congenita is likely an allelic defect in this human, skeletal-muscle, sodium channel gene.

A Met-to-Val mutation in the skeletal muscle Na+ channel α-subunit in hyperkalaemic periodic paralysis

An A - G substitution in the patient's messenger RNA that causes a Met-Val change in a highly conserved region of the α-subunit, predicted to be in a transmembrane domain is identified and discovered a voltage-gated channel mutation responsible for a human genetic disease.

Acetazolamide‐responsive myotonia congenita

Muscle biopsies showed the presence of type 1, 2A, and 2B fibers, as opposed to the absence of type 2B fiber seen in some patients with myotonia congenita, and Acetazolamide was dramatically effective in alleviatingMyotonia in all patients and was more effective than other antimyotonic agents.