Membrane defects in paramyotonia congenita with and without myotonia in a warm environment

Lehmann‐Horn, Frank; Rüdel, Reinhardt; Dengler, Reinhard; Lorković, Hrvoje; Haaß, A.; Ricker, K.

doi:10.1002/mus.880040508

Cited by 85 publications

(32 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Given some of the shared clinical features of hyperkalaemic periodic paralysis and paramyotonia congenita and the recognition of abnormal sodium conductance in both (Lehmann-Horn et al, 1981, 1987a it was proposed and subsequently confirmed that paramyotonia congenita and hyperkalaemic periodic paralysis were allelic disorders (Koch et al, 1991a;Ptacek et al, 1991a, b;Rojas et al, 1991;McClatchey et al, 1992a, b). Later the phenotypes grouped together as the potassium aggravated myotonias were also shown to be sodium channel disorders (Lerche et al, 1993;Ptacek et al, 1994;Ricker et al, 1994) All the skeletal muscle sodium channelopathies are autosomal dominant conditions and de novo mutations can occur.…”

Section: Skeletal Muscle Sodium Channelmentioning

confidence: 99%

The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment

Matthews

Fialho

Tan

et al. 2009

Brain

196

226

View full text Add to dashboard Cite

The non-dystrophic myotonias are an important group of skeletal muscle channelopathies electrophysiologically characterized by altered membrane excitability. Many distinct clinical phenotypes are now recognized and range in severity from severe neonatal myotonia with respiratory compromise through to milder late-onset myotonic muscle stiffness. Specific genetic mutations in the major skeletal muscle voltage gated chloride channel gene and in the voltage gated sodium channel gene are causative in most patients. Recent work has allowed more precise correlations between the genotype and the electrophysiological and clinical phenotype. The majority of patients with myotonia have either a primary or secondary loss of membrane chloride conductance predicted to result in reduction of the resting membrane potential. Causative mutations in the sodium channel gene result in an abnormal gain of sodium channel function that may show marked temperature dependence. Despite significant advances in the clinical, genetic and molecular pathophysiological understanding of these disorders, which we review here, there are important unresolved issues we address: (i) recent work suggests that specialized clinical neurophysiology can identify channel specific patterns and aid genetic diagnosis in many cases however, it is not yet clear if such techniques can be refined to predict the causative gene in all cases or even predict the precise genotype; (ii) although clinical experience indicates these patients can have significant progressive morbidity, the detailed natural history and determinants of morbidity have not been specifically studied in a prospective fashion; (iii) some patients develop myopathy, but its frequency, severity and possible response to treatment remains undetermined, furthermore, the pathophysiogical link between ion channel dysfunction and muscle degeneration is unknown; (iv) there is currently insufficient clinical trial evidence to recommend a standard treatment. Limited data suggest that sodium channel blocking agents have some efficacy. However, establishing the effectiveness of a therapy requires completion of multi-centre randomized controlled trials employing accurate outcome measures including reliable quantitation of myotonia. More specific pharmacological approaches are required and could include those which might preferentially reduce persistent muscle sodium currents or enhance the conductance of mutant chloride channels. Alternative strategies may be directed at preventing premature mutant channel degradation or correcting the mis-targeting of the mutant channels.

show abstract

Section: Skeletal Muscle Sodium Channelmentioning

confidence: 99%

The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment

Matthews

Fialho

Tan

et al. 2009

Brain

196

226

View full text Add to dashboard Cite

show abstract

“…Voltage-clamp experiments were performed on the same fibres with three microelectrodes in either normal or Cl--free solutions (Lehmann-Horn, Riudel, Dengler, Lorkovic, Haass & Ricker, 1981). Data were collected and analysed with a computer system (Digital Equipment Corporation, Maynard, MA, USA).…”

Section: Electrical Membrane Propertiesmentioning

confidence: 99%

Characteristics of Na+ channels and Cl‐ conductance in resealed muscle fibre segments from patients with myotonic dystrophy.

Franke¹,

Hatt²,

Iaizzo³

et al. 1990

The Journal of Physiology

View full text Add to dashboard Cite

SUMMARY1. Electrical and contractile properties of resealed fibre segments were investigated by a variety of in vitro techniques. The preparations were removed from skeletal muscles of normal subjects and of eight patients with myotonic dystrophy.2. Several hours after removal, fibre segments from normal subjects and those patients in whom myotonia was the primary symptom had resting membrane potentials of approximately -80 mV. In contrast, fibre segments obtained from patients in whom muscle dystrophy was more expressed were depolarized (-60 to -70 mV).3. Contractions induced in fibre segments of myotonic muscle which had normal potentials were characterized by slowed relaxation which was due to electrical afteractivity.4. After single stimuli, long-lasting (3-100) runs of action potentials were recorded intracellularly from the myotonic muscle. In some of these fibre segments complex repetitive discharges were observed; multiple sites of locally gated currents were identified.5. The three-electrode voltage clamp was used to determine the total membrane conductance, gm, and the ion component conductances. All fibres of a particular patient had similar conductances. However, the Cl-conductance varied from patient to patient from normal (74 % of gm) to low values (30 % of gm). The K+ conductance was normal in all fibres of all patients.6. The patch-clamp technique was used to record currents through single Na+ channels of the sarcolemma. After treatment of the fibre segments with collagenase gigaohm seals were routinely obtained. The rate of success was greater when using the cell-attached mode than the inside-out mode.7. Sodium channel currents were elicited by depolarizing voltage steps which produced an initial burst of Na+ channel openings. Up to ten channels were activated simultaneously when the patch was depolarized to potentials more positive than -30 mV. The Na+ channels re-opened very rarely in controls. The macroscopic sodium current, INa' was reconstructed by averaging depolarizing pulses. The time I Present address: Department of Anaesthesiology, Mayo Clinic, Rochester, MN 55905, USA. MS 794932C FRANKE AND OTHERS constant of rapid decay of INa reflecting macroscopic inactivation, the onset of INa and the amplitude OfINa were voltage dependent. The mean amplitude of the current produced by re-openings was on average only 0 11 + 0 04 % of the amplitude of the peak current.8. Late openings of the Na+ channels were frequent in patches on the myotonic fibre segments. The amplitude of the current produced by re-openings was as high as about 0-75 + 0.11 % of the amplitude of the peak current. These re-openings were apparently unrelated to the reduced Cl-conductance because they were observed in fibre segments of patients with normal Cl-conductance and were not detected in control muscle which was treated with the Cl-channel blocker 9-anthracene carboxylic acid. The open time of the re-openings varied between 0 7 and 0-8 ms at all potentials.9. We conclude that a reduced Cl-conductance is not essential for t...

show abstract

“…7 Meanwhile, in a second group of NDMs, impaired inactivation of voltage-gated sodium channels was observed. 8 Various researchers later independently linked PC and PAM to the skeletal muscle sodium channel gene (SCN4A (OMIM 603967)), genetically mapped to chromosome 17q23 -25. 9 -11 To date, at least 30 different missense mutations have been identified in this gene.…”

Section: Introductionmentioning

confidence: 99%

In tandem analysis of CLCN1 and SCN4A greatly enhances mutation detection in families with non-dystrophic myotonia

et al. 2008

View full text Add to dashboard Cite

Non-dystrophic myotonias (NDMs) are caused by mutations in CLCN1 or SCN4A. The purpose of the present study was to optimize the genetic characterization of NDM in The Netherlands by analysing CLCN1 and SCN4A in tandem. All Dutch consultant neurologists and the Dutch Patient Association for Neuromuscular Diseases (Vereniging Spierziekten Nederland) were requested to refer patients with an initial diagnosis of NDM for clinical assessment and subsequent genetic analysis over a full year. Based on clinical criteria, sequencing of either CLCN1 or SCN4A was performed. When previously described mutations or novel mutations were identified in the first gene under study, the second gene was not sequenced. If no mutations were detected in the first gene, the second gene was subsequently also analysed. Underlying NDM mutations were explored in 54 families. In total, 20% (8 of 40) of our probands with suspected chloride channel myotonia showed no CLCN1 mutations but subsequent SCN4A screening revealed mutations in all of them. All 14 probands in whom SCN4A was primarily sequenced showed a mutation. In total, CLCN1 mutations were identified in 32 families (59%) and SCN4A in 22 (41%), resulting in a diagnostic yield of 100%. The yield of mutation detection was 93% with three recessive and three sporadic cases not yielding a second mutation. Among these mutations, 13 in CLCN1 and 3 in SCN4A were novel. In conclusion, the current results show that in tandem analysis of CLCN1 and SCN4A affords high-level mutation ascertainment in families with NDM.

show abstract

Membrane defects in paramyotonia congenita with and without myotonia in a warm environment

Cited by 85 publications

References 15 publications

The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment

The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment

Characteristics of Na+ channels and Cl‐ conductance in resealed muscle fibre segments from patients with myotonic dystrophy.

In tandem analysis of CLCN1 and SCN4A greatly enhances mutation detection in families with non-dystrophic myotonia

Contact Info

Product

Resources

About