Spectrum of CLCN1 mutations in patients with myotonia congenita in Northern Scandinavia

Sun, Chen; Tranebjærg, Lisbeth; Torbergsen, T.; Holmgren, Gösta; Ghelue, Marijke Van

doi:10.1038/sj.ejhg.5200736

Cited by 90 publications

(83 citation statements)

References 15 publications

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“…Other studies have reported significantly higher rates; however, most of them predate genetic testing, were restricted to pediatric cases, or were performed in areas with an unusually high population frequency of mutations due to founder effects and geographical factors (e.g., Northern Scandinavia or Ravensberg Land, Germany). [1][2][3][4] This precludes direct comparison with our data. On the other hand, we cannot dismiss the possibility of incomplete case ascertainment in our study.…”

Section: E1mentioning

confidence: 67%

Prevalence study of genetically defined skeletal muscle channelopathies in England

et al. 2013

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Objectives: To obtain minimum point prevalence rates for the skeletal muscle channelopathies and to evaluate the frequency distribution of mutations associated with these disorders.Methods: Analysis of demographic, clinical, electrophysiologic, and genetic data of all patients assessed at our national specialist channelopathy service. Only patients living in the United Kingdom with a genetically defined diagnosis of nondystrophic myotonia or periodic paralysis were eligible for the study. Prevalence rates were estimated for England, December 2011.Results: A total of 665 patients fulfilled the inclusion criteria, of which 593 were living in England, giving a minimum point prevalence of 1.12/100,000 (95% confidence interval [CI] 1.03-1.21). Disease-specific prevalence figures were as follows: myotonia congenita 0.52/100,000 (95% CI 0.46-0.59), paramyotonia congenita 0.17/100,000 (95% CI 0.13-0.20), sodium channel myotonias 0.06/100,000 (95% CI 0.04-0.08), hyperkalemic periodic paralysis 0.17/100,000 (95% CI 0.13-0.20), hypokalemic periodic paralysis 0.13/100,000 (95% CI 0.10-0.17), and Andersen-Tawil syndrome (ATS) 0.08/100,000 (95% CI 0.05-0.10). In the whole sample (665 patients), 15 out of 104 different CLCN1 mutations accounted for 60% of all patients with myotonia congenita, 11 out of 22 SCN4A mutations for 86% of paramyotonia congenita/sodium channel myotonia pedigrees, and 3 out of 17 KCNJ2 mutations for 42% of ATS pedigrees. Conclusion:We describe for the first time the overall prevalence of genetically defined skeletal muscle channelopathies in England. Despite the large variety of mutations observed in patients with nondystrophic myotonia and ATS, a limited number accounted for a large proportion of cases. Neurology â 2013;80:1472-1475 GLOSSARY ATS 5 Andersen-Tawil syndrome; CACNA1S 5 calcium channel, voltage-dependent, L type, a 1S subunit gene; CI 5 confidence interval; CLCN1 5 chloride channel, voltage-sensitive 1 gene; HyperPP 5 hyperkalemic periodic paralysis; HypoPP 5 hypokalemic periodic paralysis; KCNJ2 5 potassium inwardly rectifying channel, subfamily J, member 2 gene; MC 5 myotonia congenita; NDM 5 nondystrophic myotonias; PMC 5 paramyotonia congenita; PP 5 periodic paralyses; SCM 5 sodium channel myotonias; SCN4A 5 sodium channel, voltage-gated, type 4, a subunit gene.Nondystrophic myotonias (NDM) and periodic paralyses (PP) comprise a heterogeneous group of skeletal muscle disorders caused by mutations in genes encoding ion channels.e1 NDM include myotonia congenita (MC), paramyotonia congenita (PMC), and the sodium channel myotonias (SCM). PP encompass hypokalemic periodic paralysis (HypoPP), hyperkalemic periodic paralysis (HyperPP), and Andersen-Tawil syndrome (ATS). These are autosomal dominant disorders except for MC, which is inherited in either a dominant or recessive manner. e1 Although significant progress in the clinical, electrophysiologic, and genetic characterization of the skeletal muscle channelopathies has taken place in the past 2 decades, their actual prevalence rem...

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Section: E1mentioning

confidence: 67%

Prevalence study of genetically defined skeletal muscle channelopathies in England

et al. 2013

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“…In a study of nine recessive families segregating the R894X mutation, Sun et al 27 identified three carrier individuals from different families, who all exhibited latent myotonia. Thus, even within the same family carriers of the recessive R894X mutation can exhibit distinct clinical phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Difference in allelic expression of the CLCN1 gene and the possible influence on the myotonia congenita phenotype

et al. 2004

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Mutations in the CLCN1 gene, encoding a muscle-specific chloride channel, can cause either recessive or dominant myotonia congenita (MC). The recessive form, Becker's myotonia, is believed to be caused by two loss-of-function mutations, whereas the dominant form, Thomsen's myotonia, is assumed to be a consequence of a dominant-negative effect. However, a subset of CLCN1 mutations can cause both recessive and dominant MC. We have identified two recessive and two dominant MC families segregating the common R894X mutation. Real-time quantitative RT-PCR did not reveal any obvious association between the total CLCN1 mRNA level in muscle and the mode of inheritance, but the dominant family with the most severe phenotype expressed twice the expected amount of the R894X mRNA allele. Variation in allelic expression has not previously been described for CLCN1, and our finding suggests that allelic variation may be an important modifier of disease progression in myotonia congenita.

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“…Many patients carry 'private' mutations. It is a particular feature of myotonia congenita that several mutations have been reported to be inherited in both an autosomal dominant and autosomal recessive manner in different families (George et al, 1994;MeyerKleine et al, 1995;Zhang et al, 1996;Papponen et al, 1999;Sun et al, 2001). The advent of molecular genetic testing has demonstrated that familial non-dystrophic myotonia with dominant inheritance is often caused by missense mutations in SCN4A.…”

Section: Genetics Skeletal Muscle Chloride Channelmentioning

confidence: 99%

“…However, the prevalence seems to vary considerably between geographical regions. For example, myotonia congenita alone was estimated to have a prevalence of between 7 and 10 in 100 000 in Scandinavia (Baumann et al, 1998;Sun et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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

Matthews

Fialho

Tan

et al. 2009

Brain

192

226

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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.

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Spectrum of CLCN1 mutations in patients with myotonia congenita in Northern Scandinavia

Cited by 90 publications

References 15 publications

Prevalence study of genetically defined skeletal muscle channelopathies in England

Prevalence study of genetically defined skeletal muscle channelopathies in England

Difference in allelic expression of the CLCN1 gene and the possible influence on the myotonia congenita phenotype

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

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