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

E. Matthews, D. Fialho, S. V. Tan, S. L. Venance, S. C. Cannon, D. Sternberg, B. Fontaine, A. A. Amato, R. J. Barohn, R. C. Griggs, M. G. Hanna

Research output: Contribution to journalArticle

113 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)9-22
Number of pages14
JournalBrain
Volume133
Issue number1
DOIs
StatePublished - Jan 2010

Fingerprint

Myotonia
Sodium Channels
Chloride Channels
Muscles
Genes
Skeletal Muscle
Genotype
Channelopathies
Voltage-Gated Sodium Channels
Morbidity
Phenotype
Neurophysiology
Mutation
Membranes
Muscular Diseases
Therapeutics
Natural History
Ion Channels
Membrane Potentials
Chlorides

Keywords

  • EMG
  • Genetics
  • Ion channels
  • Neuromuscular

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Matthews, E., Fialho, D., Tan, S. V., Venance, S. L., Cannon, S. C., Sternberg, D., ... Hanna, M. G. (2010). The non-dystrophic myotonias: Molecular pathogenesis, diagnosis and treatment. Brain, 133(1), 9-22. https://doi.org/10.1093/brain/awp294

The non-dystrophic myotonias : Molecular pathogenesis, diagnosis and treatment. / Matthews, E.; Fialho, D.; Tan, S. V.; Venance, S. L.; Cannon, S. C.; Sternberg, D.; Fontaine, B.; Amato, A. A.; Barohn, R. J.; Griggs, R. C.; Hanna, M. G.

In: Brain, Vol. 133, No. 1, 01.2010, p. 9-22.

Research output: Contribution to journalArticle

Matthews, E, Fialho, D, Tan, SV, Venance, SL, Cannon, SC, Sternberg, D, Fontaine, B, Amato, AA, Barohn, RJ, Griggs, RC & Hanna, MG 2010, 'The non-dystrophic myotonias: Molecular pathogenesis, diagnosis and treatment', Brain, vol. 133, no. 1, pp. 9-22. https://doi.org/10.1093/brain/awp294
Matthews E, Fialho D, Tan SV, Venance SL, Cannon SC, Sternberg D et al. The non-dystrophic myotonias: Molecular pathogenesis, diagnosis and treatment. Brain. 2010 Jan;133(1):9-22. https://doi.org/10.1093/brain/awp294
Matthews, E. ; Fialho, D. ; Tan, S. V. ; Venance, S. L. ; Cannon, S. C. ; Sternberg, D. ; Fontaine, B. ; Amato, A. A. ; Barohn, R. J. ; Griggs, R. C. ; Hanna, M. G. / The non-dystrophic myotonias : Molecular pathogenesis, diagnosis and treatment. In: Brain. 2010 ; Vol. 133, No. 1. pp. 9-22.
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