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Myotonia and the muscle chloride channel: dominant mutations show variable penetrance and founder effect
P P Koty1, E Pegoraro, G Hobson
1Department of Molecular Genetics, University of Pittsburgh School of Medicine, PA 15261, USA.
Abstract:
The delayed relaxation or sustained contraction of skeletal muscle-myotonia-is frequently seen in myotonic dystrophy and sodium channelopathies (hyperkalemic periodic paralysis, paramyotonia congenita). Many cases of congenital myotonia without other clinical symptoms have been associated with mutations in the muscle chloride channel gene. Most cases reported to date show a recessive inheritance pattern, with loss of function of the corresponding protein. Six families have been reported with dominantly inherited myotonia and mutations of the chloride channel gene. Here we report clinical and molecular data on 38 family members from four new families with dominantly inherited myotonia congenita. Three families show a previously characterized G230E mutation, and we show that these three share a common affected ancestor despite living in different regions of the United States (linkage disequilibrium). One Italian family is shown to have a novel dominant mutation-I290M. This is the sixth mutation identified in Thomsen's myotonia. Genotype/phenotype correlations in these four families showed that both of the dominant mutations resulted in a mild clinical picture in 90% of the patients, and no symptoms in 10% of mutation-positive patients. The EMG was the clinical feature that most closely correlated with mutation data; however, 3 of 16 (19%) mutation-positive patients tested negative by electromyography at least once, and 1 (6%) tested negative despite multiple tests. Only about half (55%) of the mutation-positive patients tested positive for percussion myotonia. Most of the clinically symptomatic individuals stated that cold temperatures and stress substantially worsened their myotonia. Our data show that dominantly inherited Thomsen's myotonia is most often a very mild disorder that shows considerable clinical heterogeneity.
Insights
Dominantly inherited Thomsen's myotonia, caused by chloride channel gene mutations, is typically mild. Clinical presentation varies, with symptoms often worsening due to cold and stress.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Myotonia, characterized by delayed muscle relaxation, is linked to myotonic dystrophy and sodium channelopathies.
- Congenital myotonia is often associated with muscle chloride channel gene mutations, typically with recessive inheritance.
- Dominant inheritance of myotonia due to chloride channel mutations is less common, with only six families previously reported.
Purpose of the Study:
- To investigate the clinical and molecular characteristics of dominantly inherited myotonia congenita.
- To identify novel mutations in the muscle chloride channel gene associated with dominant myotonia.
- To explore genotype-phenotype correlations in families with dominant myotonia congenita.
Main Methods:
- Clinical evaluation and molecular genetic analysis of 38 family members across four new families.
- Identification and characterization of mutations in the muscle chloride channel gene.
- Genotype-phenotype correlation analysis, including electromyography (EMG) and percussion myotonia assessments.
Main Results:
- Three families carried the known G230E mutation, suggesting a common ancestor.
- One Italian family presented with a novel dominant mutation, I290M.
- Genotype-phenotype correlation revealed a mild clinical picture in 90% of patients with dominant mutations; 10% were asymptomatic.
- EMG correlated with mutation data, though some mutation-positive patients tested negative.
- Percussion myotonia was positive in 55% of mutation-positive patients.
- Cold temperatures and stress exacerbated symptoms in symptomatic individuals.
Conclusions:
- Dominantly inherited Thomsen's myotonia is generally a mild disorder with significant clinical heterogeneity.
- The study identified two dominant mutations in the chloride channel gene, expanding the known mutation spectrum.
- Clinical variability and potential for negative diagnostic tests (EMG, percussion myotonia) highlight the complexity of diagnosing this condition.