title: Myotonia and the muscle chloride channel: dominant mutations show variable penetrance and founder effect.
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.
authors.affiliation: Department of Molecular Genetics, University of Pittsburgh School of Medicine, PA 15261, USA.
authors.forename: P P
authors.initials: PP
authors.lastname: Koty
authors.forename: E
authors.initials: E
authors.lastname: Pegoraro
authors.forename: G
authors.initials: G
authors.lastname: Hobson
authors.forename: H G
authors.initials: HG
authors.lastname: Marks
authors.forename: A
authors.initials: A
authors.lastname: Turel
authors.forename: D
authors.initials: D
authors.lastname: Flagler
authors.forename: M
authors.initials: M
authors.lastname: Cadaldini
authors.forename: C
authors.initials: C
authors.lastname: Angelini
authors.forename: E P
authors.initials: EP
authors.lastname: Hoffman
mesh_terms: D000328:Adult; D018118:Chloride Channels / Q000235:genetics*; D005260:Female; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D009154:Mutation; D009222:Myotonia / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational
chemical_list: D018118:Chloride Channels