title: Homozygosity for dominant mutations increases severity of muscle channelopathies.
abstract: Muscle channelopathies caused by mutations in the SCN4A gene that encodes the muscle sodium channel are transmitted by autosomal-dominant inheritance. We report herein the first cases of homozygous patients for sodium channel mutations responsible for paramyotonia congenita (I1393T) or hypokalemic periodic paralysis (R1132Q). A parallel was drawn between this unprecedented situation and that of myotonia congenita by including patients homozygous or heterozygous for the CLCN1 I556N channel mutation, which is known for incomplete dominance and penetrance. Standardized electromyographic (EMG) protocols combining exercise and cold served as provocative tests to compare homozygotes with heterozygotes for each of the three mutations. Surface-recorded compound muscle action potentials (CMAPs) were used to monitor muscle electrical activity, and myotonic discharges were evaluated by needle EMG. In heterozygous patients, exercise tests disclosed abnormal patterns of CMAP changes, which matched those previously described for similar dominant sodium and chloride channel mutations. Homozygotes showed much more severe clinical features and CMAP changes. We hypothesized that the presence of 100% defective ion channels in the homozygotes could account for the most severe phenotype. This suggests that the severity of muscle channelopathies depends both on the degree of channel impairment caused by the mutation and on the number of mutant channels engaged in the pathophysiological process. Overall, this study has practical consequences for the diagnosis of muscle channelopathies and raises new questions about their pathophysiology.
authors.affiliation: Centre de référence des canalopathies musculaires, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Arzel-Hézode
authors.forename: Damien
authors.initials: D
authors.lastname: Sternberg
authors.forename: Nacira
authors.initials: N
authors.lastname: Tabti
authors.forename: Savine
authors.initials: S
authors.lastname: Vicart
authors.forename: Cyril
authors.initials: C
authors.lastname: Goizet
authors.forename: Bruno
authors.initials: B
authors.lastname: Eymard
authors.forename: Bertrand
authors.initials: B
authors.lastname: Fontaine
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Fournier
mesh_terms: D000328:Adult; D053447:Channelopathies / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D005080:Exercise Test / Q000379:methods; D005260:Female; D005799:Genes, Dominant / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D012720:Severity of Illness Index; D055815:Young Adult