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Homozygosity for dominant mutations increases severity of muscle channelopathies
Author(s) -
Arzelhézode Marianne,
Sternberg Damien,
Tabti Nacira,
Vicart Savine,
Goizet Cyril,
Eymard Bruno,
Fontaine Bertrand,
Fournier Emmanuel
Publication year - 2010
Publication title -
muscle and nerve
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.025
H-Index - 145
eISSN - 1097-4598
pISSN - 0148-639X
DOI - 10.1002/mus.21520
Subject(s) - myotonia , myotonia congenita , sodium channel , periodic paralysis , penetrance , hypokalemic periodic paralysis , medicine , channelopathy , pathophysiology , myotonic dystrophy , mutation , genetics , heterozygote advantage , mexiletine , endocrinology , phenotype , genotype , biology , paralysis , gene , chemistry , sodium , surgery , hypokalemia , organic chemistry
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. Muscle Nerve, 2010