MYOTONIA AND THE MUSCLE CHLORIDE CHANNEL - DOMINANT MUTATIONS SHOW VARIABLE PENETRANCE AND FOUNDER EFFECT

The delayed relaxation or sustained contraction of skeletal muscle-myo tonia-is frequently seen in myotonic dystrophy and sodium channelopath ies (hyperkalemic periodic paralysis, paramyotonia congenita). Many ca ses of congenital myotonia without other clinical symptoms have been a ssociated with mutations in the muscle chloride channel gene. Most cas es reported to date show a recessive inheritance pattern, with loss of function of the corresponding protein. Six families have been reporte d with dominantly inherited myotonia and mutations of the chloride cha nnel gene. Here we report clinical and molecular data on 38 family mem bers from four new families with dominantly inherited myotonia congeni ta. Three families show a previously characterized G230E mutation, and we show that these three share a common affected ancestor despite liv ing 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 EM G was the clinical feature that most closely correlated with mutation data; however, 3 of 16 (19%) mutation-positive patients tested negativ e by electromyography at least once, and 1 (6%) tested negative despit e multiple tests. Only about half (55%) of the mutation-positive patie nts tested positive for percussion myotonia. Most of the clinically sy mptomatic individuals stated that cold temperatures and stress substan tially worsened their myotonia. Our data show that dominantly inherite d Thomsen's myotonia is most often a very mild disorder that shows con siderable clinical heterogeneity.