Nongenomic actions of progesterone and 17ß-estradiol on the chloride conductance of skeletal muscle.

INTRODUCTION: Myotonia congenita, caused by mutations in ClC-1, tends to be more severe in men and is often exacerbated by pregnancy. METHODS: We performed whole-cell patch clamp of mouse muscle chloride currents in the absence/presence of 100 µM progesterone or 17ß-estradiol. RESULTS: 100 µM progesterone rapidly and reversibly shifted the ClC-1 activation curve of mouse skeletal muscle (V50 changed from -52.6 ± 9.3 to +35.5 ± 6.7; P < 0.01) and markedly reduced chloride currents at depolarized potentials. 17ß-estradiol at the same concentration had a similar but smaller effect (V50 change from -57.2 ± 7.6 to -40.5 ± 9.8; P < 0.05). 1 µM progesterone produced no significant effect. CONCLUSIONS: Although the data support the existence of a nongenomic mechanism in mammalian skeletal muscle through which sex hormones at high concentration can rapidly modulate ClC-1, the influence of hormones on muscle excitability in vivo remains an open question.

Prevalence study of genetically defined skeletal muscle channelopathies in England.

OBJECTIVES: To obtain minimum point prevalence rates for the skeletal muscle channelopathies and to evaluate the frequency distribution of mutations associated with these disorders. METHODS: Analysis of demographic, clinical, electrophysiologic, and genetic data of all patients assessed at our national specialist channelopathy service. Only patients living in the United Kingdom with a genetically defined diagnosis of nondystrophic myotonia or periodic paralysis were eligible for the study. Prevalence rates were estimated for England, December 2011. RESULTS: A total of 665 patients fulfilled the inclusion criteria, of which 593 were living in England, giving a minimum point prevalence of 1.12/100,000 (95% confidence interval [CI] 1.03-1.21). Disease-specific prevalence figures were as follows: myotonia congenita 0.52/100,000 (95% CI 0.46-0.59), paramyotonia congenita 0.17/100,000 (95% CI 0.13-0.20), sodium channel myotonias 0.06/100,000 (95% CI 0.04-0.08), hyperkalemic periodic paralysis 0.17/100,000 (95% CI 0.13-0.20), hypokalemic periodic paralysis 0.13/100,000 (95% CI 0.10-0.17), and Andersen-Tawil syndrome (ATS) 0.08/100,000 (95% CI 0.05-0.10). In the whole sample (665 patients), 15 out of 104 different CLCN1 mutations accounted for 60% of all patients with myotonia congenita, 11 out of 22 SCN4A mutations for 86% of paramyotonia congenita/sodium channel myotonia pedigrees, and 3 out of 17 KCNJ2 mutations for 42% of ATS pedigrees. CONCLUSION: We describe for the first time the overall prevalence of genetically defined skeletal muscle channelopathies in England. Despite the large variety of mutations observed in patients with nondystrophic myotonia and ATS, a limited number accounted for a large proportion of cases.

Novel insights into the pathomechanisms of skeletal muscle channelopathies.

The nondystrophic myotonias and primary periodic paralyses are an important group of genetic muscle diseases characterized by dysfunction of ion channels that regulate membrane excitability. Clinical manifestations vary and include myotonia, hyperkalemic and hypokalemic periodic paralysis, progressive myopathy, and cardiac arrhythmias. The severity of myotonia ranges from severe neonatal presentation causing respiratory compromise through to mild later-onset disease. It remains unclear why the frequency of attacks of paralysis varies greatly or why many patients develop a severe permanent fixed myopathy. Recent detailed characterizations of human genetic mutations in voltage-gated muscle sodium (gene: SCN4A), chloride (gene: CLCN1), calcium (gene: CACNA1S), and inward rectifier potassium (genes: KCNJ2, KCNJ18) channels have resulted in new insights into disease mechanisms, clinical phenotypic variation, and therapeutic options.

Refined exercise testing can aid DNA-based diagnosis in muscle channelopathies.

OBJECTIVE: To improve the accuracy of genotype prediction and guide genetic testing in patients with muscle channelopathies we applied and refined specialized electrophysiological exercise test parameters. METHODS: We studied 56 genetically confirmed patients and 65 controls using needle electromyography, the long exercise test, and short exercise tests at room temperature, after cooling, and rewarming. RESULTS: Concordant amplitude-and-area decrements were more reliable than amplitude-only measurements when interpreting patterns of change during the short exercise tests. Concordant amplitude-and-area pattern I and pattern II decrements of >20% were 100% specific for paramyotonia congenita and myotonia congenita, respectively. When decrements at room temperature and after cooling were <20%, a repeat short exercise test after rewarming was useful in patients with myotonia congenita. Area measurements and rewarming distinguished true temperature sensitivity from amplitude reduction due to cold-induced slowing of muscle fiber conduction. In patients with negative short exercise tests, symptomatic eye closure myotonia predicted sodium channel myotonia over myotonia congenita. Distinctive "tornado-shaped" neuromyotonia-like discharges may be seen in patients with paramyotonia congenita. In the long exercise test, area decrements from pre-exercise baseline were more sensitive than amplitude decrements-from-maximum-compound muscle action potential (CMAP) in patients with Andersen-Tawil syndrome. Possible ethnic differences in the normative data of the long exercise test argue for the use of appropriate ethnically-matched controls. INTERPRETATION: Concordant CMAP amplitude-and-area decrements of >20% allow more reliable interpretation of the short exercise tests and aid accurate DNA-based diagnosis. In patients with negative exercise tests, specific clinical features are helpful in differentiating sodium from chloride channel myotonia. A modified algorithm is suggested.