Homozygosity for dominant mutations increases severity of muscle channelopathies.

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.

Glucocorticoids may trigger attacks in several types of periodic paralysis.

Hypokalemic periodic paralysis is a rare disorder characterized by episodic attacks of muscle flaccidity associated with low serum potassium levels. We report twelve patients with normokalemic and hypokalemic periodic paralysis due to various mutations who developed hypokalemic paralytic episodes following a single dose or short-term administration of glucocorticoids. We hypothesize that glucocorticoids cause hypokalemia due to their stimulation of the Na(+)-K(+) ATPase mediated by insulin and amylin and due to their side effect of insulin resistance resulting in hyperglycemia. This report adds to the clinical description of glucocorticoids as a trigger of attacks of hypokalemic periodic paralysis indicating that glucocorticoids should be administered with caution in patients with periodic paralysis.

Cold extends electromyography distinction between ion channel mutations causing myotonia.

OBJECTIVE: Myotonias are inherited disorders of the skeletal muscle excitability. Nondystrophic forms are caused by mutations in genes coding for the muscle chloride or sodium channel. Myotonia is either relieved or worsened by repeated exercise and can merge into flaccid weakness during exposure to cold, according to causal mutations. We designed an easy electromyography (EMG) protocol combining repeated short exercise and cold as provocative tests to discriminate groups of mutations. METHODS: Surface-recorded compound muscle action potential was used to monitor muscle electrical activity. The protocol was applied on 31 unaffected control subjects and on a large population of 54 patients with chloride or sodium channel mutations known to cause the different forms of myotonia. RESULTS: In patients, repeated short exercise test at room temperature disclosed three distinct abnormal patterns of compound muscle action potential changes (I-III), which matched the clinical symptoms. Combining repeated exercise with cold exposure clarified the EMG patterns in a way that enabled a clear correlation between the electrophysiological and genetic defects. INTERPRETATION: We hypothesize that segregation of mutations into the different EMG patterns depended on the underlying pathophysiological mechanisms. Results allow us to suggest EMG guidelines for the molecular diagnosis, which can be used in clinical practice.