Isolated eyelid closure myotonia in two families with sodium channel myotonia.

Sodium channelopathies (NaCh), as part of the non-dystrophic myotonic syndromes (NDMs), reflect a heterogeneous group of clinical phenotypes accompanied by a generalized myotonia. Because of recent availability of diagnostic genetic testing in NDM, there is a need for identification of clear clinical genotype-phenotype correlations. This will enable clinicians to distinguish NDMs from myotonic dystrophy, thus allowing them to inform patients promptly about the disease, perform genetic counseling, and orient therapy (Vicart et al. Neurol Sci 26:194-202, 2005). We describe the first distinctive clinical genotype-phenotype correlation within NaCh: a strictly isolated eyelid closure myotonia associated with the L250P mutation in SCN4A. Using clinical assessment and needle EMG, we identified this genotype-phenotype correlation in six L250P patients from one NaCh family and confirmed this finding in another, unrelated NaCh family with three L250P patients.

Prevalence and mutation spectrum of skeletal muscle channelopathies in the Netherlands.

Few reliable data exist on the prevalence of skeletal muscle channelopathies. We determined the minimum point prevalence of genetically-defined skeletal muscle channelopathies in the Netherlands and report their mutation spectrum. Minimum point prevalence rates were calculated as number of genetically-confirmed skeletal muscle channelopathy patients (CLCN1, SCN4A, CACNA1S and KCNJ2 gene mutations) in the Netherlands (1990-2015) divided by the total number of at-risk individuals. Rates were expressed as cases/100.000 and 95% confidence intervals were calculated based on Poisson distribution. Results of standardized genetic diagnostic procedures were used to analyze mutation spectra. We identified 405 patients from 234 unrelated pedigrees, resulting in a minimum point prevalence of 2.38/100.000 (95% CI 2.16-2.63) for skeletal muscle channelopathies in the Netherlands. Minimum point prevalence rates for the disease groups, non-dystrophic myotonia and periodic paralysis, were 1.70/100.000 and 0.69/100.000 respectively. Sixty-one different CLCN1 mutations (including 12 novel mutations) were detected in myotonia congenita. Twenty-eight different SCN4A missense mutations (including three novel mutations) were identified in paramyotonia congenita/sodium channel myotonia, hypokalemic periodic paralysis and hyperkalemic periodic paralysis. Four different CACNA1S missense mutations were detected in hypokalemic periodic paralysis and five KCNJ2 missense mutations in Andersen-Tawil syndrome. The minimum point prevalence rates for genetically-defined skeletal muscle channelopathies confirm their rare disease status in the Netherlands. Rates are almost twice as high as in the UK and more in line with pre-genetic prevalence estimates in parts of Scandinavia. Future diagnostic and therapeutic studies may benefit from knowledge of the mutation spectrum of skeletal muscle channelopathies.