A novel founder SCN4A mutation causes painful cold-induced myotonia in French-Canadians

Myotonia is observed in classic congenital myotonia caused by CLCN1 mutations and in sodium-channel myotonia (SCM) due to SCN4A mutations.

We assessed 66 electrically proven cases of myotonia belonging to 17 French-Canadian families living in the Saguenay Lac St-Jean area of Quebec, a region well known for its genetic founder effects. The CLCN1 gene was sequenced in one affected member of each family. SCN4A exons with known SCM mutations were subsequently sequenced in families where no CLCN1 mutations were found.

Six families, 33% of cases (22/66), presenting classic congenital myotonia phenotypes were found to carry two previously identified CLCN1 mutations. In the other 11 families comprising 66% of cases (44/66), a new dominant SCN4A mutation in exon 24 (M1476I) was uncovered and segregated with a variable SCM phenotype. Although all carriers of this novel mutation had electrical myotonia, some were asymptomatic (25%) and age at onset was variable in the others (5 to 67, mean 21). Cold aggravated myotonia was observed in 41% of cases and painful myotonia in 18%. Additional features observed include aggravation of symptoms with pregnancies (7%), localized muscle swelling (2%), myotonic reactions to anesthesia (2%), and food-induced paralysis (2%).

This cohort is the largest described with a variable sodium-channel myotonia phenotype caused by a single SCN4A mutation. The clinical variability observed in this cohort underlines the phenotypic heterogeneity of SCN4A mutations and suggests that variants in other genes likely modulate clinical expression.