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M1476I, a French Canadian founder mutation of Na⁺ channel Nav1.4, causes potassium-aggravated myotonia, with cold-induced myotonia as the most distinctive clinical feature. Mexiletine, a class 1B local anaesthetic, relieves the myotonic symptoms of patients carrying the M1476I mutation. We used the patch-clamp method to investigate the functional characteristics of this mutation by heterologous expression in tsA201 cells. The M1476I mutation caused an increased persistent Na⁺ current, a 2- to 3-fold slower fast inactivation, a 6.4 mV depolarizing shift in the midpoint of steady-state inactivation, and an accelerated recovery from fast inactivation compared to the wild-type (WT) channel. Cooling slowed the kinetics of both channel types and increased the amplitude of the persistent current in M1476I channels.Mexiletine suppressed the persistent Na⁺ current generated by the M1476I mutation and blocked both WT and M1476I channels in a use- dependent manner. The inactivation-deficient M1476I channels were less susceptible to mexiletine during repetitive pulses. The decreased use-dependent block of M1476I channels might have resulted from the slower onset of mexiletine block, and/or the faster recovery from mexiletine block, given that the affinity of mexiletine for the inactivated state of the WT and mutant channels was similar. Increased extracellular concentrations of potassium had no effect on either M1476I or WT currents. These results indicated that cooling can augment the disruption of the voltage dependence of fast inactivation by M1476I channels.

Objective: The aim of this study was to evaluate whether magnetic resonance imaging (MRI) can be used as a noninvasive approach to assessment of disease severity and muscle damage in Myotonic Dystrophy type 1 (DM1)., Methods: The MRI findings in legs of 41 patients with DM1 were evaluated with respect to the tibialis anterior (TA) skeletal muscle impairment. Magnetic resonance imaging findings were compared with TA strength measurements obtained by quantitative manual testing, duration of the disease and with the length of the CTG repeats., Results: Muscle MRI abnormalities were observed in 80% of DM1 patients, ranging from edema-like abnormalities alone to severe atrophy/fatty replacement. Edema-like abnormalities seem to be an earlier MRI marker of the disease. Fatty infiltration/atrophy correlated with the TA muscle force (r = 0.95), the severity (P = 0.00001) of the disease but not with the duration of the disease (P = 0.3) or the length of the CTG repeats (P > 0.10), measured in peripheral leukocytes. Evaluation of other muscles of the legs revealed that the medial gastrocnemius and soleus muscles were the most frequently and severely affected muscles, while tibialis posterior muscles were relatively spared. Edema-like abnormalities are most frequently observed in the skeletal muscles of the anterior compartment., Conclusion: Muscle MRI is helpful to depict muscle abnormalities but does not seem to be a reliable indicator of skeletal muscle involvement in DM1 since the decrease in TAmuscle force is not correlated with MRI abnormalities in some patients.

Charcot-Marie-Tooth polyneuropathies (CMT) are clinically and genetically heterogeneous. We describe a French-Canadian cluster of 17 recessive CMT cases belonging to 10 families with variable early-onset CMT and scoliosis. The patients demonstrate great intra- and inter-familial variability. Linkage analysis confirmed that all families are linked to CMT4C locus on chromosome 5q32 (multipoint LOD score of 9.06). Haplotype analysis suggests that two SH3TC2 mutations are present in this cohort. The majority of carrier chromosomes, 26 of 34 (76%), carry the c.2860C-->T mutation. Despite extensive sequencing, the other mutation is not yet uncovered. This study demonstrates that the clinical variability observed in CMT4C is due to other factors than the nature of the mutation and that further work is needed to better define the SH3TC2 gene to ensure the identification of all CMT4C mutations.

We studied mutations in the mtDNA control region (CR) using deep-rooting French-Canadian pedigrees. In 508 maternal transmissions, we observed four substitutions (0.0079 per generation per 673 bp, 95% CI 0.0023-0.186). Combined with other familial studies, our results add up to 18 substitutions in 1,729 transmissions (0.0104), confirming earlier findings of much greater mutation rates in families than those based on phylogenetic comparisons. Only 12 of these mutations occurred at independent sites, whereas three positions mutated twice each, suggesting that pedigree studies preferentially reveal a fraction of highly mutable sites. Fitting the data through use of a nonuniform rate model predicts the presence of 40 (95% CI 27-54) such fast sites in the whole CR, characterized by the mutation rate of 274 per site per million generations (95% CI 138-410). The corresponding values for hypervariable regions I (HVI; 1,729 transmissions) and II (HVII; 1,956 transmissions), are 19 and 22 fast sites, with rates of 224 and 274, respectively. Because of the high probability of recurrent mutations, such sites are expected to be of no or little informativity for the evaluation of mutational distances at the phylogenetic time scale. The analysis of substitution density in the alignment of 973 HVI and 650 HVII unrelated European sequences reveals that the bulk of the sites mutate at relatively moderate and slow rates. Assuming a star-like phylogeny and an average time depth of 250 generations, we estimate the rates for HVI and HVII at 23 and 24 for the moderate sites and 1.3 and 1.0 for the slow sites. The fast, moderate, and slow sites, at the ratio of 1:2:13, respectively, describe the mutation-rate heterogeneity in the CR. Our results reconcile the controversial rate estimates in the phylogenetic and familial studies; the fast sites prevail in the latter, whereas the slow and moderate sites dominate the phylogenetic-rate estimations.

Background: The aim of the present study was to identify the mutations in the connexin 32 gene in French-Canadian families with X-linked Charcot-Marie-Tooth disease (CMTX)., Methods: Molecular analysis was performed by nonisotopic single strand conformation polymorphism (SSCP) analysis and sequencing. Clinical evaluation was carried out according to the scale defined by the European Hereditary Motor and Sensory Neuropathy Consortium., Results: In one family, the mutation Arg142Trp was located in the transmembrane domain III whereas, in four other families we identified a novel mutation (Ser26Trp) located in the transmembrane domain I of the connexin 32 gene. Haplotype analysis revealed that these four families are related and suggests a founder mutation. Sixteen patients from these four families were studied. As expected, all the affected males were more clinically affected than the females and all affected patients exhibited some electrophysiological characteristics of demyelination., Conclusion: Our study suggests that the Ser26Trp mutation may cause a primary demyelinating neuropathy that is not associated with a specific clinical phenotype. We also find evidence that the majority of kindreds share a common ancestor.