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The MYOMEX study was a multicentre, randomised, double-blind, placebo-controlled, cross-over study aimed to compare the effects of mexiletine vs. placebo in patients with myotonia congenita (MC) and paramyotonia congenita (PC). The primary endpoint was the self-reported score of stiffness severity on a 100 mm visual analogic scale (VAS). Mexiletine treatment started at 200 mg/day and was up-titrated by 200 mg increment each three days to reach a maximum dose of 600 mg/day for total treatment duration of 18 days for each cross-over period. The modified intent-to-treat population included 25 patients (13 with MC and 12 with PC; mean age, 43.0 years; male, 68.0%). The median VAS score for mexiletine was 71.0 at baseline and decreased to 16.0 at the end of the treatment while the score did not change for placebo (81.0 at baseline vs. 78.0 at end of treatment). A mixed effects linear model analysis on ranked absolute changes showed a significant effect of treatment (p < 0.001). The overall score of the Individualized Neuromuscular Quality of Life questionnaire (INQoL) was significantly improved (p < 0.001). No clinically significant adverse events were reported. In conclusion, mexiletine improved stiffness and quality of life in patients with nondystrophic myotonia and was well tolerated., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The spectrum of RYR1 mutation associated disease encompasses congenital myopathies, exercise induced rhabdomyolysis, malignant hyperthermia susceptibility and King-Denborough syndrome. We report the clinical phenotype of two siblings who presented in infancy with hypotonia and striking fatigable ptosis. Their response to pyridostigimine was striking, but genetic screening for congenital myasthenic syndromes was negative, prompting further evaluation. Muscle MRI was abnormal with a selective pattern of involvement evocative of RYR1-related myopathy. This directed sequencing of the RYR1 gene, which revealed two heterozygous c.6721C>T (p.Arg2241X) nonsense mutations and novel c.8888T>C (p.Leu2963Pro) mutations in both siblings. These cases broaden the RYR1-related disease spectrum to include a myasthenic-like phenotype, including partial response to pyridostigimine. RYR1-related myopathy should be considered in the presence of fatigable weakness especially if muscle imaging demonstrates structural abnormalities. Single fibre electromyography can also be helpful in cases like this., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Myotonia congenita is an inherited muscle disorder sustained by mutations in the skeletal muscle chloride channel gene CLCN1. Symptoms vary from mild to severe and generalized myotonia and worsen with cold, stressful events and hormonal fluctuations. Here we report the case of a young woman who sought medical attention because of subacute onset of diffuse and severe limb myotonia. CLCN1 gene sequencing showed a heterozygous transversion (T550M), two polymorphisms and one silent mutation. Thyroid function screening revealed severe hypothyroidism. She was placed on l-thyroxine replacement therapy which dramatically improved myotonia. We conclude that hypothyroidism unmasked a genetically determined, clinically asymptomatic chloride channelopathy. Diagnostic work-up in patients with clinically isolated myotonia should not be limited to genetic screening of non-dystrophic or dystrophic myotonias. Considering the high prevalence of hypothyroidism in females, systematic thyroid function screening by looking for additional hypothyroid symptoms and serum TSH levels measurement is mandatory in these patients., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Tocainide is effective in the symptomatic treatment of myotonic syndromes for its ability to reduce the high frequency discharges of action potentials typical of the disease, by blocking voltage-gated sodium channels. However, its use is restricted by serious side effects. In spite of its chiral structure, tocainide is clinically used as a racemic mixture. Since the optical isomers may differ in their efficacy and toxicity, the present study was aimed at evaluating the antimyotonic activity of the pure R(-) and S(+) enantiomers of tocainide, on the abnormal membrane hyperexcitability of external intercostal muscle fibers of congenitally myotonic goats. The excitability parameters were recorded in vitro by means of the standard two-microelectrode current-clamp technique before and after the addition of the compounds. The R(-) enantiomer of tocainide at concentrations as low as 10 microM potently counteracted the abnormal excitability of myotonic fibers, by increasing the threshold current, and decreasing the latency of the action potential and firing capability. Also, this concentration of R-(-) tocainide almost completely abolished the abnormal spontaneous electrical activity occurring in about 70-80% of the myotonic fiber. The S(+) enantiomer was remarkably less potent since up to 100 microM did not restore the normal excitability pattern. The results show that most of the antimyotonic activity of tocainide resides in the R(-) enantiomer suggesting that its clinical use may allow a significant reduction of the doses and possibly of the side effects.