Mexiletine is an effective antimyotonia treatment in myotonic dystrophy type 1

Logigian, Eric L.; Martens, William; Moxley, Richard T.; McDermott, Michael P.; Dilek, Nuran; Wiegner, Allen W.; Pearson, Alexander T.; Barbieri, C.A.; Annis, Christine; Thornton, Charles A.

doi:10.1212/wnl.0b013e3181dc1a3a

Cited by 172 publications

(90 citation statements)

References 34 publications

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“…However, mexiletine is effective in reducing myotonia based on evidence from randomized controlled trials (RCTs). 6 In a small RCT, methylphenidate was found to decrease excessive somnolence seen in this disorder. 7 There are some promising disease-modifying therapies entering clinical trials.…”

Section: Treatments Are Symptomaticmentioning

confidence: 96%

Myotonic dystrophy type 1

Nguyen

Campbell

2016

CMAJ

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Section: Treatments Are Symptomaticmentioning

confidence: 96%

Myotonic dystrophy type 1

Nguyen

Campbell

2016

CMAJ

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“…Whether some of the subsequent outcomes would be preventable with medical therapy is not known. In a small crossover trial, 19 the class I antiarrhythmic mexiletine has been shown to reduce myotonia, whereas definitive trials of class I antiarrhythmics have consistently shown harm in patients with structural heart disease. The correlation between repeat length and increased arrhythmia risk could be confounded by excess mexiletine use in the highest risk subgroup.…”

Section: Wheelermentioning

confidence: 99%

Repeats and Survival in Myotonic Dystrophy Type 1

Wheeler

2017

Circ Cardiovasc Genet

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T he myotonic dystrophies are multisystem disorders characterized by progressive skeletal muscle weakness, myotonia, cataracts, endocrine abnormalities, cognitive impairment, and cardiomyopathy. Myotonic dystrophy type 1 (DM1) is the most common of the myotonic dystrophies. The cardiac-specific phenotypes of DM1 include progressive atrioventricular conduction delay, atrial and ventricular arrhythmias, impaired left ventricular diastolic and systolic dysfunction, impaired contractile reserve, and mesocardial fibrosis. Cardiac conduction abnormalities in patients with DM1 range from asymptomatic preclinical conduction system disease to complete heart block or ventricular arrhythmias leading to sudden death. In addition, DM1 patients are at increased risk for left ventricular dysfunction, ranging from impaired global longitudinal strain and impaired contractile reserve with preserved resting ejection fraction to overt left ventricular systolic dysfunction leading to overt heart failure. See Article by Chong-Nguyen et alMuch concerning the pathogenesis of DM1 has been elucidated. Abnormal repeat expansion of a CTG triplet repeat in the 3′ untranslated region of the DMPK gene (dystrophia myotonica protein kinase) 1 leads to accumulation of mutant transcripts in the nuclei of cells that in turn lead to dysregulated splicing and altered transcription.2,3 Sequestration of RNA-binding proteins including MBNL1 by DMPK mRNA CUG repeats and compensatory upregulation and activation of CUGBP1 (CUG-binding protein) lead to altered splicing of multiple transcripts. [4][5][6] In addition to splicing defects, reduction of the DM protein kinase itself may contribute to the cardiac conduction defect seen in patients with DM1. 7,8 Aberrant differential splicing of the SCN5A mRNA, with switching of exon 6 from the adult exon 6B to fetal 6A, is likely contributory to reductions in cardiomyocyte excitability and increased atrioventricular conduction delay. There is extensive evidence of a relationship between age-dependent neuromuscular dysfunction and DMPK CTG repeat length in DM1. Indeed, clinical phenotypes of lateadult-onset, classical-adult-onset, childhood-onset, and congenital-onset disease are differentiated in part by CTG repeat lengths of 50 to 100, 50 to 1000, >800, and >1000 CTG repeats, respectively.There is conflicting evidence on the importance of CTG repeat length with regard to cardiac conduction, arrhythmias, and survival in DM1. Early analysis of the arrhythmias in DM1 multicenter registry 10 of 395 myotonic dystrophy patients, of whom 342 had confirmatory genotyping, found severity of muscular disability, conduction abnormalities, and likelihood of arrhythmia diagnosis each correlated with CTG repeat length treated as a continuous variable. The correlation of PR and QRS prolongation with repeat length was confirmed in additional studies.11,12 Breton and Mathieu, 13 in a separate cohort of 428 patients followed up for a mean of 11.7 years, did not find an association between CTG repeat length and risk of sudden death...

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“…Mexiletine is applied in extracardiac disorders, too. It is widely administered in the therapy of myotonic disorders (Logigian et al 2010;Statland et al 2012), in Timothy syndrome (Gao Y. et al 2013), in neuropathies (O'Connor and Dworkin 2009) and in chronic pain (Park and Moon 2010). A recent study (Weiss et al 2016) have provided Class I evidence that mexiletine has been safe when given daily to patients with amyotrophic lateral sclerosis (ALS).…”

Section: Introductionmentioning

confidence: 99%

Different electrophysiological effects of the levo- and dextro-rotatory isomers of mexiletine in isolated rabbit cardiac muscle

Gurabi

Patocskai

Györe

et al. 2017

Can. J. Physiol. Pharmacol.

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Racemic mexiletine is a widely used antiarrhythmic agent which blocks sodium channels. The effects of R-(-) and S-(+) mexiletine stereoisomers on maximum rate of depolarization (Vmax), conduction time and repolarization have not yet been investigated in isolated cardiac preparations. We studied the effect of the R-(-) and S-(+) mexiletine on rabbit cardiac action potential parameters by using the conventional microelectrode technique. Both enantiomers at 20 µM of therapeutically and experimentally relevant concentration, significantly depressed the Vmax at fast heart rates (BCLs 300 -700 ms). R-(-) mexiletine has more potent inhibitory effect than S-(+) mexiletine. Both R-(-) and S-(+) mexiletine significantly inhibited the Vmax of early extrasystoles measured at 70 ms diastolic interval induced by S1-S2 stimuli. R-(-) mexiletine has more pronounced inhibitory effect than S-(+) mexiletine. Both R-(-) and S-(+) mexiletine increased significantly the ERP/APD 90 ratio. The time constant (τ) of recovery of Vmax was found to be τ = 376.0 ± 77.8 ms for R-(-) mexiletine and τ = 227.1 ± 23.4 ms for S-(+) mexiletine which indicates a slower offset kinetics for R-(-) mexiletine from sodium channels than that of the S-(+) enantiomer. These data suggest that R-(-) mexiletine might be more potent antiarrhythmic agent than S-(+) mexiletine.

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Mexiletine is an effective antimyotonia treatment in myotonic dystrophy type 1

Abstract: Objective: To determine if mexiletine is safe and effective in reducing myotonia in myotonic dystrophy type 1 (DM1). Background:Myotonia is an early, prominent symptom in DM1 and contributes to decreased

Cited by 172 publications

References 34 publications

Myotonic dystrophy type 1

Myotonic dystrophy type 1

Repeats and Survival in Myotonic Dystrophy Type 1

Different electrophysiological effects of the levo- and dextro-rotatory isomers of mexiletine in isolated rabbit cardiac muscle

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