Drug treatment for myotonia

Trip, J.; Drost, Gea; Engelen, Baziel G. van; Faber, Catharina G.

doi:10.1002/14651858.cd004762.pub2

Cited by 63 publications

(31 citation statements)

References 87 publications

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“…12 Our patients showed a dramatic response to carbamazepine treatment, resulting in abolition of life-threatening laryngeal spasms and marked improvement of the myotonia and muscle stiffness, corresponding to observations in recently reported cases with a similar genetic background. 13 Similar beneficial effects have been reported in response to drugs with a comparable mechanism of action, such as phenytoin and mexiletine.…”

Section: Discussionsupporting

confidence: 89%

Mutations inSCN4A: A Rare but Treatable Cause of Recurrent Life-Threatening Laryngospasm

et al. 2014

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Laryngospasm is a rare but potentially life-threatening occurrence in infants and usually has infective, allergic, metabolic, or anatomic causes. Underlying genetic conditions are rarely considered. Mutations in SCN4A encoding the voltage-gated sodium channel NaV1.4 have been implicated in a wide spectrum of neuromuscular disorders with variable onset, ranging from a rare form of congenital myasthenic syndrome to both hypokalemic and hyperkalemic forms of periodic paralysis and paramyotonia congenita. Here we report on 3 unrelated patients without family history presenting with recurrent, life-threatening episodes of laryngospasm from the first months of life. Clinical features more typically associated with SCN4A-related disorders such as generalized muscle hypertrophy with clinical or electrical myotonia evolved later in life. All patients were found to be heterozygous for the same SCN4A mutation, c.3917G>A; p.Gly1306Glu. Treatment with carbamazepine resulted in complete abolition of recurrent laryngospasm and alleviated symptoms associated with myotonia and muscle stiffness. We conclude that SCN4A mutations ought to be considered in the differential diagnosis of recurrent infantile laryngospasm because timely institution of treatment can be life-saving.

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Section: Discussionsupporting

confidence: 89%

Mutations inSCN4A: A Rare but Treatable Cause of Recurrent Life-Threatening Laryngospasm

et al. 2014

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“…Single case reports have shown that mexiletine is effective in treating myotonia in both sodium and chloride channel disorders (Ceccarelli et al, 1992;Jackson et al, 1994). However, a recent Cochrane review highlighted the lack of adequate randomized double blind placebo controlled trials to prove efficacy (Trip et al, 2006). The ability to conduct such trials is partly hampered by the difficulty in quantitating myotonia (Torres et al, 1983;Hammaren et al, 2005;Logigian et al, 2005;Moxley et al, 2007;Hogrel, 2009) and in recruiting adequate numbers of patients to achieve statistical power.…”

Section: Treatmentmentioning

confidence: 99%

The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment

Matthews

Fialho

Tan

et al. 2009

Brain

198

226

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The non-dystrophic myotonias are an important group of skeletal muscle channelopathies electrophysiologically characterized by altered membrane excitability. Many distinct clinical phenotypes are now recognized and range in severity from severe neonatal myotonia with respiratory compromise through to milder late-onset myotonic muscle stiffness. Specific genetic mutations in the major skeletal muscle voltage gated chloride channel gene and in the voltage gated sodium channel gene are causative in most patients. Recent work has allowed more precise correlations between the genotype and the electrophysiological and clinical phenotype. The majority of patients with myotonia have either a primary or secondary loss of membrane chloride conductance predicted to result in reduction of the resting membrane potential. Causative mutations in the sodium channel gene result in an abnormal gain of sodium channel function that may show marked temperature dependence. Despite significant advances in the clinical, genetic and molecular pathophysiological understanding of these disorders, which we review here, there are important unresolved issues we address: (i) recent work suggests that specialized clinical neurophysiology can identify channel specific patterns and aid genetic diagnosis in many cases however, it is not yet clear if such techniques can be refined to predict the causative gene in all cases or even predict the precise genotype; (ii) although clinical experience indicates these patients can have significant progressive morbidity, the detailed natural history and determinants of morbidity have not been specifically studied in a prospective fashion; (iii) some patients develop myopathy, but its frequency, severity and possible response to treatment remains undetermined, furthermore, the pathophysiogical link between ion channel dysfunction and muscle degeneration is unknown; (iv) there is currently insufficient clinical trial evidence to recommend a standard treatment. Limited data suggest that sodium channel blocking agents have some efficacy. However, establishing the effectiveness of a therapy requires completion of multi-centre randomized controlled trials employing accurate outcome measures including reliable quantitation of myotonia. More specific pharmacological approaches are required and could include those which might preferentially reduce persistent muscle sodium currents or enhance the conductance of mutant chloride channels. Alternative strategies may be directed at preventing premature mutant channel degradation or correcting the mis-targeting of the mutant channels.

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“…Moreover, a recent Cochrane review concluded that none of the myotonia treatment studies reported as of 2006 were of sufficiently high quality to conclude that any available drug treatment of myotonia is effective and safe. 26 Given the need for a more definitive antimyotonia treatment trial, we prospectively evaluated the effect of mexiletine on grip myotonia and cardiac conduction in DM1 in 2 randomized, double-blind, placebocontrolled crossover trials, the first using a dosage of 150 mg 3 times daily (TID) and the second using 200 mg TID. Patients were eligible if they were between the ages of 18 and 80, could walk 15 feet independently, had sufficient finger flexor strength to grasp a handle, met standard clinical criteria for the presence of myotonia (time for fingers to fully uncurl following maximal hand grip estimated by visual inspection to be 3 seconds or more, or percussion myotonia in wrist extensor and thenar muscles), satisfied clinical criteria for DM1, 27 and had genetic confirmation of the diagnosis.…”

mentioning

confidence: 99%