Open-label trial of ranolazine for the treatment of myotonia congenita

Arnold, W. David; Kline, David; Sanderson, Alan; Hawash, Ahmed; Bartlett, Amy; Novak, Kevin R.; Rich, Mark M.; Kissel, John T.

doi:10.1212/wnl.0000000000004229

Cited by 30 publications

(29 citation statements)

References 10 publications

(16 reference statements)

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“…Dosage was 500 mg twice a day and was further increased to 1000 mg twice a day. Larger studies are needed to confirm the benefits of treatment [66].…”

Section: Therapeutic Options In Ndmmentioning

confidence: 99%

Skeletal Muscle Channelopathies

Phillips

Trivedi

2018

Neurotherapeutics

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Skeletal muscle channelopathies are rare heterogeneous diseases with marked genotypic and phenotypic variability. These disorders cause lifetime disability and impact quality of life. Despite advances in understanding of the molecular pathology of these disorders, the diverse phenotypic manifestations remain a challenge in diagnosis, therapeutic, genetic counseling, and research planning. Electrodiagnostic testing is useful in directing the diagnosis, but has several limitations: patient discomfort, time consuming, and significant overlap of findings in muscle channelopathies. Although genetic testing is the gold standard in making a definitive diagnosis, a mutation might not be identified in many patients with a well-supported clinical diagnosis of periodic paralysis. In the recent past, there have been landmark clinical trials in non-dystrophic myotonia and periodic paralysis which are encouraging as they demonstrate the ability of robust clinical research consortia to conduct well-controlled trials of rare diseases.

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“…Dosage was 500 mg twice a day and was further increased to 1000 mg twice a day. Larger studies are needed to confirm the benefits of treatment [66].…”

Section: Therapeutic Options In Ndmmentioning

confidence: 99%

Skeletal Muscle Channelopathies

Phillips

Trivedi

2018

Neurotherapeutics

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“…However, the drug does have proarrhythmic potential, and use is contraindicated in second-or third-degree AV block which may increase risk in some patients with DM. Lamotrigine, another sodium channel blocker, has been shown to be effective in nondystrophic myotonia, and ranolazine, which increases slow inactivation of sodium channels, may be effective for the treatment of myotonic dystrophy as well as nondystrophic forms of myotonia such as paramyotonia congenita and myotonia congenita [28][29][30][31][32].…”

Section: Skeletal Musclementioning

confidence: 99%

Myotonic Dystrophies: Targeting Therapies for Multisystem Disease

2018

Self Cite

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Myotonic dystrophy is an autosomal dominant muscular dystrophy not only associated with muscle weakness, atrophy, and myotonia but also prominent multisystem involvement. There are 2 similar, but distinct, forms of myotonic dystrophy; type 1 is caused by a CTG repeat expansion in the DMPK gene, and type 2 is caused by a CCTG repeat expansion in the CNBP gene. Type 1 is associated with distal limb, neck flexor, and bulbar weakness and results in different phenotypic subtypes with variable onset from congenital to very late-onset as well as variable signs and symptoms. The classically described adult-onset form is the most common. In contrast, myotonic dystrophy type 2 is adult-onset or late-onset, has proximal predominant muscle weakness, and generally has less severe multisystem involvement. In both forms of myotonic dystrophy, the best characterized disease mechanism is a RNA toxic gain-of-function during which RNA repeats form nuclear foci resulting in sequestration of RNA-binding proteins and, therefore, dysregulated splicing of premessenger RNA. There are currently no disease-modifying therapies, but clinical surveillance, preventative measures, and supportive treatments are used to reduce the impact of muscular impairment and other systemic involvement including cataracts, cardiac conduction abnormalities, fatigue, central nervous system dysfunction, respiratory weakness, dysphagia, and endocrine dysfunction. Exciting preclinical progress has been made in identifying a number of potential strategies including genome editing, small molecule therapeutics, and antisense oligonucleotide-based therapies to target the pathogenesis of type 1 and type 2 myotonic dystrophies at the DNA, RNA, or downstream target level.

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“…This study used a stopwatch to measure the duration of myotonia . In 2017, the authors of an open‐label trial with ranolazine similarly chose stopwatch and subjective grading of stiffness severity by participants . The computerized approach requires special equipment that is not available in most centers, possibly explaining the choice of subjective questionnaires and less accurate measurement using stopwatches by other authors.…”

mentioning

confidence: 99%

“…7 In 2017, the authors of an open-label trial with ranolazine similarly chose stopwatch and subjective grading of stiffness severity by participants. 8 The computerized approach 3 requires special equipment that is not available in most centers, possibly explaining the choice of subjective questionnaires and less accurate measurement using stopwatches by other authors.We sought to develop a simple method of quantitating myotonia using a commercially available dynamometer and to prove it suitable as an outcome measure in clinical trials and as part of routine examinations. Our objectives were to assess the reliability of the method, strength of correlation between RT and MBS, and differences of both RT and MBS between patients with DM1 and DM2.…”

mentioning

confidence: 99%

Quantitative myotonia assessment with a commercially available dynamometer in myotonic dystrophy types 1 and 2

et al. 2019

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Introduction: The objective of this study was to develop a simple method for quantitative assessment of myotonia in patients with myotonic dystrophy type 1 (DM1) and DM2, to compare the myotonia severity, and to correlate this objective outcome with a subjective scale, the Myotonia Behaviour Scale (MBS). Methods: A commercially available dynamometer was used for all measurements. The relaxation time after voluntary contraction was measured in 20 patients with DM1, 25 patients with DM2, and 35 healthy controls. Results: The average relaxation time was 0.17 s in controls, 2.96 s in patients with DM1, and 0.4 s in patients with DM2. The correlation between relaxation time and MBS score was significant, 0.627 in patients with DM1 and 0.581 in patients with DM2. Discussion: Our method provides a valid and reliable quantitative measure of grip myotonia suitable as an outcome measure in clinical trials and as part of routine examinations to gather data on the natural history of myotonic disorders. Muscle Nerve 59:431–435, 2019

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Open-label trial of ranolazine for the treatment of myotonia congenita

Abstract: This study provides Class IV evidence that ranolazine improves myotonia in myotonia congenita.

Cited by 30 publications

References 10 publications

Skeletal Muscle Channelopathies

Skeletal Muscle Channelopathies

Myotonic Dystrophies: Targeting Therapies for Multisystem Disease

Quantitative myotonia assessment with a commercially available dynamometer in myotonic dystrophy types 1 and 2

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