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Introduction: NaMuscla, (mexiletine), is the first licensed treatment for the Non-Dystrophic Myotonias (NDM). NDM are categorized by genetic ion channel dysfunction and cause significant morbidity....

Title Eyelid myotonia and face stiffness in skeletal muscle sodium channelopathy Video Legend Video 1. Notice the delayed relaxation of the eyelids after forced eye closure (eyelid myotonia). Also, notice the full facial hair to prevent facial muscle stiffening exacerbation with cold weather. AuthorsSrijan Adhikari, MBBS, Jeffrey Statland, MD, Constantine Farmakidis, MD Authors information: Srijan Adhikari, MBBS, ORCID ID: 0000-0001-9653-3079, University of Kansas Medical Center, Department of Neurology, Kansas City, Kansas, USAJeffrey Statland, MD, ORCID ID: 0000-0003-0790-5315 University of Kansas Medical Center, Department of Neurology, Kansas City, Kansas, USAConstantine Farmakidis, MD, ORCID ID: 0000-0002-4688-9224, University of Kansas Medical Center, Department of Neurology, Kansas City, Kansas, USA Corresponding Author Srijan Adhikari, MBBS,Department of Neurology,University of Kansas Medical Center,3901 Rainbow Boulevard., MS 2012,Kansas City, KS 66160sadhikari@kumc.edu Author Conflict of Interests Dr Adhikari has nothing to disclose.Dr. Statland reports grants from NIH, grants from MDA, grants from FSHD Society, grants from Friends of FSH Research, personal fees from Dyne, personal fees from Fulcrum, personal fees from Avidity, personal fees from MT Pharma, personal fees from Acceleron, personal fees from Sarepta, personal fees from Strongbridge, outside the submitted work. Dr. Farmakidis reports personal fees from Argnex, personal fees from Momenta, personal fees from Terumo BCT, outside the submitted work.

Background: The aim of our study was to characterize the genetic, pathological and clinical alterations of 17 patients in China presenting with non-dystrophic myotonia (NDM). Methods: We first sequenced the CLCN-1 gene in patients having clinical features and muscle pathology indicative of NDM. If no mutations were detected, we subsequently analyzed the SCN4A, KCNE3 and CACNA1S genes. Results: As determined by needle electromyography, patients may have accompanying atypical myopathy as well as muscle hypertrophy, secondary dystonia and joint contracture All participants in this study were administered mexiletine in combination with carbamazepine and showed significant improvements in their myotonia symptoms. Routine pathological examinations showed mild abnormalities in muscle pathology. Oxidative enzyme activity was decreased in many fibers. ATPase studies of fiber subtypes demonstrated a predominance of type 2A fibers and a complete absence of type 2B muscle fibers in patients with CLCN-1 mutations. CLCN-1 gene mutations were found in 8 cases diagnosed with myotonia congenital by gene screening. The detected mutations included 5 missense, 2 nonsense, 1 deletion and 2 insertions, and these CLCN-1 mutations were concentrated in exons 8 and 12. Further gene analysis showed 4 mutations in the SCN4A gene in patients diagnosed with paramyotonia congenita. One of these mutations was consistent with a previously reported mutation, whereas 3 mutations were novel. All of these novel mutations occurred within “hot spots” of exons 22 and 24. Five patients with NDM lacked any identifiable mutations in CLCN-1, SCN4A, CACNA1S or KCNE3. Conclusions: Myotonia congenita and paramyotonia congenita are the predominant forms of NDM in China. NDM may be best diagnosed using genetic analysis in combination with clinical features. New mutations of the CLCN-1 and SCN4A genes in patients with NDM were detected, we postulate that novel pathogenic genes for NDM occur in China.

Background: There are only few reports of pregnancy and delivery in non-dystrophic myotonia or periodic paralysis caused by CLCN1 or SCN4A gene mutations. Methods: We report the medical histories and personal attitudes of 5 unrelated German patients, 2 following autosomal recessive inheritance (case 1; most likely and case 2; confirmed Becker disease) and 3 following autosomal dominant inheritance (case 3; CLCN1 mutation, cases 4-5; SCN4A mutations), who delivered a total of 9 children. Results: Apart from case 5 with periodic paralysis, who had 5 early miscarriages and pre-eclampsia resulting in cesarean delivery, there was no evidence of increased obstetric complication rates, and neonatal outcome was favorable. In all patients, there was aggravation of myotonia or weakness in pregnancy, followed by a short-term improvement after delivery in cases 2 and 3. Mexiletine medication improved the clinical features significantly in case 2 but was unable to control pregnancy-related deterioration. In case 4 (and her sister) and case 5, there was a clear disease aggravation in pregnancy resulting in hospitalization or repeated neurological examinations. Conclusion: Pregnancy can be regarded as a strong triggering factor in inherited non-dystrophic myotonias and periodic paralysis, regardless of the underlying gene defect.

Non-dystrophic myotonia (NDM) is caused by mutations in muscle chloride and sodium channels. Currently, there is no standardized instrument for documenting symptom frequency and severity in NDM.Subjects used an automated, interactive, telephone-based voice response diary (IVR) to record frequency and severity of stiffness, weakness, pain, and tiredness once a week for 8 weeks, after their baseline visits.We describe the IVR and report data on 76 subjects for a total of 385 person-weeks. Overall there were 5.1 calls per subject. Forty-eight subjects called in 5 or more times, and 14 called in 8 times. Stiffness was both the most frequent and severe symptom. Warm-up and handgrip myotonia were associated with higher severity scores for stiffness.IVR is a convenient technology to allow patient reporting of repeated and real-time symptom frequency and severity, and it is presently being used in a trial of mexiletine in NDM.

Objective: To describe genotype-phenotype correlations in non-dystrophic myotonia (NDM). Background NDM are heterogeneous disorders caused by mutations in skeletal muscle sodium (SCN4A) and chloride channel (CLCN1) genes. Although NDMs are distinct, it is at times difficult to distinguish them clinically. Design/Methods: 95 participants with NDM were recruited from 6 centers across the United States, England, and Canada. Mutational and clinical analyses were performed in 93. They were categorized into chloride channel (CLCN1), sodium channel (SCN4A), myotonic dystrophy type 2 (DM2), and unknown mutations. We included DM2 since they clinically present as NDM. We quantitated symptoms and myotonia measurements. Results: Of the 93 subjects reviewed, 29 had CLCN1, 31 SCN4A, and 7 DM2 mutations with 26 as yet unknown. Stiffness was the most prominent symptom in all subtypes and occurred earlier in the SCN (median-5 yrs) vs CLCN (10 yrs) and DM2 (35 yrs) (p=0.0001). Painful myotonia was reported in SCN (25/31), CLCN (16/29), and DM2 (5/7) (p=0.19). Episodic weakness was reported in all subtypes: 23/31 SCN, 12/29 CLCN, and 4/7 DM2. Frequency of fixed weakness was higher in DM2 (6/7) compared to SCN (7/30) and CLCN (9/29) (p=0.012). Muscle hypertrophy was most common in CLCN (21/29) followed by SCN (13/31). DM2 patients did not have hypertrophy. Eye closure myotonia was observed more in SCN (23/31) compared to CLCN (7/29) or DM2 (2/7) (p=0.0005). Grip myotonia warm-up was noted in 20/29 CLCN, 8/31 SCN, and 1/7 DM2 subjects. Paradoxical hand grip & eye closure myotonia was seen in 16/31 SCN. Conclusions: While clinical features can help differentiate various NDM subtypes, mutational analysis is required due to an overlap in the clinical findings in NDM patients. Supported by: NIH/Office of Rare Disease Research Network sponsored Consortium for Clinical Investigations of Neurological Channelopathies (CINCH). Disclosure: Dr. Trivedi has nothing to disclose. Dr. Bundy has nothing to disclose. Dr. Raja Rayan has nothing to disclose. Dr. Salajegheh has nothing to disclose. Dr. Statland has nothing to disclose. Dr. Venance has received personal compensation for activities with Genzyme Corporation. Dr. Wang has nothing to disclose. Dr. Fialho has nothing to disclose. Dr. Hart has nothing to disclose. Dr. Gorham has nothing to disclose. Dr. Herbelin has nothing to disclose. Dr. Amato has received personal compensation for activities with MedImmune, Amgen, and Biogen Idec as a medical advisory board member. Dr. Hanna has nothing to disclose. Dr. Griggs has nothing to disclose. Dr. Barohn has received personal compensation for activities with Talecris Biotherapeutics, Genzyme Corporation and Speakers Bureau. Dr. Barohn has received research support from Alexion Pharmaceuticals.

Introduction The ionic channels are complex glycoprotein structures, which cross the lipidic cellular membrane and allow the passage of electrically charged ions from one side of it to the other, thanks to the electrochemical gradient. A channelopathy is a disorder due to anomalous function of the ionic channels. Development In this study we analyze particularly the hereditary channelopathies with neuromuscular involvement non dystrophic myotonia, paramyotonias and periodic paralysis, and classify the clinical, physiopathological, molecular, genetic and therapeutic aspects. As far as possible we have divided the different conditions according to the channel involved, due to mutations which affect the sodium, calcium, chloride and potassium channels. We have also included neuromyotonic phenomena which are probably caused by channelopathies. Conclusions Probably it will not be long before many of the conditions considered in this article have a better physiopathological explanation, more specific diagnostic procedures and a more rational approach to treatment.