Expert Insights from a Delphi-driven Neurologists' Panel: Real-world Mexiletine use in Patients with Myotonic Disorders in Italy.

Background: Myotonic disorders, such as non-dystrophic myotonias (NDMs) and myotonic dystrophies (DMs) are characterized by a delay in muscle relaxation after a contraction stimulus. There is general consensus that protocols to treat myotonia need to be implemented. Objective: Mexiletine is the only pharmacological agent approved for the symptomatic treatment of myotonia in adult patients with NDM and is considered to be the first-line treatment for DMs; however, its production in Italy was halted in 2022 making its availability to patients problematic. Methods: A panel of 8 Italian neurologists took part in a two-round Delphi panel between June and October 2022, analyzing the current use of mexiletine in Italian clinical practice. Results: The panelists assist 1126 patients (69% DM type1, 18% NDM and 13% DM type2). Adult NDM patients receive, on average, 400-600 mg of mexiletine hydrochloride (HCl) while adult DM patients receive 100-600 mg, per day in the long-term. The severity of symptoms is considered the main reason to start mexiletine treatment for both NDM and DM patients. Mexiletine is reckoned to have a clinical impact for both NDM and DM patients, but currently drug access is problematic. Conclusions: Mexiletine treatment is recognized to have a role in the reduction of the symptomatic burden for NDM and DM patients. Patient management could be improved by facilitating access to therapy and developing new drug formulations.

Afterdischarges in myotonic dystrophy type 1.

OBJECTIVE: Electrodiagnostic testing is an important screening test for myotonic dystrophy type 1 (DM1). Although myotonic discharges are observed on electromyography in cases of DM1, it is difficult to distinguish DM1 from other myotonic disorders clinically. In the present study, afterdischarges, another type of pathological potential revealed by electrodiagnostic testing, were analyzed, and their role in distinguishing DM1 from other myotonic disorders was explored. METHODS: Data from 33 patients with myotonic discharges on electromyography were analyzed retrospectively. According to gene testing, the patients were divided into DM1 (n = 20) and non-DM1 myotonia (n = 13) groups. Afterdischarges were investigated by retrospectively evaluating the electrodiagnostic findings of motor nerve conduction studies, F-waves, and repetitive nerve stimulations. RESULTS: Afterdischarges were observed in 17 of the 20 patients with DM1, with an occurrence rate of approximately 85%. However, afterdischarges were absent in all patients with non-DM1 myotonia. There were significant differences in the occurrence rate between the two groups (P < 0.01). CONCLUSION: Afterdischarges may serve as a suggestive role in clinical diagnosis of DM1. The discovery that DM1 can present with afterdischarges may pave a new way to study the pathogenesis of DM1.

Diagnostics in skeletal muscle channelopathies.

INTRODUCTION: Skeletal muscle channelopathies (SMCs) are a heterogenous group of disorders, caused by mutations in skeletal ion channels leading to abnormal muscle excitability, resulting in either delayed muscle relaxation (myotonia) which characterizes non-dystrophic myotonias (NDMs), or membrane transient inactivation, causing episodic weakness, typical of periodic paralyses (PPs). AREAS COVERED: SMCs include myotonia congenita, paramyotonia congenita, and sodium-channel myotonia among NDMs, and hyper-normokalemic, hypokalemic, or late-onset periodic paralyses among PPs. When suspecting an SMC, a structured diagnostic approach is required. Detailed personal and family history and clinical examination are essential, while neurophysiological tests should confirm myotonia and rule out alternative diagnosis. Moreover, specific electrodiagnostic studies are important to further define the phenotype of de novo cases and drive molecular analyses together with clinical data. Definite diagnosis is achieved through genetic testing, either with Sanger sequencing or multigene next-generation sequencing panel. In still unsolved patients, more advanced techniques, as exome-variant sequencing or whole-genome sequencing, may be considered in expert centers. EXPERT OPINION: The diagnostic approach to SMC is still mainly based on clinical data; moreover, definite diagnosis is sometimes complicated by the difficulty to establish a proper genotype-phenotype correlation. Lastly, further studies are needed to allow the genetic characterization of unsolved patients.

Idiopathic Inflammatory Myopathy with Delayed Finger Opening Resembling Grip Myotonia.

Grip myotonia can be a clue for the diagnosis of myotonic disorders. However, several clinical conditions cause delayed finger opening mimicking grip myotonia. We herein report a 44-year-old man with idiopathic inflammatory myopathy who presented with delayed finger opening resembling grip myotonia. The delayed finger opening differed from grip myotonia given the absence of the warm-up phenomenon and percussion myotonia, relative sparing of the thumb extension, and pronounced weakness of the extensor digitorum. Focusing on the extension of the thumb and other fingers may aid in the differentiation between delayed finger opening and true grip myotonia.

Impact of restricted access to, and low awareness of, mexiletine on people with myotonia: a real-world European survey.

Although mexiletine effectively treats myotonia, supply disruptions affected Europe between 2008-2018. MyoPath was a mixed-methods, cross-sectional, market research survey conducted January-June 2018 to evaluate consequences of limited access to/awareness of mexiletine in people with myotonia. Part A: qualitative structured interviews (clinicians; advocates for adult patients); Part B: quantitative online questionnaire completed by people with self-reported history of myotonia. Part A: Interviews (clinicians, n=12; patient advocates, n=5; 12 countries) indicated poor mexiletine awareness among general neurologists. Patients chose between living with myotonia (other treatments were generally unsatisfactory) or importing mexiletine. Part B: Questionnaire respondents, myotonic dystrophy (DM)1, n=213; DM2, n=128; non-dystrophic myotonia (NDM), n=41; other n=8; (11 countries). Of the respondents, 76/390 (20%) people with awareness of/access to mexiletine described profound improvements in myotonia and health-related quality of life following treatment. Respondents with NDM had greatest mexiletine experience (n=28/41). Mexiletine was associated with fewer falls, less muscle stiffness, increased mobility. Treatment interruptions worsened myotonia and were associated with fatigue, pain, dysphagia, breathing difficulty, impaired digestion, poor sleep. However, 36/54 (67%) of currently treated people expressed anxiety about mexiletine's availability: this finding was expected (MyoPath was undertaken before mexiletine's approval in NDM). MyoPath provides the largest European exploration of patients' views regarding impact of mexiletine on myotonia. Anticipated effects of mexiletine differ between people with different myotonic disorders: myotonia is the main symptom in NDM but one of many potential symptoms affecting those with DM. Nevertheless, findings indicate substantial harm caused to people with myotonia when mexiletine awareness/access is limited.

Muscle Channelopathies.

PURPOSE OF REVIEW: This article describes the clinical features, diagnosis, pathophysiology, and management of nondystrophic myotonia and periodic paralysis. RECENT FINDINGS: An increasing awareness exists about the genotype-phenotype overlap in skeletal muscle channelopathies, and thus genetic testing is needed to make a definitive diagnosis. Electrodiagnostic testing in channelopathies is highly specialized with significant overlap in various mutation subtypes. Randomized clinical trials have now been conducted in these disorders with expanded treatment options for patients with muscle channelopathies. SUMMARY: Skeletal muscle channelopathies are rare heterogeneous conditions characterized by lifelong symptoms that require a comprehensive management plan that includes pharmacologic and nonpharmacologic interventions. The significant variability in biophysical features of various mutations, coupled with the difficulties of performing clinical trials in rare diseases, makes it challenging to design and implement treatment trials for muscle channelopathies.

Clinical comparison and functional study of the L703P: a recurrent mutation in human SCN4A that causes sodium channel myotonia.

The non-dystrophic myotonias are inherited skeletal muscle disorders characterized by skeletal muscle stiffness after voluntary contraction, without muscle atrophy. Based on their clinical features, non-dystrophic myotonias are classified into myotonia congenita, paramyotonia congenita, and sodium channel myotonia. Using whole-exome next-generation sequencing, we identified a L703P mutation (c.2108T>C, p.L703P) in SCN4A in a Chinese family diagnosed with non-dystrophic myotonias. The clinical findings of patients in this family included muscle stiffness and hypertrophy. The biophysical properties of wildtype and mutant channels were investigated using whole-cell patch clamp. L703P causes both gain-of-function and loss-of-function changes in Nav1.4 properties, including decreased current density, impaired recovery, enhanced activation and slow inactivation. Our study demonstrates that L703P is a pathogenic variant for myotonia, and provides additional electrophysiological information for understanding the pathogenic mechanism of SCN4A-associated channelopathies.

Sequence CLCN1 and SCN4A genes in patients with nondystrophic myotonia in Chinese people.

BACKGROUND: This study aimed to characterize the genetic, pathological, and clinical alterations of 17 patients in China presenting with nondystrophic myotonia (NDM) and to analyze the relationship between genotype and clinical phenotype. METHODS: CLCN1 and SCN4A genes in patients with clinical features and muscle pathology indicative of NDM were sequenced. Furthermore, KCNE3 and CACNA1S genes were assessed in patients with wild-type CLCN1 and SCN4A. RESULTS: Patients may have accompanying atypical myopathy as well as muscle hypertrophy, secondary dystonia, and joint contracture as determined by needle electromyography. All the study participants were administered mexiletine in combination with carbamazepine and showed significant improvements in myotonia symptoms in response to this therapy. CLCN1 gene mutation was detected in 8 cases diagnosed with myotonia congenital using gene screening. The detected mutations included 5 missense, 2 nonsense, 1 deletion, and 2 insertions. Further gene analysis showed 4 mutations in the SCN4A gene in patients diagnosed with paramyotonia congenita. CONCLUSIONS: Myotonia congenita and paramyotonia congenita are the predominant forms of NDM in China. NDM may be best diagnosed using genetic analysis in associated with clinical features.

Non-dystrophic myotonia: 2-year clinical and patient reported outcomes.

INTRODUCTION/AIMS: Consistency of differences between non-dystrophic myotonias over time measured by standardized clinical/patient-reported outcomes is lacking. Evaluation of longitudinal data could establish clinically relevant endpoints for future research. METHODS: Data from prospective observational study of 95 definite/clinically suspected non-dystrophic myotonia participants (six sites in the United States, United Kingdom, and Canada) between March 2006 and March 2009 were analyzed. Outcomes included: standardized symptom interview/exam, Short Form-36, Individualized Neuromuscular Quality of Life (INQoL), electrophysiological short/prolonged exercise tests, manual muscle testing, quantitative grip strength, modified get-up-and-go test. Patterns were assigned as described by Fournier et al. Comparisons were restricted to confirmed sodium channelopathies (SCN4A, baseline, year 1, year 2: n = 34, 19, 13), chloride channelopathies (CLCN1, n = 32, 26, 18), and myotonic dystrophy type 2 (DM2, n = 9, 6, 2). RESULTS: Muscle stiffness was the most frequent symptom over time (54.7%-64.7%). Eyelid myotonia and paradoxical handgrip/eyelid myotonia were more frequent in SCN4A. Grip strength and combined manual muscle testing remained stable. Modified get-up-and-go showed less warm up in SCN4A but remained stable. Median post short exercise decrement was stable, except for SCN4A (baseline to year 2 decrement difference 16.6% [Q1, Q3: 9.5, 39.2]). Fournier patterns type 2 (CLCN1) and 1 (SCN4A) were most specific; 40.4% of participants had a change in pattern over time. INQoL showed higher impact for SCN4A and DM2 with scores stable over time. DISCUSSION: Symptom frequency and clinical outcome assessments were stable with defined variability in myotonia measures supporting trial designs like cross over or combined n-of-1 as important for rare disorders.

Simple and economical HandClench Relaxometer device for reliable and sensitive measurement of grip myotonia in myotonic dystrophy.

Grip myotonia and weakness are attractive treatment response biomarkers in clinical trials of myotonic dystrophy type 1 (DM1). There is a need to develop simple, patient-friendly and reproducible methods of quantifying grip myotonia in multisite trial settings. We designed a HandClench Relaxometer (HCR) that measures grip myotonia and strength. In contrast with the existing quantitative myometry (QMA) setup, the HCR is portable, economical, can be used with any laptop and generates automated command prompts. We demonstrate the feasibility and reliability of HCR device in twenty DM1 individuals and ten age-matched controls; patients returned for follow up within two months. The device showed excellent day to day reproducibility (ICC >0.80) in patients. The HCR device detected myotonia in milder muscle disease and measured longer myotonia duration than QMA indicating enhanced sensitivity for quantifying myotonia in DM1. The reaction time to the relax but not squeeze command was delayed and showed warm up similar to myotonia in DM1. HCR outcomes were correlated with key pinch strength, hand dexterity test, and fat replacement in the MRI of the long finger flexor muscles. Use of the HCR is warranted for grip myotonia and strength measurements in longitudinal observational and interventional studies of DM1.

A Myotonic Dystrophy Type I patient with Predominant Proximal Muscle Weakness without Action Myotonia- A Case Report and Review of Pathology.

PURPOSE: Early distal muscle weakness and myotonia are typical clinical presentations in type I myotonic dystrophy (DM1). We present a DM1 case with unusual predominant proximal weakness without action myotonia. CASE REPORT: The chief complaint of this 48-year-old female was difficulty in raising her arms and frequent falling in recent years. On neurological examination, proximal muscle weakness was more pronounced than the distal muscle groups, in addition to facial involvement. Although she did not experience any action myotonia throughout her life, hand and tongue myotonia were readily inducible by percussion during neurological examination. The diagnosis of DM1 was later supported by electromyography and neuropathological studies, and confirmed by molecular testing. The pathological findings in this patient and the characteristic features in typical DM1 patients were briefly reviewed. CONCLUSION: The unusual presentation of this DM1 patient suggests the importance of comprehensive neurological examination including percussion of thenar and tongue muscles, even in a patient with atypical distribution of muscle weakness and without a clear personal and family history of myotonia. In addition to molecular testing, muscle biopsy remains supportive in making the diagnosis.

Myotonic Muscular Dystrophy Type 2 in CT, USA: A Single-Center Experience With 50 Patients.

ABSTRACT: Myotonic dystrophy type 2 (DM2) is an autosomal dominant disorder due to a (CCTG)n repeat expansion in intron 1 of the CNBP gene. In this article, we report the clinicopathologic findings in 50 patients seen at a single site over a 27 year period. DM2 was the fifth most common type of muscular dystrophy seen at our center with a 5-fold lower frequency as compared to DM1. Age of symptom onset ranged from 15 to 72 years, and the mean duration between symptom onset and diagnosis was 7.4 years. Weakness referable to the proximal lower extremities was the presenting symptom in 62% of patients. The degree of generalized weakness varied from severe in 30% to no weakness in 20% of patients. Clinical myotonia was noted in 18% and myotonic discharges on electromyography in 97% of patients. Pain symptoms were uncommon in our cohort. A significant correlation was noted between limb weakness and degree of muscle pathologic changes. There was no correlation between CCTG repeat size and other clinicopathologic findings. Six patients (12%) had cardiac abnormalities including one who developed progressive nonischemic dilated cardiomyopathy ultimately leading to cardiac transplantation. In 21 patients followed for 2 or more years, we noted a mean rate of decline in total Medical Research Council score of about 1% per year.

[Non-inflammatory muscle pain]. / Nichtentzündliche Muskelschmerzen.

Muscle pain as a common symptom in daily practice frequently occurs as a non-specific accompanying symptom in multiple internal and neurological diseases. Primarily inflammatory or autoimmune muscular diseases are causing muscle pain. However, a number of non-inflammatory causes of pain can also be considered for differential diagnosis. These are presented in this article. In principle, a distinction must be made between focal and diffuse muscle pain. As an invasive diagnostic procedure, a muscle biopsy should only be performed as the last step in the diagnostic alogorithm. If diffuse muscle pain is only associated with slight muscle weakness or is completely absent, there is usually a primary rheumatic cause. Statins (HMG-CoA reductase inhibitors) can lead to rhabdomyolysis, muscle fiber atrophy and muscle necrosis by damaging the muscle fiber membrane. Myotonias are autosomal dominant or autosomal recessive inherited disorders of muscle function. The genetic defect leads to pronounced muscle stiffness. The cause of metabolic myopathies can be disorders of the carbohydrate, fat or purine metabolism. Fibromyalgia syndrome (FMS) is a non-inflammatory disease and, according to the current knowledge, recognized as the result of an exposure to physical, biological and psychosocial factors (biopsychological disease model). To help diagnosing FMS, pain regions and core symptoms (fatigue, sleep disturbances) can be detected using questionnaires (Widespread Pain Index [WPI] and Symptom Severity Scale [SSS]).

"Status myotonicus" in Nav1.4-M1592V channelopathy.

Nav1.4 channelopathies due to SCN4A mutations can present with episodic attacks of myotonia triggered by fluctuation in the potassium level (potassium-aggravated myotonia). We report a case of potassium-aggravated myotonia due to Nav1.4-M1592V channelopathy with severe and long-lasting focal attacks of myotonia resembling dystonic posturing with diffuse muscle edema in the affected muscles in magnetic resonance imaging and almost constant presence of myotonic discharges in electromyography that can best be described as focal "status myotonicus".

Episodic Muscle Disorders.

PURPOSE OF REVIEW: This article reviews the episodic muscle disorders, including benign cramp-fasciculation syndrome, the periodic paralyses, and the nondystrophic myotonias. The core diagnostic criteria for a diagnosis of primary periodic paralysis, including clues to distinguish between the hypokalemic and hyperkalemic forms, and the distinctive elements that characterize Andersen-Tawil syndrome are discussed. Management of patients with these disorders is also discussed. RECENT FINDINGS: Childhood presentations of periodic paralysis have recently been described, including atypical findings. Carbonic anhydrase inhibitors, such as dichlorphenamide, have recently been approved by the US Food and Drug Administration (FDA) for the treatment of both hypokalemic and hyperkalemic forms of periodic paralysis. Muscle MRI may be a useful outcome measure in pharmacologic trials in periodic paralysis. Genetic research continues to identify additional gene mutations responsible for periodic paralysis. SUMMARY: This article will help neurologists diagnose and manage episodic muscle disorders and, in particular, the periodic paralyses and the nondystrophic myotonias.