非ジストロフィー性ミオトニー症候群

INTRODUCTION: Myotonia permanens (MP), a life-threatening condition, is prevalent in Chile, and is frequently associated with the SCN4A p.Gly1306Glu variant (exon 22), likely due to a founder effect in this population. Low clinical suspicion and the high cost of genetic testing contribute to delayed diagnosis and impaired quality of life. This study aimed to develop a clinical prediction rule (CPR) for early MP-p.Gly1306Glu detection specially in Chile, and confirm diagnosis through genetic testing. METHODS: This cross-sectional study was conducted at five Chilean hospitals and included healthy controls and patients with non-dystrophic myotonia (NDM). Participants were classified as controls, MP-p.Gly1306Glu, or non-permanens myotonia (NPM). Diagnosis was confirmed by SCN4A exon 22 sequencing or a gene panel (SCN4A, CLCN1). Fisher's exact test and logistic regression were used to identify clinical predictors of MP. RESULTS: A total of 19 controls and 17 patients with NDM (MP-p.Gly1306Glu/NPM = 8/9; mean age: 36 years) were included. Four predictors of MP-p.Gly1306Glu were identified: eyelid myotonia before age 2 (predictive value [PV] = 100%), myotonic discharges ≥28/30 s (PV = 95%), laryngospasm before age 2 (PV = 94%), and generalized myotonia before age 5 (PV = 88%). If all four predictors are present, MP-p.Gly1306Glu is highly probable and SCN4A exon 22 sequencing is recommended. If one to three predictors are present, targeted sequencing or a gene panel is advised, depending on clinical context. CONCLUSION: This CPR may facilitate early diagnosis of MP-p.Gly1306Glu and improve clinical outcomes, especially in Chile, and possibly other resource-limited settings, by guiding timely genetic confirmation and management. These predictors may support diagnostic criteria for MP/NPM, and guide future clinical trial design.

Non-dystrophic myotonias are rare skeletal muscle channelopathies characterized by delayed muscle relaxation and clinical stiffness. This study investigates the molecular mechanisms underlying three missense variants in SCN4A encoding for the voltage gated skeletal muscle sodium channel NaV1.4-p.K1308R, p.R1451H, and p.M1701V-identified in patients with non-dystrophic myotonia. All probands carried these variants in combination with the ClC-1 p.G190S mutation, a digenic configuration likely contributing to the heterogeneous clinical manifestations. An integrated approach combining electrophysiology, protein trafficking assessment, and evaluation of endoplasmic reticulum stress, revealed distinct pathogenic signatures for each variant. p.K1308R and p.M1701V primarily altered channel gating, whereas p.R1451H exhibited profound cellular impairment, including intracellular retention, reduced membrane expression, and robust activation of endoplasmic reticulum-stress pathways. Functionally, p.K1308R and p.R1451H caused marked reductions in current density and slowed activation kinetics, while p.M1701V produced milder perturbations consistent with its generally less severe phenotype. Because cold exposure exacerbated symptoms in carriers of p.R1451H and p.M1701V, the functional behaviour of these variants was examined at 37 °C. Both showed recovery of current amplitude to wild-type values and normalization of activation voltage dependence, although inactivation defects persisted. These temperature-dependent improvements were accompanied by increased window current probability, indicating partial temperature-dependent stabilization of channel gating. Pharmacological testing revealed that mexiletine modulates gating abnormalities in a variant-specific manner, reinforcing the clinical relevance of mechanistic stratification. Overall, the findings showed that clinically similar myotonic phenotypes may arise from divergent molecular defects and emphasize the relevance of precision medicine approaches tailored to variant-specific pathogenic mechanisms.

Myotonia is a non-neurotypical muscle physiology of sarcolemmal hyperexcitability due to alterations in the structure and/or function of ion channels in the muscle cell membrane. This hyperexcitability can be observed electrically as spontaneous myotonic discharges during needle electromyography. Myotonic discharges consist of continuous sequential fibrillation or positive sharp wave morphology potentials which exhibit unstable, gradually changing, firing frequencies and amplitudes. In myotonic disorders, a clinical correlate of muscle stiffness is often present. Myotonic disorders are broadly divided into myotonic dystrophies (Types 1 and 2) and non-dystrophic myotonias (myotonia congenita, paramyotonia congenita, and sodium channel myotonias). The myotonic dystrophies are systemic disorders of dysregulated RNA splicing clinically exhibiting fixed weakness, cataracts, diabetes and cardiac disease. Non-dystrophic myotonic disorders are due to specific sarcolemmal ion channel genetic variants and generally clinically limited to muscle stiffness (myotonia) sometimes with muscle weakness which can be fixed or periodic. Although electrical myotonia is a distinctive feature of myotonic disorders, it is nonspecific and may occur in other neuromuscular conditions. Widespread myotonic discharges strongly suggest a myotonic disorder or a handful of other conditions including necrotizing autoimmune myopathy, some toxic myopathies, Pompe disease and several congenital myopathies. This monograph reviews clinical myotonia and mimics, electrical myotonic discharges, electrodiagnostic testing in myotonic disorders and clinical features of myotonic disorders and other myopathies with myotonia.

BACKGROUND AND PURPOSE: Local anaesthetics and class I anti-arrhythmic drugs block voltage-gated Na+ channels, but the molecular basis for the isoform differences in drug sensitivity remains unclear. Understanding these mechanisms is essential for optimizing therapeutic efficacy and safety. Flecainide, a class Ic anti-arrhythmic agent, is also used for non-dystrophic myotonias but lacks use in epilepsy. This study aimed to elucidate the mechanisms underlying the isoform differences in the state-dependent block of flecainide. EXPERIMENTAL APPROACH: We employed site-directed mutagenesis, electrophysiological recordings and structural modelling with docking simulations to analyse flecainide interactions with Nav1.2 (brain), Nav1.4 (skeletal muscle) and Nav1.5 (cardiac) isoforms in the resting, open and inactivated states. KEY RESULTS: Flecainide showed the highest affinity for Nav1.5, followed by Nav1.4 and the lowest for Nav1.2 across all states. Within each isoform, affinity ranked as inactivated > open > resting. In Nav1.5, alanine substitution of a phenylalanine (Phe) residue in DIV-S6 caused the greatest affinity reduction, particularly in the open and inactivated states. Structural models revealed isoform- and state-dependent binding poses, with the piperidine nitrogen consistently pointing towards the selectivity filter and positioned higher in the open and inactivated states. Phe in DIV-S6 contributed to high-affinity binding, and the distance between the aromatic ring centers of flecainide and Phe correlated with the isoform differences in high affinities and the state-dependent block within each isoform. CONCLUSION AND IMPLICATIONS: This study clarifies the structural basis for isoform- and state-dependent drug affinities, providing insights that may guide development of isoform-selective drugs with improved therapeutic profiles.