BACKGROUND:Myotonic Dystrophy Type 1 is a rare multisystem disorder, with symptoms including progressive muscle weakness, myotonia and fatigue. Although mobility measures are now common in several tests performed in clinics, their quantification using wearable sensors have not been significantly explored in the literature. This study investigated variation of gait characteristics during prolonged walking in individuals with Myotonic Dystrophy Type 1 using a single wearable sensor, and their association with gait fatigability proxies. METHODS:Forty-two subjects with Myotonic Dystrophy Type 1 and 15 healthy controls performed a 6-min walk test while wearing a single lumbar-mounted inertial measurement unit. Minute-by-minute gait parameters were extracted and compared between groups using repeated-measures ANOVA. Correlation analysis was performed to examine whether changes in gait parameters were related to motor functional ability levels. RESULTS:Patients demonstrated significantly impaired gait compared to controls, with reduced speed, cadence, step length, and increased stride time variability. While controls and mildly affected subjects showed similar temporal patterns, including a speed decrease in mid-test followed by recovery in the final minute, moderately affected subjects maintained a stable but slower pace throughout. Changes in cadence across the test were weakly but significantly correlated with clinical disability measures. CONCLUSION:Wearable sensors worn during prolonged walking assessments can detect subtle gait alterations in Myotonic Dystrophy Type 1 that vary by disability level, potentially serving as objective outcome measures for monitoring disease progression and evaluating therapeutic interventions. TRIAL REGISTRATION:The trial was retrospectively registered in Clinicaltrials.gov (NCT06666816, date of registration 31/10/2024). URL: https://clinicaltrials.gov/study/NCT06666816.

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.

Myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by expanded CTG repeats in the 3'-UTR of the DMPK gene that lead to nuclear foci accumulation and splicing defects. Circular RNAs (circRNAs) are emerging regulators of muscular disorders, but their role in DM1 remains largely unknown. By analyzing available RNA-sequencing datasets from DM1 patients, followed by validation in patients and matching control muscle biopsies, we identified seven circRNAs that were significantly increased in DM1 muscles and displayed high circular-to-linear isoform ratios. Among them, circARHGAP10 correlated positively with CTG repeat length and inversely with muscle strength, indicating its potential as a biomarker. Silencing of circARHGAP10 in DM1 myogenic cells reduced DMPK expression, decreased nuclear foci, and partially rescued normal splicing. Bioinformatics prediction and pull-down of circARHGAP10 indicated that circARHGAP10 binds miR-409-3p. circARHGAP10 and miR-409-3p were both found to be upregulated in DM1 muscle biopsies and silencing of circARHGAP10 led to the downregulation of miR-409-3p, indicating their co-regulation. Interestingly, miR-409-3p overexpression blocked the beneficial effects of circARHGAP10 silencing on DMPK levels, foci, and splicing. Thus, circARHGAP10-dependent regulation of DM1-associated mechanisms is mediated, at least in part, via interaction with miR-409-3p. In conclusion, circARHGAP10 exhibits promising potential as a biomarker and therapeutic target for DM1.

Myotonic dystrophy type 1 (DM1) is a genetic disease which affects multiple systems including the central nervous system. One of its key neuroimaging biomarkers are white matter hyperintensities (WMHs). The clinical relevance of WMHs remains unclear, and treating them as a uniform entity may overlook their heterogeneous composition and spatial distribution. To assess WMHs heterogeneity we applied intra-voxel incoherent motion (IVIM) modelling, an advanced magnetic resonance imaging technique, to a cohort of 23 patients with DM1 (age [mean ± std]: 44.1 ± 11.9 years; M/F = 8/15). WMHs were distinguished into periventricular (PWMHs) and deep (DWMHs) subtypes using criteria based on continuity and distance rules. A quantitative evaluation of their distribution among white matter tracts was conducted, together with correlation analysis between WMHs and clinical scales. Our research reveals that PWMHs have higher parenchymal diffusivity than DWMHs, consistently with their closeness to the ventricles. Significant positive correlation is identified between PWMH volumes and age, while DWMHs seem to be more strongly associated with an impairment of cognitive functions. Overall, these findings could have possible implications in clinics, highlighting the importance of considering WMHs heterogeneity and opening the door to a better comprehension of their role in the disease.

Background/Objectives: Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disorder characterized by respiratory dysfunction that significantly impacts quality of life and longevity. This study aimed to explore the outcomes of pulmonary function tests and sleep-disordered breathing (SDB) workups in children with DM1 and to identify the factors contributing to SDB. Methods: A retrospective study examined patients’ medical records, including genetic analyses, clinical characteristics, and noninvasive pulmonary function testing (PFT), when possible. The Pediatric Sleep Questionnaire (PSQ), arterial blood gases, polygraphy, and overnight transcutaneous capnometry (PtcCO2) were used to assess SDB. Results: The size of CTG expansion in the DMPK gene directly correlated with the severity of respiratory complications and the need for early tracheostomy tube insertion in 7/20 (35%) patients. A total of 13/20 (65%) children were available for respiratory evaluation during spontaneous breathing. While moderate/severe obstructive sleep apnea syndrome (OSAS) and hypoventilation were confirmed in 4/13 (31%) children, none of the patients had mixed or dominantly central sleep apnea syndrome. There was no correlation between apnea–hypopnea index (AHI) or PtcCO2 and the presence of SDB-related symptoms or the PSQ score. Although a significant correlation between AHI and PtcCO2 was not confirmed (p = 0.447), the oxygen desaturation index directly correlated with PtcCO2 (p = 0.014). Conclusions: While SDB symptoms in children with DM1 may not fully correlate with observed respiratory events or impaired gas exchange during sleep, a comprehensive screening for SDB should be considered for all patients with DM1. Further research into disease-specific recommendations encompassing the standardization of PFT, as well as overnight polygraphic and capnometry recordings, could help to guide timely, personalized treatment.

The 288th ENMC workshop (16-18 May 2025) brought together a group of 26 healthcare professionals, researchers, and patient representatives to advance understanding and clinical management of gastrointestinal (GI) manifestations in individuals with myotonic dystrophy (DM). GI symptoms are common in DM but are not systematically addressed in clinical care and are frequently left untreated or treated incorrectly. This workshop highlighted the breadth and impact of GI manifestations in DM, addressing symptoms in the oropharynx, oesophagus, liver, gallbladder, stomach, small and large intestines, and pelvic floor muscles. Attention was given to nutritional, cognitive, and behavioural influences on these symptoms and differences across males and females. Developments in genetic and animal studies that contribute to an increased understanding of the pathophysiology and potential treatment of GI manifestations were discussed, and recommendations are provided for their use. Building on these discussions, this report extends and substantiates the workshop content by incorporating additional literature and expert interpretation. Practical clinical recommendations to optimise the care and treatment of GI symptoms in DM were provided and, together with patient representatives, a list of 10 questions has been developed that can be used in the consultation room to identify whether a patient is experiencing GI symptoms. Next steps include the development of a DM-specific assessment instrument for GI symptoms and the selection of outcome measures to monitor changes in symptoms over time, during treatment, or in clinical trials.

IntroductionNon-invasive evaluation of myocardial tissue is a major goal of cardiac imaging. This is the case of myocardial fibrosis which is crucial in many myocardial diseases. Cardiac extracellular volume (ECV) was shown to indicate myocardial fibrosis and early cardiac involvement. With this study, our objective is to evaluate ECV measured with cardiac magnetic resonance (CMR) in patients with myotonic dystrophy type 1 (DM1) and 2 (DM2) as potential imaging biomarkers of subclinical cardiac pathology, and its relationship with demographic and clinical parameters, ECG-derived measures of cardiac conduction, and neuromuscular performance status.Materials and methodsWe retrospectively analyzed 18 DM1 patients and 4 DM2 patients without apparent cardiac disease who had CMR at our center. Differences between independent distributions were evaluated using Mann–Whitney U test, while correlations were evaluated using Spearman’s ρ.ResultsGlobal ECV in DM1 patients (median 28.36; IQR 24.81–29.77) was significantly higher (p = 0.0141) than in DM2 patients (median 22.93; IQR 21.25–24.35), and than that reported in literature in healthy subjects (p = 0.0374; median 25.60; IQR 19.90–31.90). Septal ECV was significantly higher (p = 0.0074) in DM1 (median 27.37; IQR 25.97–29.74) than in DM2 patients (median 22.46; 21.57–23.19). Global ECV showed a strong, positive correlation with septal ECV (ρ = 0.9282, p < 0.0001). We observed that DM1 women showed significantly higher global (p = 0.0012) and septal (p < 0.0001) ECV values compared to men.DiscussionWe found a significant increase in global and septal cardiac ECV in patients with DM1. These values might thus suggest that DM1 patients present an increased cardiovascular risk, mainly due to cardiac fibrosis, even in absence of overt cardiac pathology at other common cardiovascular exams. DM1 patients may also be at increased risk of early septal fibrosis, with important implications on the risk for fatal arrhythmias. In addition, our results suggest the presence of gender-related differences, with DM1 women being more prone to myocardial fibrosis. Physicians dealing with DM1 may consider CMR as a screening tool for the early identification of patients with increased cardiovascular risk.

Congenital myotonic dystrophy type 1 (CDM1) is a rare neuromuscular disease. The aim of our study was to evaluate clinical variability of CDM1 and factors that may influence survival in CDM1. Research included 24 pediatric patients with CDM1. Most of our patients had some form of hypoxic ischemic encephalopathy (HIE) (74%), from mild to severe. Prolonged and complicated deliveries (75%), high percentage of children resuscitated at birth (57%) and respiratory insufficiency (46%) with consequent hypoxia were the main reasons that could explain high percentage of HIE. Therapeutic hypothermia was applied in three children with poor outcome. Median survival of all CDM1 was 14.2 ±1.5 years. Six patients had a fatal outcome (25%). Their mean age of death was 3.0±2.8 years. Poor prognostic factors for the survival of our CDM1 patients were: preterm delivery, resuscitation at birth, severe HIE, hypothermia treatment and permanent mechanical ventilation. Respiratory insufficiency was the main life-threatening factor. Our data clearly indicates the need to develop natural history studies in CDM1 in order to enhance the standards of care and to develop clinical trials investigating causative therapies in pediatric patients with CDM1.

Wearable sensors are becoming increasingly popular for complementing standard clinical assessments of gait deficits and for remote monitoring patient's motor function in real world. Monitoring gait during the 6MWT offers an opportunity to investigate the dynamic changes that occur in prolonged walking. Besides, continuous monitoring at home gives information on patient's daily physical activity. Our first aim is to determine if gait parameters worsen during sustained walking in patients affected by myotonic dystrophy (MD). Our secondary aim is to evaluate the feasibility of acquiring physical activity biomarkers in daily living conditions. We collected data of 30 patients with MD during a standard 6MWT wearing a sensor (GSensor, BTS) at L5 level. Gait parameters were extracted from raw signals, corresponding to early, middle and late segments of the 6MWT and we applied non-parametric tests to compare gait segments. Home monitoring for extraction of physical activity data will be performed using a wearable sensor (DynaPort 7, McRoberts) worn consecutively for 7-days. Preliminary results show an increase in gait acceleration and significant changes in smoothness and stability of gait in the MD group between the early and the late section of the 6MWT. Our preliminary results suggest that gait parameters associated to fatigability can be measured during a 6MWT using a wearable device and that the method allows to highlight variations during sections of the 6MWT in patients with MD. Evaluating patients with a neuromuscular disease in their ecologic setting could significantly impact rehabilitation management with the aim of promoting an active lifestyle.

Myotonia congenita, both in a dominant (Thomsen disease) and recessive form (Becker disease), is caused by molecular defects in CLCN1 that encodes the major skeletal muscle chloride channel, ClC-1. This channel is important for the normal repolarization of muscle action potentials and consequent relaxation of the muscle, and its dysfunction leads to impaired muscle relaxation after voluntary or evoked contraction and muscle stiffness. More than 300 CLCN1 pathogenic variants have been found in association with congenital myotonia, inherited as recessive or dominant traits (with complete or incomplete penetrance). In this study, we describe the case of a 44-year-old woman complaining of “leg stiffness” since the age of 20 years and presenting with transient muscle weakness, especially after sitting for several minutes, with grip myotonia and feet myotonia, cold-sensitive and warm-up. The strength was normal, but muscle hypertrophy in the lower limbs was evident. EMG myotonia was detected in all explored muscles. The patient’s father had precocious cataract correction but did not show myotonic discharges at EMG. Examination of the patient’s sons (aged 18 years and 12 years) was unremarkable. The patient started treatment with mexiletine, with improvement in grip myotonia and limb stiffness, but it was soon interrupted due to gastrointestinal disturbances. Direct sequencing of CLCN1 identified the previously described heterozygous intronic variant c.1471 + 1G > A, which resulted in the skipping of exon 13 in the CLCN1 muscle transcript. In addition, the rare heterozygous synonymous nucleotide change c.762C > T p.Cys254Cys was identified and predicted to alter physiological splicing. The detection of multiple splicing abnormalities leading to premature termination codons supported the in silico prediction. We developed a Western blot assay to assess the ClC-1 protein in muscle biopsy, and we observed that ClC-1 levels were consistently reduced in the patient’s muscle, supporting the pathogenic behavior of the variants disclosed. Overall, we report a novel case of Becker myotonia and highlight the importance of multiple levels of analysis to achieve a firm molecular diagnosis.

Introduction: Myotonic dystrophy type 1 (DM1) and 2 (DM2) are genetically determined progressive muscular disorders with multisystemic affection, including brain involvement. Transcranial sonography (TCS) is a reliable diagnostic tool for the investigation of deep brain structures. We sought to evaluate TCS findings in genetically confirmed DM1 and DM2 patients, and further correlate these results with patients’ clinical features. Methods: This cross-sectional study included 163 patients (102 DM1, 61 DM2). Echogenicity of the brainstem raphe (BR) and substantia nigra (SN) as well as the diameter of the third ventricle (DTV) were assessed by TCS. Patients were evaluated using the Hamilton Depression Rating Scale, Fatigue Severity Scale and Daytime Sleepiness Scale. Results: SN hyperechogenicity was observed in 40% of DM1 and 34% of DM2 patients. SN hypoechogenicity was detected in 17% of DM1 and 7% of DM2 patients. BR hypoechogenicity was found in 36% of DM1 and 47% of DM2 subjects. Enlarged DTV was noted in 19% of DM1 and 15% of DM2 patients. Older, weaker, depressive, and fatigued DM1 patients were more likely to have BR hypoechogenicity (p < 0.05). DTV correlated with age and disease duration in DM1 (p < 0.01). In DM2 patients SN hyperechogenicity correlated with fatigue. Excessive daytime sleepiness was associated with hypoechogenic BR (p < 0.05) and enlarged DVT (p < 0.01) in DM2 patients. Conclusions: TCS is an easy applicable and sensitive neuroimaging technique that could offer new information regarding several brainstem structures in DM1 and DM2. This may lead to better understanding of the pathogenesis of the brain involvement in DM with possible clinical implications.

IntroductionCACNA1S related congenital myopathy is an emerging recently described entity. In this report we describe 2 sisters with mutations in the CACNA1S gene and the novel phenotype of congenital myopathy and infantile onset episodic weakness.Clinical descriptionBoth sisters had neonatal onset hypotonia, muscle weakness, and delayed walking. Episodic weakness started in infancy and continued thereafter, provoked mostly by cold exposure. Muscle imaging revealed fat replacement of gluteus maximus muscles. Next generation sequencing found the missense p.Cys944Tyr variant and the novel splicing variant c.3526-2A>G in CACNA1S. Minigene assay revealed the splicing variant caused skipping of exon 28 from the transcript, potentially affecting protein folding and/or voltage dependent activation.ConclusionThis novel phenotype supports the notion that there are age related differences in the clinical expression of CACNA1S gene mutations. This expands our understanding of mutations located in regions of the CACNA1S outside the highly conserved S4 segment, where most mutations thus far have been identified.

Myotonic dystrophies (DM) encompass a group of complex genetic disorders characterized by progressive muscle weakness with myotonia and multisystemic involvement. The aim of our paper is to synthesize key findings and advancements in the understanding of DM, and to underline the multidisciplinary approach to DM, emphasizing the importance of genetic counseling, comprehensive clinical care, and symptom management. We discuss the genetic basis of DM, emphasizing the role of repeat expansions in disease pathogenesis, as well as cellular and animal models utilized for studying DM mechanisms and testing potential therapies. Diagnostic challenges, such as determining the size of disease expansions and assessing mosaicism, are elucidated alongside emerging genetic testing methods. Therapeutic strategies, mainly for DM1, are also explored, encompassing small molecules, nucleic acid-based therapies (NATs), and genome/transcriptome engineering. The challenges of such a therapeutic delivery and immunogenic response and the importance of innovative strategies, including viral vectors and AAV serotypes, are highlighted within the text. While no curative treatments have been approved, supportive and palliative care remains essential, with a focus on addressing multisystemic complications and maintaining functional independence. Continued exploration of these therapeutic advancements offers hope for comprehensive disease management and potentially curative therapies for DM1 and related disorders.

INTRODUCTION:Myotonic dystrophy type 1 (DM1) is the most prevalent muscular dystrophy in adults. People with DM1 might represent a high-risk population for respiratory infections, including COVID-19. Our aim was to evaluate the characteristics of COVID-19 infection and vaccination rate in DM1 patients.METHODS:This cross-sectional cohort study included 89 patients from the Serbian registry for myotonic dystrophies. Mean age at testing was 48.4 ± 10.4 years with 41 (46.1%) male patients. Mean duration of the disease was 24.0 ± 10.3 years.RESULTS:COVID-19 infection was reported by 36 (40.4%) DM1 patients. Around 14% of patients had a more severe form of COVID-19 requiring hospitalization. The severity of COVID-19 was in accordance with the duration of DM1. A severe form of COVID-19 was reported in 20.8% of patients who were not vaccinated against SARS-CoV-2 and in none of the vaccinated ones. The majority of 89 tested patients (66.3%) were vaccinated against SARS-CoV-2. About half of them (54.2%) received three doses and 35.6% two doses of vaccine. Mild adverse events after vaccination were recorded in 20.3% of patients.CONCLUSIONS:The percentage of DM1 patients who suffered from COVID-19 was like in general population, but with more severe forms in DM1, especially in patients with longer DM1 duration. The study indicated an overall favorable safety profile of COVID-19 vaccines among individuals with DM1 and its ability to protect them from severe COVID-19.

Introduction Myotonic dystrophy type 2 (DM2) is a rare, multisystemic, autosomal dominant disease with highly variable clinical presentation. DM2 is considered to be highly underdiagnosed. Objective The aim of this study was to determine which symptoms, signs, and diagnostic findings in patients referred to neurological outpatient units are the most indicative to arouse suspicion of DM2. We tried to make a useful and easy-to-administer clinical scoring system for early diagnosis of DM2-DM2 early diagnosis score (DM2-EDS). Patients and methods Two hundred ninety-one patients with a clinical suspicion of DM2 were included: 69 were genetically confirmed to have DM2, and 222 patients were DM2 negative. Relevant history, neurological, and paraclinical data were obtained from the electronic medical records. Results The following parameters appeared as significant predictors of DM2 diagnosis: cataracts (beta = 0.410, p < 0.001), myotonia on needle EMG (beta = 0.298, p < 0.001), hand tremor (beta = 0.211, p = 0.001), positive family history (beta = 0.171, p = 0.012), and calf hypertrophy (beta = 0.120, p = 0.043). In the final DM2-EDS, based on the beta values, symptoms were associated with the following values: cataracts (present 3.4, absent 0), myotonia (present 2.5, absent 0), tremor (present 1.7, absent 0), family history (positive 1.4, negative 0), and calf hypertrophy (present 1.0, absent 0). A cut-off value on DM2-EDS of 3.25 of maximum 10 points had a sensitivity of 84% and specificity of 81% to diagnose DM2. Conclusion Significant predictors of DM2 diagnosis in the neurology outpatient unit were identified. We made an easy-to-administer DM2-EDS score for early diagnosis of DM2.

Non-dystrophic myotonias (NDM) encompass chloride and sodium channelopathy. Mutations in CLCN1 lead to either the autosomal dominant form or the recessive form of myotonia congenita (MC). The main symptom is stiffness worsening after rest and improving by physical exercise. Patients with recessive mutations often show muscle hypertrophy, and transient weakness mostly in their lower limbs. Mutations in SCN4A can lead to Hyper-, Hypo- or Normo-kalemic Periodic Paralysis or to different forms of myotonia (Paramyotonia Congenita-PMC and Sodium Channel Myotonia-SCM and severe neonatal episodic laryngospasm-SNEL). SCM often presents facial muscle stiffness, cold sensitivity, and muscle pain, whereas myotonia worsens in PMC patients with the repetition of the muscle activity and cold. Patients affected by chloride or sodium channelopathies may show similar phenotypes and symptoms, making the diagnosis more difficult to reach. Herein we present a woman in whom sodium and chloride channelopathies coexist yielding a complex phenotype with features typical of both MC and PMC. Disease onset was in the second decade with asthenia, weakness, warm up and limb stiffness, and her symptoms had been worsening through the years leading to frequent heavy retrosternal compression, tachycardia, stiffness, and symmetrical pain in her lower limbs. She presented severe lid lag myotonia, a hypertrophic appearance at four limbs and myotonic discharges at EMG. Her symptoms have been triggered by exposure to cold and her daily life was impaired. All together, clinical signs and instrumental data led to the hypothesis of PMC and to the administration of mexiletine, then replaced by acetazolamide because of gastrointestinal side effects. Analysis of SCN4A revealed a new variant, p.Glu1607del. Nonetheless the severity of myotonia in the lower limbs and her general stiffness led to hypothesize that the impairment of sodium channel, Nav1.4, alone could not satisfactorily explain the phenotype and a second genetic "factor" was hypothesized. CLCN1 was targeted, and p.Met485Val was detected in homozygosity. This case highlights that proper identification of signs and symptoms by an expert neurologist is crucial to target a successful genetic diagnosis and appropriate therapy.

TDP-43 (TAR DNA-binding protein 43) aggregation and redistribution are recognised as a hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. As TDP-43 inclusions have recently been described in the muscle of inclusion body myositis patients, this highlights the need to understand the role of TDP-43 beyond the central nervous system. Using RNA-seq, we directly compare TDP-43-mediated RNA processing in muscle (C2C12) and neuronal (NSC34) mouse cells. TDP-43 displays a cell-type-characteristic behaviour targeting unique transcripts in each cell-type, which is due to characteristic expression of RNA-binding proteins, that influence TDP-43’s performance and define cell-type specific splicing. Among splicing events commonly dysregulated in both cell lines, we identify some that are TDP-43-dependent also in human cells. Inclusion levels of these alternative exons are altered in tissues of patients suffering from FTLD and IBM. We therefore propose that TDP-43 dysfunction contributes to disease development either in a common or a tissue-specific manner.