Ameliorated cellular hallmarks of myotonic dystrophy in hybrid myotubes from patient and unaffected donor cells.

BACKGROUND: Cell-based strategies are being explored as a therapeutic option for muscular dystrophies, using a variety of cell types from different origin and with different characteristics. Primary pericytes are multifunctional cells found in the capillary bed that exhibit stem cell-like and myogenic regenerative properties. This unique combination allows them to be applied systemically, presenting a promising opportunity for body-wide muscle regeneration. We previously reported the successful isolation of ALP+ pericytes from skeletal muscle of patients with myotonic dystrophy type 1 (DM1). These pericytes maintained normal growth parameters and myogenic characteristics in vitro despite the presence of nuclear (CUG)n RNA foci, the cellular hallmark of DM1. Here, we examined the behaviour of DM1 pericytes during myogenic differentiation. METHODS: DMPK (CTG)n repeat lengths in patient pericytes were assessed using small pool PCR, to be able to relate variation in myogenic properties and disease hallmarks to repeat expansion. Pericytes from unaffected controls and DM1 patients were cultured under differentiating conditions in vitro. In addition, the pericytes were grown in co-cultures with myoblasts to examine their regenerative capacity by forming hybrid myotubes. Finally, the effect of pericyte fusion on DM1 disease hallmarks was investigated. RESULTS: Small pool PCR analysis revealed the presence of somatic mosaicism in pericyte cell pools. Upon differentiation to myotubes, DMPK expression was upregulated, leading to an increase in nuclear foci sequestering MBNL1 protein. Remarkably, despite the manifestation of these disease biomarkers, patient-derived pericytes demonstrated myogenic potential in co-culture experiments comparable to unaffected pericytes and myoblasts. However, only the unaffected pericytes improved the disease hallmarks in hybrid myotubes. From 20% onwards, the fraction of unaffected nuclei in myotubes positively correlated with a reduction of the number of RNA foci and an increase in the amount of free MBNL1. CONCLUSIONS: Fusion of only a limited number of unaffected myogenic precursors to DM1 myotubes already ameliorates cellular disease hallmarks, offering promise for the development of cell transplantation strategies to lower disease burden.

The Role of Cognition, Affective Symptoms, and Apathy in Treatment Adherence with Noninvasive Home Mechanical Ventilation in Myotonic Dystrophy.

Background: Chronic respiratory failure often occurs in myotonic dystrophy type 1 (DM1) and can be treated with noninvasive home mechanical ventilation (HMV). Treatment adherence with HMV is often suboptimal in patients with DM1, but the reasons for that are not well understood. Objective: The aim of this exploratory study was to gain insight in the prevalence of mild cognitive impairment, affective symptoms, and apathy and to investigate their role in HMV treatment adherence in DM1. Methods: The Montreal Cognitive Assessment (MoCA), the Hospital Anxiety and Depression Scale (HADS), and the Apathy Evaluation Scale (AES) were used to assess cognition, affective symptoms, and apathy in DM1 patients that use HMV. Patients with low treatment adherence (average daily use HMV <5 h or <80% of the days) were compared with patients with high treatment adherence (average daily use of HMV≥5 h and ≥80% of the days). Results: Sixty patients were included. Abnormal scores were found in 40% of the total group for the MoCA, in 72-77% for the AES, and in 18% for HADS depression. There was no difference between the high treatment adherence group (n = 39) and the low treatment adherence group (n = 21) for the MoCA, AES, and HADS depression. The HADS anxiety was abnormal in 30% of the total group, and was significantly higher in the low treatment adherence group (p = 0.012). Logistic regression analysis revealed that a higher age and a higher BMI were associated with a greater chance of high treatment adherence. Conclusions: This exploratory study showed that cognitive impairment and apathy are frequently present in DM1 patients that use HMV, but they are not associated with treatment adherence. Feelings of anxiety were associated with low treatment adherence. Higher age and higher BMI were associated with high treatment adherence with HMV.

Resistance training in women with myotonic dystrophy type 1: a multisystemic therapeutic avenue.

Myotonic dystrophy type 1 (DM1) is a hereditary disease characterized by muscular impairments. Fundamental and clinical positive effects of strength training have been reported in men with DM1, but its impact on women remains unknown. We evaluated the effects of a 12-week supervised strength training on physical and neuropsychiatric health. Women with DM1 performed a twice-weekly supervised resistance training program (3 series of 6-8 repetitions of squat, leg press, plantar flexion, knee extension, and hip abduction). Lower limb muscle strength, physical function, apathy, anxiety and depression, fatigue and excessive somnolence, pain, and patient-reported outcomes were assessed before and after the intervention, as well as three and six months after completion of the training program. Muscle biopsies of the vastus lateralis were also taken before and after the training program to assess muscle fiber growth. Eleven participants completed the program (attendance: 98.5 %). Maximal hip and knee extension strength (p < 0.006), all One-Repetition Maximum strength measures (p < 0.001), apathy (p = 0.0005), depression (p = 0.02), pain interference (p = 0.01) and perception of the lower limb function (p = 0.003) were significantly improved by training. Some of these gains were maintained up to six months after the training program. Strength training is a good therapeutic strategy for women with DM1.

Main features and disease outcome of congenital myotonic dystrophy - experience from a single tertiary center.

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.

Diagnosis and Management of Myotonic Dystrophy Type 1.

This JAMA Insights discusses the signs and symptoms, diagnosis, and treatment of myotonic dystrophy type 1.

Suitability of the Respicheck questionnaire and Epworth sleepiness scale for therapy monitoring in myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1) is an autosomal dominant trinucleotide disorder that often leads to respiratory dysfunction resulting in hypoventilation symptoms, reduced quality of life and causing premature death if untreated. To early identify symptoms of hypoventilation, the Respicheck questionnaire was developed as a screening tool. Symptomatic therapies like inspiratory muscle training (IMT) are recommended to strengthen respiratory muscles and reduce or even prevent hypoventilation symptoms. Our study aimed to evaluate the Respicheck questionnaire's suitablility to monitor the efficacy of IMT. Patients with genetically confirmed DM1 were randomly assigned to either IMT - endurance or strength training, or control group. At baseline, end of study and four interim visits, pulmonary function tests, Respicheck questionnaire and Epworth sleepiness scale were assessed. While patients in training groups achieved a substantial improvement after nine months of regular IMT in pulmonary function tests, the Respicheck score did not improve likewise. Similarly, the ESS score did not change significantly in both training and control groups. Consequently, we conclude that either improvement of respiratory function is not necessarily associated with clinical improvement, or respiratory muscle weakness was not the only reason for hypoventilation syndrome, or both questionnaires are not sensitive enough to detect slight clinical changes.

Øyesykdom ved dystrophia myotonica type 1.

Myotonic dystrophy type 1 is one of the most common genetic neuromuscular diseases in adults. The disease not only affects the musculoskeletal system, but is multisystemic, and ocular involvement with cataract formation is a frequent additional finding. To avoid recurrence of secondary opacification that is difficult to treat, the cataract should not be treated with traditional lens replacement. This clinical review article presents ophthalmological findings in cases of myotonic dystrophy type 1 and describes a new surgical method for cataracts in this patient group.

The current clinical perception of myotonic dystrophy type 2.

PURPOSE OF REVIEW: Myotonic dystrophy type 2 (DM2) is a genetic disorder belonging to the spectrum of myotonic dystrophies. DM2 is characterized by progressive muscle weakness, wasting and muscle pain (myalgia), but can also affect many other organ systems. In this review, we provide an updated overview on the research literature on DM2 with a focus on the management of multisystemic involvement and atypical clinical phenotypes. RECENT FINDINGS: Recent studies have focused on different aspects of multisystemic involvement. Early and severe cardiac involvement can occur in DM2 and needs to be managed appropriately. Diabetes has been shown to be more common in DM2 than in DM1, while a combination of symptoms (cataracts, myotonia, tremor) can be used to raise clinical suspicion and initiate genetic testing for DM2. Autoimmune disease has been shown to occur in up to one-third of DM2 patients, possibly due to altered immune pathways. New evidence also suggests a childhood-onset phenotype presenting with foot deformities. SUMMARY: The multisystemic aspects of the disease require a multidisciplinary approach for some patients, most likely even including state-of-the-art cardiac and brain imaging to detect and treat complications earlier. Of note, our concept of DM2 as an adult-onset disease is somewhat challenged by evidence suggesting a few pediatric DM2 patients and possibly anticipation, at least in some DM2 families. More studies, including larger cohorts, are needed to better understand this possible early-onset DM2 phenotype variant.

Role of respiratory characteristics in treatment adherence with noninvasive home mechanical ventilation in myotonic dystrophy type 1, a retrospective study.

Chronic respiratory insufficiency is common in patients with myotonic dystrophy type 1 (DM1) and can be treated with noninvasive home mechanical ventilation (HMV). HMV is not always tolerated well resulting in low treatment adherence. We aimed to analyze if baseline respiratory characteristics such as pulmonary function, level of pCO2 and presence of sleep apnea are associated with HMV treatment adherence in DM1 patients. Pulmonary function testing, polysomnography and blood gas measurement data of DM1 patients were retrospectively collected. Initiation of HMV and treatment adherence after one year was documented. Patients with low treatment adherence (average daily use of HMV <5 h) were grouped with patients that discontinued HMV and compared with patients with high treatment adherence (average daily use of HMV >5 h). HMV was initiated in 101 patients. After one year, 58 patients had low treatment adherence. There were no differences between the low and high treatment adherence group regarding the respiratory characteristics. None of the included predictors (gender, age, body mass index, cytosine-thymine-guanine repeat length, FVC, daytime pCO2, bicarbonate, nighttime pCO2, nighttime base excess, apnea-hypopnea index and mean saturation during sleep) was able to significantly predict high treatment adherence. In conclusion, the respiratory characteristics are not associated with treatment adherence with HMV in DM1 patients and cannot be used to identify patients at risk for low HMV treatment adherence.

Individual transcriptomic response to strength training for patients with myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1), the most common form of adult-onset muscular dystrophy, is caused by a CTG expansion resulting in significant transcriptomic dysregulation that leads to muscle weakness and wasting. While strength training is clinically beneficial in DM1, molecular effects had not been studied. To determine whether training rescued transcriptomic defects, RNA-Seq was performed on vastus lateralis samples from 9 male patients with DM1 before and after a 12-week strength-training program and 6 male controls who did not undergo training. Differential gene expression and alternative splicing analysis were correlated with the one-repetition maximum strength evaluation method (leg extension, leg press, hip abduction, and squat). While training program-induced improvements in splicing were similar among most individuals, rescued splicing events varied considerably between individuals. Gene expression improvements were highly varied between individuals, and the percentage of differentially expressed genes rescued after training were strongly correlated with strength improvements. Evaluating transcriptome changes individually revealed responses to the training not evident from grouped analysis, likely due to disease heterogeneity and individual exercise response differences. Our analyses indicate that transcriptomic changes are associated with clinical outcomes in patients with DM1 undergoing training and that these changes are often specific to the individual and should be analyzed accordingly.

AMPK is mitochondrial medicine for neuromuscular disorders.

Duchenne muscular dystrophy (DMD), myotonic dystrophy type 1 (DM1), and spinal muscular atrophy (SMA) are the most prevalent neuromuscular disorders (NMDs) in children and adults. Central to a healthy neuromuscular system are the processes that govern mitochondrial turnover and dynamics, which are regulated by AMP-activated protein kinase (AMPK). Here, we survey mitochondrial stresses that are common between, as well as unique to, DMD, DM1, and SMA, and which may serve as potential therapeutic targets to mitigate neuromuscular disease. We also highlight recent advances that leverage a mutation-agnostic strategy featuring physiological or pharmacological AMPK activation to enhance mitochondrial health in these conditions, as well as identify outstanding questions and opportunities for future pursuit.

The current status of medical care for myotonic dystrophy type 1 in the national registry of Japan.

INTRODUCTION/AIMS: Myotonic dystrophy (DM) is a systemic disease with multiple organ complications, making the standardization of medical care a challenge. We analyzed data from Japan's national registry to clarify the current treatment patterns and demographic features of Japanese DM patients. METHODS: Using the Japanese National Registry of Muscular Dystrophy (Remudy), we analyzed medical care practice for the multisystemic issues associated with adult DM type 1 patients, excluding congenital DM. RESULTS: We included 809 patients with a median age of 44.2 years. Among these patients, 15.8% used ventilators; 31.7% met the index considered at risk for sudden death due to cardiac conduction defects (PR interval over 240 milliseconds or QRS duration over 120 milliseconds) and 2.8% had implanted cardiac devices. Medication for heart failure was prescribed to 9.6% of patients. Overall, 21.2% of patients had abnormal glucose metabolism, of whom 42.9% were treated with oral medications. Among the oral medications, dipeptidyl peptidase-4 inhibitors were the most common. Cancers were observed in 3.7% of the patients, and endometrial and breast cancers were dominant. Mexiletine was prescribed for myotonia in 1.9% of the patients, and only 1% of the patients received medication for daytime sleepiness. DISCUSSION: This study shows difference in treatment patterns for DM1 in Japan compared with other countries, such as lower rates of use of implantable cardiac devices and higher rates of ventilator use. These data may be useful in discussions aimed at standardizing medical care for patients with DM.

Development of prediction models based on respiratory assessments to determine the need for non-invasive ventilation in patients with myotonic dystrophy type 1.

INTRODUCTION: Myotonic dystrophy type 1 is a slowly progressive, multisystem, autosomal dominant disorder, in which the impairments of respiratory systems represent one of the main causes of death. OBJECTIVE: The aim of our study is to develop prediction models to identify the most appropriate test(s) providing indication for NIV. METHODS: DM1 patients attending the NEMO Clinical Center (Milan) between January 2008 and July 2020, who had been subjected to a complete battery of respiratory tests, were retrospectively recruited. Demographic, clinical, and anthropometric characteristics were collected, as well as arterial blood gas (ABG) analysis, spirometry, respiratory muscle strength, cough efficacy, and nocturnal oximetry as respiratory assessments. Patients were stratified in those requiring NIV and those with normal respiratory function. RESULTS: Out of 151 DM1 patients (median age: 44 years [35.00-53.00]; male/female ratio: 0.80 (67/84)), 76 had an indication for NIV initiation (50.33%). ABG, spirometry, and nocturnal oximetry prediction models resulted in an excellent discriminatory ability in distinguishing patients who needed NIV from those who did not (AUC of 0.818, 0.808, and 0.935, respectively). An easy-to-use calculator was developed to automatically determine a score of NIV necessity based on the prediction equations generated from each aforementioned prediction model. CONCLUSIONS: The proposed prediction models may help to identify which patients are at a higher risk of requiring ventilator support and therefore help in defining individual management plans and criteria for specific interventions early in the disease course.

[Medical emergency card for Steinert's disease: an unmet need]. / Tarjeta de emergencias médicas para la enfermedad de Steinert: una necesidad desatendida.

INTRODUCTION: Myotonic dystrophy type 1 (DM1) or Steinert's disease (ORPHA 273; OMIM #160900) is a rare disorder of genetic origin with muscular manifestations (muscle weakness and myotonia), early-onset cataracts (before 50 years of age) and systemic manifestations (cerebral, endocrine, cardiac, gastrointestinal tract, uterus, skin and immune system). Its clinical expressivity is highly variable and ranges from lethal forms in infancy to mild late-onset disease. Its low frequency prevents emergency medical professionals from becoming familiar with the essential precautions for its treatment. In order to alleviate this lack of information, those affected by DM1 have, in the countries of our environment, a medical emergency card (Tarjeta de Emergencias Medicas, TEM) that the patient should always carry with him/her and give to the physician before receiving emergency care. OBJECTIVES: To define the TEM. To describe the TEM for DM1 already implemented. To list the advantages for patients and professionals of their use. MATERIAL AND METHODS: Some of the TEM for DM1 currently in use in France and the United Kingdom are described. RESULTS: The arguments justifying their implantation in our setting are presented in detail. CONCLUSIONS: The TEM for DM1 managed by a physician can improve the emergency medical care of patients affected by Steinert's disease.

TITLE: Tarjeta de emergencias médicas para la enfermedad de Steinert: una necesidad desatendida.Introducción. La distrofia miotónica de tipo 1 (DM1), o enfermedad de Steinert (ORPHA 273; OMIM #160900), es un trastorno de origen genético poco frecuente con manifestaciones musculares (debilidad muscular y miotonía), cataratas de inicio temprano (antes de los 50 años) y manifestaciones sistémicas (cerebral, endocrina, cardíaca, del tubo digestivo, del útero, de la piel y del sistema inmunitario). Su expresividad clínica es muy variable y se extiende desde formas letales en la lactancia hasta una enfermedad leve de aparición tardía. Su baja frecuencia impide que los profesionales de urgencias médicas se familiaricen con las precauciones imprescindibles para su tratamiento. Con el propósito de paliar esta falta de información, los afectados por DM1 disponen, en los países de nuestro entorno, de una tarjeta de emergencia médica (TEM) que el paciente siempre debe llevar consigo y entregar al facultativo antes de recibir asistencia urgente. Objetivos. Definir la TEM, describir las TEM para la DM1 ya implantadas y enumerar las ventajas para pacientes y profesionales que supone su utilización. Material y métodos. Se describen algunas de las TEM para la DM1 actualmente en uso en Francia y el Reino Unido. Resultados. Se exponen pormenorizadamente los argumentos que justifican su implantación en nuestro medio. Conclusiones. La TEM para la DM1 gestionada por un facultativo puede mejorar la asistencia en emergencias médicas de los pacientes afectados por la enfermedad de Steinert.

Peptide-Conjugated PMOs for the Treatment of Myotonic Dystrophy.

Antisense oligonucleotides (ASOs) have shown great therapeutic potential in the treatment of many neuromuscular diseases including myotonic dystrophy 1 (DM1). However, systemically delivered ASOs display poor biodistribution and display limited penetration into skeletal muscle. The conjugation of cell-penetrating peptides (CPPs) to phosphorodiamidate morpholino oligonucleotides (PMOs), a class of ASOs with a modified backbone, can be used to enhance ASO skeletal muscle penetration. Peptide-PMOs (P-PMOs) have been shown to be highly effective in correcting the DM1 skeletal muscle phenotype in both murine and cellular models of DM1 and at a molecular and functional level. Here we describe the synthesis and conjugation of P-PMOs and methods for analyzing their biodistribution and toxicity in the HSA-LR DM1 mouse model and their efficacy both in vitro and in vivo using FISH and RT-PCR splicing analysis.

Complications After Dental Sedation: A Myotonic Mystery Case Report.

Myotonic dystrophy (dystrophia myotonica; DM) is an uncommon progressive hereditary muscle disorder that can present with variable severity at birth, in early childhood, or most commonly as an adult. Patients with DM, especially type 1 (DM1), are extremely sensitive to the respiratory depressant effects of sedative-hypnotics, anxiolytics, and opioid agonists. This case report describes a 37-year-old male patient with previously undiagnosed DM1 who received dental care under minimal sedation using intravenous midazolam. During the case, the patient experienced 2 brief episodes of hypoxemia, the second of which required emergency intubation after propofol and succinylcholine and resulted in extended hospital admission. A lipid emulsion (Liposyn II 20%) infusion was given approximately 2 hours after the last local anesthetic injection due to slight ST elevation and suspicion of local anesthetic toxicity (LAST). Months after treatment, the patient suffered a fall resulting in a fatal traumatic brain injury. Complications noted in this case report were primarily attributed to the unknown diagnosis of DM1, although additional precipitating factors were likely present. This report also provides a basic review of the literature and clinical guidelines for managing myotonic dystrophy patients for dental care with local anesthesia, sedation, or general anesthesia.

Myotonic Dystrophy.

PURPOSE OF REVIEW: Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) are genetic disorders affecting skeletal and smooth muscle, heart, brain, eyes, and other organs. The multisystem involvement and disease variability of myotonic dystrophy have presented challenges for clinical care and research. This article focuses on the diagnosis and management of the disease. In addition, recent advances in characterizing the diverse clinical manifestations and variability of the disease are discussed. RECENT FINDINGS: Studies of the multisystem involvement of myotonic dystrophy, including the most lethal cardiac and respiratory manifestations and their molecular underpinnings, expand our understanding of the myotonic dystrophy phenotype. Advances have been made in understanding the molecular mechanisms of both types of myotonic dystrophy, providing opportunities for developing targeted therapeutics, some of which have entered clinical trials in DM1. SUMMARY: Continued efforts focus on advancing our molecular and clinical understanding of DM1 and DM2. Accurately measuring and monitoring the diverse and variable clinical manifestations of myotonic dystrophy in clinic and in research is important to provide adequate care, prevent complications, and find treatments that improve symptoms and life quality.

Challenging Neuromuscular Disease Cases.

The diagnosis of neuromuscular disorders requires a thorough history including family history and examination, with the next steps broadened now beyond electromyography and neuropathology to include genetic testing. The challenge in diagnosis can often be putting all the information together. With advances in genetic testing, some diagnoses that adult patients may have received as children deserve a second look and may result in diagnoses better defined or alternative diagnoses made. Clearly defining or redefining a diagnosis can result in understanding of potential other systems involved, prognosis, or potential treatments. This article presents several cases and approach to diagnosis as well as potential treatment and prognostic concerns, including seipinopathy, congenital myasthenic syndrome, central core myopathy, and myotonic dystrophy type 2.