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.

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.

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.

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.

Clinical improvement of DM1 patients reflected by reversal of disease-induced gene expression in blood.

BACKGROUND: Myotonic dystrophy type 1 (DM1) is an incurable multisystem disease caused by a CTG-repeat expansion in the DM1 protein kinase (DMPK) gene. The OPTIMISTIC clinical trial demonstrated positive and heterogenous effects of cognitive behavioral therapy (CBT) on the capacity for activity and social participations in DM1 patients. Through a process of reverse engineering, this study aims to identify druggable molecular biomarkers associated with the clinical improvement in the OPTIMISTIC cohort. METHODS: Based on full blood samples collected during OPTIMISTIC, we performed paired mRNA sequencing for 27 patients before and after the CBT intervention. Linear mixed effect models were used to identify biomarkers associated with the disease-causing CTG expansion and the mean clinical improvement across all clinical outcome measures. RESULTS: We identified 608 genes for which their expression was significantly associated with the CTG-repeat expansion, as well as 1176 genes significantly associated with the average clinical response towards the intervention. Remarkably, all 97 genes associated with both returned to more normal levels in patients who benefited the most from CBT. This main finding has been replicated based on an external dataset of mRNA data of DM1 patients and controls, singling these genes out as candidate biomarkers for therapy response. Among these candidate genes were DNAJB12, HDAC5, and TRIM8, each belonging to a protein family that is being studied in the context of neurological disorders or muscular dystrophies. Across the different gene sets, gene pathway enrichment analysis revealed disease-relevant impaired signaling in, among others, insulin-, metabolism-, and immune-related pathways. Furthermore, evidence for shared dysregulations with another neuromuscular disease, Duchenne muscular dystrophy, was found, suggesting a partial overlap in blood-based gene dysregulation. CONCLUSIONS: DM1-relevant disease signatures can be identified on a molecular level in peripheral blood, opening new avenues for drug discovery and therapy efficacy assessments.

Study of an RNA-Focused DNA-Encoded Library Informs Design of a Degrader of a r(CUG) Repeat Expansion.

A solid-phase DNA-encoded library (DEL) was studied for binding the RNA repeat expansion r(CUG)exp, the causative agent of the most common form of adult-onset muscular dystrophy, myotonic dystrophy type 1 (DM1). A variety of uncharged and novel RNA binders were identified to selectively bind r(CUG)exp by using a two-color flow cytometry screen. The cellular activity of one binder was augmented by attaching it with a module that directly cleaves r(CUG)exp. In DM1 patient-derived muscle cells, the compound specifically bound r(CUG)exp and allele-specifically eliminated r(CUG)exp, improving disease-associated defects. The approaches herein can be used to identify and optimize ligands and bind RNA that can be further augmented for functionality including degradation.

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.

Development of Therapeutic Approaches for Myotonic Dystrophies Type 1 and Type 2.

Myotonic Dystrophies type 1 (DM1) and type 2 (DM2) are complex multisystem diseases without disease-based therapies. These disorders are caused by the expansions of unstable CTG (DM1) and CCTG (DM2) repeats outside of the coding regions of the disease genes: DMPK in DM1 and CNBP in DM2. Multiple clinical and molecular studies provided a consensus for DM1 pathogenesis, showing that the molecular pathophysiology of DM1 is associated with the toxicity of RNA CUG repeats, which cause multiple disturbances in RNA metabolism in patients' cells. As a result, splicing, translation, RNA stability and transcription of multiple genes are misregulated in DM1 cells. While mutant CCUG repeats are the main cause of DM2, additional factors might play a role in DM2 pathogenesis. This review describes current progress in the translation of mechanistic knowledge in DM1 and DM2 to clinical trials, with a focus on the development of disease-specific therapies for patients with adult forms of DM1 and congenital DM1 (CDM1).

Impact of a 12-week Strength Training Program on Fatigue, Daytime Sleepiness, and Apathy in Men with Myotonic Dystrophy Type 1.

BACKGROUND: Myotonic dystrophy type 1 (DM1) is a multisystemic neuromuscular disorder causing a plea of impairments, of which fatigue and apathy are some of the most frequent non-muscular symptoms. No curative treatment exists to date, and patients only have access to limited effective care, which are intended to decrease the burden of specific symptoms in daily life. OBJECTIVE: This study aimed to assess whether a 12-week strength training program has an impact on fatigue/daytime sleepiness, apathy, and disease bruden in men with DM1. METHODS: Eleven participants completed the Fatigue and Daytime Sleepiness Scale (FDSS) and the Myotonic Dystrophy Health Index (MDHI) at baseline, at 6 and 12 weeks, and at 6 and 9 months. Also, the Apathy Evaluation Scale (AES) was filled out at baseline, at 12 weeks, and at 6 and 9 months. RESULTS: Results show significant effects of the training program both on apathy and fatigue/daytime sleepiness, effects that are respectively greater at three and six months after the end of the program than at its very end. However, no difference was observed regarding the overall disease burden. CONCLUSION: These findings are promising for patients with DM1 considering that few non-pharmacological treatments are available.