Myotonic Dystrophy Research Articles

Comprehensive Cardiovascular Management of Myotonic Dystrophy Type 1 Patients: A Report from the Italian Neuro-Cardiology Network.

Myotonic dystrophy is a hereditary disorder with systemic involvement. The Italian Neuro-Cardiology Network-"Rete delle Neurocardiologie" (INCN-RNC) is a unique collaborative experience involving neurology units combined with cardio-arrhythmology units. The INCN facilitates the creation of integrated neuro-cardiac teams in Neuromuscular Disease Centers for the management of cardiovascular involvement in the treatment of myotonic dystrophy type 1 (MD1).

Cardiovascular magnetic resonance in muscular dystrophies: looking ahead.

Cardiac magnetic resonance (CMR) is an established tool for risk stratification in several cardiomyopathies, and its role in muscular dystrophies (MuD) looks promising. We sought to assess how CMR performs in predicting cardiac events in a real cohort of MuD patients. A prospective single-center study with the enrollment of consecutive adult MuD patients referred to cardiac screening from 2012 to 2018 with the collection of clinical and CMR data. During follow-up (FUP), major adverse cardiac events were considered a composite of device implantation, ventricular tachycardia (VT), hospitalization due to heart failure, and death. Sixty-five patients were included (mean age of 32±16, 51% female); the majority had myotonic dystrophy (34; 52.3%); most were asymptomatic (60; 92.3%) and at sinus rhythm (64; 98.5%). CMR was abnormal in 23 (43.3%) patients: left ventricle ejection fraction (LVEF) <55% was found in 7 patients, and late gadolinium enhancement (LGE) was present in 23 patients, mainly intra-myocardial or subepicardial (10 and 8 patients, respectively). During a median FUP of 77 months (interquartile range: 33), there were 7 deaths, 8 implanted devices, and one sustained VT. LVEF<55% and the presence of LGE were associated with the occurrence of all events (log rank test, p=0.002 and p=0.045, respectively). LVEF<55% was associated with a 6-fold higher risk of events (crude hazard ratio of 6.15; 95% confidence interval of 1.65-22.93), that remained significant after adjusting for LGE presence (adjusted hazard ratio of 4.81, 95% confidence interval of 1.07-15.9). In our cohort, CMR LVEF<55% and the presence of LGE were significantly associated with adverse events during follow-up, reinforcing the role of this technique on risk stratification of MuD populations.

Diagnostic uplift through the implementation of short tandem repeat analysis using exome sequencing

To date, approximately 50 short tandem repeat (STR) disorders have been identified; yet, clinical laboratories rarely conduct STR analysis on exomes. To assess its diagnostic value, we analyzed STRs in 6099 exomes from 2510 families with mostly suspected neurogenetic disorders. We employed ExpansionHunter and REViewer to detect pathogenic repeat expansions, confirming them using orthogonal methods. Genotype-phenotype correlations led to the diagnosis of thirteen individuals in seven previously undiagnosed families, identifying three autosomal dominant disorders: dentatorubral-pallidoluysian atrophy (n = 3), spinocerebellar ataxia type 7 (n = 2), and myotonic dystrophy type 1 (n = 2), resulting in a diagnostic gain of 0.28% (7/2510). Additionally, we found expanded ATXN1 alleles (≥39 repeats) with varying patterns of CAT interruptions in twelve individuals, accounting for approximately 0.19% in the Korean population. Our study underscores the importance of integrating STR analysis into exome sequencing pipeline, broadening the application of exome sequencing for STR assessments.

Electrophysiological aspects of myotonic dystrophy type 1 in cardiomyocytes derived from patient-specific induced pluripotent stem cells

Electrophysiological aspects of myotonic dystrophy type 1 in cardiomyocytes derived from patient-specific induced pluripotent stem cells

Late Presentation of Myotonic Dystrophy Presenting With Dyspnea and Hypoxemia

Late Presentation of Myotonic Dystrophy Presenting With Dyspnea and Hypoxemia

Case report of congenital myotonic dystrophy with multiple prenatal sonographic findings

Abstract Objectives Myotonic dystrophy 1 (DM1) is an autosomal dominant inherited neuromuscular disorder. The most severe form is congenital myotonic dystrophy (cDM). Prenatal diagnosis is complicated and sonographic findings of cDM that are not pathognomonic occur in the late second or early third trimester of pregnancy. Case presentation It is the case of prenatally diagnosed cDM. In 32 weeks of pregnancy multiple sonographic findings such as severe polyhydramnios, bilateral talipes, fetal legs akinesia, macrocephaly with mild bilateral ventriculomegaly, right-sided pleural effusion and diaphragmatic pathology were observed by fetal medicine specialist. As the patient complained of weakness in her limbs, she was consulted by a neurologist. The neurological examination revealed a pathognomonic sign of DM1 – grip myotonia. The amniotic fluid and the mother’s blood sample were further tested for DM1. This identified &gt;150 repeats in one copy of the DMPK gene of the both, which is consistent with the diagnosis DM1. Conclusions The sonographic findings of fetal limb abnormalities with progressive polyhydramnios is an indication for maternal neurological examination and genetic testing due to myotonic dystrophy.

Multi-level profiling unravels mitochondrial dysfunction in myotonic dystrophy type 2

Myotonic dystrophy type 2 (DM2) is an autosomal-dominant multisystemic disease with a core manifestation of proximal muscle weakness, muscle atrophy, myotonia, and myalgia. The disease-causing CCTG tetranucleotide expansion within the CNBP gene on chromosome 3 leads to an RNA-dominated spliceopathy, which is currently untreatable. Research exploring the pathophysiological mechanisms in myotonic dystrophy type 1 has resulted in new insights into disease mechanisms and identified mitochondrial dysfunction as a promising therapeutic target. It remains unclear whether similar mechanisms underlie DM2 and, if so, whether these might also serve as potential therapeutic targets. In this cross-sectional study, we studied DM2 skeletal muscle biopsy specimens on proteomic, molecular, and morphological, including ultrastructural levels in two separate patient cohorts consisting of 8 (explorative cohort) and 40 (confirmatory cohort) patients. Seven muscle biopsy specimens from four female and three male DM2 patients underwent proteomic analysis and respiratory chain enzymology. We performed bulk RNA sequencing, immunoblotting of respiratory chain complexes, mitochondrial DNA copy number determination, and long-range PCR (LR-PCR) to study mitochondrial DNA deletions on six biopsies. Proteomic and transcriptomic analyses revealed a downregulation of essential mitochondrial proteins and their respective RNA transcripts, namely of subunits of respiratory chain complexes I, III, and IV (e.g., mt-CO1, mt-ND1, mt-CYB, NDUFB6) and associated translation factors (TACO1). Light microscopy showed mitochondrial abnormalities (e.g., an age-inappropriate amount of COX-deficient fibers, subsarcolemmal accumulation) in most biopsy specimens. Electron microscopy revealed widespread ultrastructural mitochondrial abnormalities, including dysmorphic mitochondria with paracrystalline inclusions. Immunofluorescence studies with co-localization of autophagy (p62, LC-3) and mitochondrial marker proteins (TOM20, COX-IV), as well as immunohistochemistry for mitophagy marker BNIP3 indicated impaired mitophagic flux. Immunoblotting and LR-PCR did not reveal significant differences between patients and controls. In contrast, mtDNA copy number measurement showed a reduction of mtDNA copy numbers in the patient group compared to controls. This first multi-level study of DM2 unravels thus far undescribed functional and structural mitochondrial abnormalities. However, the molecular link between the tetranucleotide expansion and mitochondrial dysfunction needs to be further elucidated.

Hospital admissions from the emergency department of adult patients affected by myopathies.

Myopathies are associated with classic signs and symptoms, but also with possible life-threatening complications that may require assistance in an emergency setting. This phenomenon is understudied in the literature. We aimed to assess the presentation, management, and outcomes of clinical manifestations potentially related to a muscle disorder requiring referral to the adult emergency department (ED) and hospitalization. Anonymized patient data retrieved using the International Classification of Diseases, Ninth Revision codes related to muscle disorders over 4 years were retrospectively analyzed. Medical reports were evaluated to extract demographic and clinical variables, along with outcomes. Two groups were defined based on the presence (known diagnosis [KD] group) or absence (unknown diagnosis [UD] group) of a diagnosed muscle disorder at arrival. A total of 244 patients were included, 51% of whom were affected by a known myopathy, predominantly limb-girdle muscular dystrophies and myotonic dystrophies. The main reasons for ED visits in the KD group were respiratory issues, worsening of muscle weakness, and gastrointestinal problems. Heart complications were less prevalent. In the UD group, 27 patients received a new diagnosis of a specific primary muscle disorder after the ED access, mostly an inflammatory myopathy. Death during hospitalization was recorded in 26 patients, with a higher rate in the KD group and in patients affected by mitochondrial and inflammatory myopathies. Sepsis and dyspnea were associated with increased death risk. Respiratory complications are the most common reason for myopathic patients accessing the ED, followed by gastrointestinal issues. Infections are severe threats and, once hospitalized, these patients have relatively high mortality.

Outcomes of BRCA pre-implantation genetic testing according to the parental mutation origin: a cohort study

BackgroundThe process of gamete formation and early embryonic development involves rapid DNA replication, chromosome segregation and cell division. These processes may be affected by mutations in the BRCA1/2 genes. The aim of this study was to evaluate BRCA mutation inheritance and its effect on early embryonic development according to the parental origin of the mutation. The study question was approached by analyzing in vitro fertilization cycles (IVF) that included pre-implantation testing (PGT-M) for a BRCA gene mutation.MethodsThis retrospective cohort study compared cycles of pre-implantation genetic testing for mutations (PGT-M) between male and female patients diagnosed with BRCA 1/2 mutations (cases), to a control group of two other mutations with dominant inheritance (myotonic dystrophy (MD) and polycystic kidney disease (PKD)). Results were compared according to mutation type and through a generalized linear model analysis.ResultsThe cohort included 88 PGT-M cycles (47 BRCA and 41 non-BRCA) among 50 patients. Maternal and paternal ages at oocyte retrieval were comparable between groups. When tested per cycle, FSH dose, maximum estradiol level, oocytes retrieved, number of zygotes, and number of embryos available for biopsy and affected embryos, were not significantly different among mutation types. All together 444 embryos were biopsied: the rate of affected embryos was comparable between groups. Among BRCA patients, the proportion of affected embryos was similar between maternal and paternal mutation origin (p = 0.24). In a generalized linear model analysis, the relative oocyte yield in maternal BRCA patients was significantly lower (0.7, as related to the non BRCA group)(p < 0.001). Zygote formation and blastulation were not affected by the BRCA gene among paternal cases (P = 0.176 and P = 0.293 respectively), nor by paternal versus maternal BRCA carriage (P = 0.904 and P = 0.149, respectively).ConclusionsBRCA PGT-M cycles performed similarly compared to non-BRCA cycles. Inheritance rate and cycle parameters were not affected by the parental origin of the mutation.

Verapamil mitigates chloride and calcium bi-channelopathy in a myotonic dystrophy mouse model.

Myotonic dystrophy type 1 (DM1) involves misregulated alternative splicing for specific genes. We used exon or nucleotide deletion to mimic altered splicing of genes central to muscle excitation-contraction coupling in mice. Mice with forced skipping of exon 29 in the CaV1.1 calcium channel combined with loss of ClC-1 chloride channel function displayed markedly reduced lifespan, whereas other combinations of splicing mimics did not affect survival. The Ca2+/Cl- bi-channelopathy mice exhibited myotonia, weakness, and impairment of mobility and respiration. Chronic administration of the calcium channel blocker verapamil rescued survival and improved force generation, myotonia, and respiratory function. These results suggest that Ca2+/Cl- bi-channelopathy contributes to muscle impairment in DM1 and is potentially mitigated by common clinically available calcium channel blockers.

Combinatorial effects of ion channel mis-splicing as a cause of myopathy in myotonic dystrophy.

Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder caused by an unstable expanded CTG repeat located in the 3'-UTR of the DM1 protein kinase (DMPK) gene. The pathogenic mechanism results in misregulated alternative splicing of hundreds of genes, creating the dilemma of establishing which genes contribute to the mechanism of DM1 skeletal muscle pathology. In this issue of the JCI, Cisco and colleagues systematically tested the combinatorial effects of DM1-relevant mis-splicing patterns in vivo and identified the synergistic effects of mis-spliced calcium and chloride channels as a major contributor to DM1 skeletal muscle impairment. The authors further demonstrated the therapeutic potential for calcium channel modulation to block the synergistic effects and rescue myopathy.

Patient engagement in clinical trial design for rare neuromuscular disorders: impact on the DELIVER and ACHIEVE clinical trials

BackgroundEngaging individuals living with disease in drug development and regulatory processes leads to more thoughtful and sensitive trial designs, drives more informative and meaningful outcomes from clinical studies, and builds trust between the public, government, and industry stakeholders. This engagement is especially important in the case of rare diseases, where affected individuals and their families face many difficulties getting information, treatment, and support. Dyne Therapeutics is developing therapeutics for people with genetically-driven muscle diseases. During the development of potential treatments for Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1), Dyne sought the opinions of individuals living with these diseases to inform its clinical trial design and to decrease the difficulties that participants and families might experience participating in them.MethodsDyne engaged individuals and families living with DMD and DM1 as expert partners in its clinical development programs. Dyne convened panels of affected individuals and care partners/parents of individuals living with DMD (n = 8) or DM1 (n = 18). Workshops focused on how affected individuals and their families evaluate and select clinical trials for participation, the importance, quality, and burden associated with individual trial design elements, participation considerations such as site location and the study visit design, patient privacy, the suitability and scope of travel and participant support programs, and the accessibility of content in the informed consent (or assent) forms. Dyne also engaged the DMD Community Advisory Board (CAB) to collect feedback and advice on designing optimal and meaningful clinical trials and measuring relevant outcomes.ResultsThe issues most important to individuals living with DM1 and DMD regarding clinical trials were the ability to participate/access to the trial, perceptions of benefit and risk of trials and potential treatments, the flexibility of participation, clear communication from the sponsor, availability of information from trusted sources, and patient enrollment. In response to the patient advisory workshops and CAB feedback, Dyne refined clinical trial inclusion/exclusion criteria and clinic visit design, developed a travel service program to address the burden of clinical trial travel and enable long-distance and cross-border participation, planned for home visits when feasible, and allowed for adequate rest before clinic visit initiation and between assessments. Additionally, Dyne developed and implemented a transparent and consistent communications plan (including age-appropriate content) for trial participants and community members, and assessed and adjusted procedures to provide maximum participant comfort and lower anxiety, particularly with younger participants.ConclusionsOngoing communication with the Duchenne CAB and with DMD and DM1 patient advisory committee members allows Dyne to stay current with disease community perspectives and feedback on the needs and preferences of those affected and has provided valuable insights into the participant experience thereby helping Dyne initiate clinical trials that better meet the needs of affected individuals and their families.

Characterization of the neuropathic pain component contributing to myalgia in patients with myotonic dystrophy type 1 and 2.

Chronic muscle pain is common in myotonic dystrophies (DM). Little is known about its pathophysiology. We aimed to investigate the characteristics of the neuropathic pain component contributing contributes to the pathogenesis of chronic pain in DM. Twenty-one DM1 and 32 DM2 patients completed pain questionnaires (Brief pain inventory-BPI, PAIN-DETECT, pain disability index-PDI) and underwent neurological examination, nerve conduction studies (NCS), quantitative sensory testing (QST, dorsum of the right hand and right thigh) and skin biopsy to determine the intraepidermal nerve fiber density (IENFD, distal and proximal site of lower extremity). NCS and QST results at the thigh were compared to 27 healthy controls and IENFD and QST at the dorsum of the hand to published reference values. The sensory profile of DM2 patients was characterized by a loss in thermal and mechanical detection, while DM1 patients showed reduced mechanical and heat pain thresholds and higher mechanical pain sensitivity. Both DM groups showed pressure hyperalgesia. IENFD was reduced in 63% of DM1 patients and 50% of DM2. The slightly higher pain interference and disability found in DM2 was rather due to age difference than disease. Similar pain mechanisms likely occur in both DM1 and DM2, even though a tendency toward more pain sensitivity was observed in DM1 and more sensory loss in DM2. Both QST and reduced IENFD highlight the presence of peripheral nerve damage in DM. This must be considered for the best pain management strategies.

Management of Anesthesia in a Patient with Myotonic Dystrophy

Management of Anesthesia in a Patient with Myotonic Dystrophy

Epidemiology and molecular characterization of adult genetic myopathies in a southeastern region of Spain.

Genetic myopathies constitute a collection of rare diseases that significantly impact patient functionality and quality of life. Early diagnosis of genetic myopathies can prevent future complications and provide families with genetic counselling. Despite the substantial impact of genetic myopathies on the adult population, the global epidemiology of these disorders is inadequately addressed in the literature. To enhance understanding of both the epidemiology and genetics of these disorders within the province of Alicante, situated in southeastern Spain. Between 2020 and 2022, a prospective observational study was conducted at the Alicante Health Area-General Hospital, enrolling patients aged 16 years or older with suspected genetic myopathies. Sociodemographic, clinical, and genetic data were collected. The reference date for prevalence calculation was established as December 31, 2022. Official demographic data of the health area were used to set the population at risk. In total, 83 patients were identified with confirmed genetically related myopathy, resulting in an overall prevalence of 29.59 cases per 100,000 inhabitants. The diagnostic yield for molecular genetic testing was found to be 69.16%. The most prevalent genetic myopathies identified included myotonic dystrophy (27.5%), dystrophinopathies (15.7%), and facioscapulohumeral dystrophy (15.7%). The prevalence of GMs can vary considerably depending on the geographical region and the studied population. The analysis of diagnostic yield suggests that genetic studies should be considered useful in the diagnosis of genetic myopathies.

Sleep Disorders and Fatigue in Patients with Different Forms of Myotonic Dystrophy Type 1

Sleep Disorders and Fatigue in Patients with Different Forms of Myotonic Dystrophy Type 1

Myotonic Dystrophy Type 1 (DM1): Clinical Characteristics and Disease Progression in a Large Cohort.

DM1 is a multisystem disorder caused by expansion of a CTG triplet repeat in the 3' non-coding region of DMPK. Neuropsychological consequences and sleep abnormalities are important associations in DM1. To describe the clinical phenotype, disease progression and characterize the sleep alterations and cognitive abnormalities in a sub-set of patients. A retrospective study on 120 genetically confirmed DM1 cases. Findings in neuropsychological assessment and multiple sleep questionnaires were compared with 14 age and sex matched healthy individuals. All 120 patients were contacted through letters/telephonic consultation/hospital visits to record their latest physical and functional disabilities. The mean age at symptom onset was 23.1 ± 11.4 years, M: F = 3.8:1, mean duration of illness = 14.3 ± 9.5 years. Clinically 54.2% had adult onset form, juvenile = 27.5%, infantile = 10.8%, late adult onset = 7.5%. Paternal transmission occurred more frequently. The predominant initial symptoms were myotonia (37.5%), hand weakness (21.7%), lower limb weakness (23.3%) and bulbar (10%). Twenty patients completed sleep questionnaires (SQ). Abnormal scores were noted in Epworth sleepiness scale (55%); Pittsburgh sleep quality index (45%); Berlin SQ (30%); Rapid eye movement sleep Behaviour Disorder SQ (15%); Restless leg syndrome rating scale (10%). Neuropsychological assessment of 20 patients revealed frontal executive dysfunction, attention impairment and visuospatial dysfunction. Frontal lobe was most affected (72%) followed by parietal (16%) and temporal lobe (12%). The current study provides a comprehensive account of the clinical characteristics in Indian patients with DM1. Hypersomnolence was most commonly seen. Excessive daytime sleepiness and Sleep disordered breathing were the most common sleep related abnormality. Cognitive impairment comprised predominantly of frontal lobe dysfunction.

Multiple hydrogen bonding driven supramolecular architectures and their biomedical applications.

Supramolecular chemistry combines the strength of molecular assembly via various molecular interactions. Hydrogen bonding facilitated self-assembly with the advantages of directionality, specificity, reversibility, and strength is a promising approach for constructing advanced supramolecules. There are still some challenges in hydrogen bonding based supramolecular polymers, such as complexity originating from tautomerism of the molecular building modules, the assembly process, and structure versatility of building blocks. In this review, examples are selected to give insights into multiple hydrogen bonding driven emerging supramolecular architectures. We focus on chiral supramolecular assemblies, multiple hydrogen bonding modules as stimuli responsive sources, interpenetrating polymer networks, multiple hydrogen bonding assisted organic frameworks, supramolecular adhesives, energy dissipators, and quantitative analysis of nano-adhesion. The applications in biomedical materials are focused with detailed examples including drug design evolution for myotonic dystrophy, molecular assembly for advanced drug delivery, an indicator displacement strategy for DNA detection, tissue engineering, and self-assembly complexes as gene delivery vectors for gene transfection. In addition, insights into the current challenges and future perspectives of this field to propel the development of multiple hydrogen bonding facilitated supramolecular materials are proposed.

Multifaceted nucleic acid probing with a rationally upgraded molecular rotor.

Probing the sequence alterations, structures, interactions, and other important aspects of nucleic acids serves as the cornerstone of understanding nucleic acid-mediated biology and etiology, as well as the development of nucleic acid-based therapeutics. New strategies capable of accommodating these imperatives without necessitating specialized instrument or skills and potentially complementing existing methods are highly desired. Herein, we describe a rationally designed molecular rotor CCVJ-H ((9-(2-carboxy-2-cyanovinyl)julolidine-hydrazide)) and its superior performances compared to the universal base excision reporter probe CCVJ-1 in applications such as nucleic acid detection and DNA glycosylase assays. Furthermore, we showcase that the CCVJ-H probe accurately profiles the interactions between nucleic acids and small molecules, providing binding affinity and binding site information in a single reaction. We subsequently demonstrate the feasibility of applying the CCVJ-H system in high-throughput screening to identify nucleic acid-binding small molecules such as DNA CTG repeat expansion binders, potentially providing therapeutic interventions for myotonic dystrophy type 1. Finally, we profile the recognition difference between DNA/DNA and DNA/RNA against a library of small molecules, uncovering two drug-like molecules that preferentially bind DNA/RNA. We anticipate the versatile CCVJ-H probe will be a useful tool for both fundamental and translational nucleic acid research and application.

The Muscleblind-like protein MBL-1 regulates microRNA expression in Caenorhabditis elegans through an evolutionarily conserved autoregulatory mechanism.

The Muscleblind-like (MBNL) family is a highly conserved set of RNA-binding proteins (RBPs) that regulate RNA metabolism during the differentiation of various animal tissues. Functional insufficiency of MBNL affects muscle and central nervous system development, and contributes to the myotonic dystrophies (DM), a set of incurable multisystemic disorders. Studies on the regulation of MBNL genes are essential to provide insight into the gene regulatory networks controlled by MBNL proteins and to understand how dysregulation within these networks causes disease. In this study, we demonstrate the evolutionary conservation of an autoregulatory mechanism that governs the function of MBNL proteins by generating two distinct protein isoform types through alternative splicing. Our aim was to further our understanding of the regulatory principles that underlie this conserved feedback loop in a whole-organismal context, and to address the biological significance of the respective isoforms. Using an alternative splicing reporter, our studies show that, during development of the Caenorhabditis elegans central nervous system, the orthologous mbl-1 gene shifts production from long protein isoforms that localize to the nucleus to short isoforms that also localize to the cytoplasm. Using isoform-specific CRISPR/Cas9-generated strains, we showed that expression of short MBL-1 protein isoforms is required for healthy neuromuscular function and neurodevelopment, while expression of long MBL-1 protein isoforms is dispensable, emphasizing a key role for cytoplasmic functionalities of the MBL-1 protein. Furthermore, RNA-seq and lifespan analyses indicated that short MBL-1 isoforms are crucial regulators of miRNA expression and, in consequence, required for normal lifespan. In conclusion, this study provides support for the disruption of cytoplasmic RNA metabolism as a contributor in myotonic dystrophy and paves the way for further exploration of miRNA regulation through MBNL proteins during development and in disease models.