Search Results (136)

Background: GSK3β is an intracellular regulatory kinase that is dysregulated in multiple tissues in Type 1 myotonic dystrophy (DM-1). Tideglusib inhibits GSK3β activity in preclinical models of DM-1 and promotes cellular maturation, normalising aberrant molecular and behavioural phenotypes. It is currently in clinical development for the treatment of paediatric and adult patients affected by congenital and juvenile-onset DM-1. Here, we summarise the development of a population pharmacokinetic model and subsequent characterisation of influential demographic and clinical factors on the systemic exposure to tideglusib. The availability of a population PK model will allow further evaluation of age-and weight-related changes in drug disposition, supporting the dose rationale and implementation of a paediatric extrapolation plan. Methods: Given the sparse pharmacokinetic sampling scheme in patients receiving tideglusib, model development was implemented in two steps. First, data from Phase I studies in healthy elderly subjects (i.e., 1832 plasma samples, n = 54) were used to describe the population pharmacokinetics of tideglusib in adults. Then, pharmacokinetic model parameter estimates obtained from healthy subjects were used as priors for the evaluation of the disposition of tideglusib in adolescent and adult DM-1 patients (51 plasma samples, n = 16), taking into account demographic and clinical baseline characteristics, as well as food intake. Secondary pharmacokinetic parameters (AUC, C_max and T_max) were derived and summarised by descriptive statistics. Results: Tideglusib pharmacokinetics was described by a two-compartment model with first-order elimination and dose-dependent bioavailability. There were no significant differences in disposition parameters between healthy subjects and DM-1 patients. Body weight was a significant covariate on clearance and volume of distribution. Median AUC_(0–12) and C_max were 1218.1 vs. 3145.7 ng/mL∙h and 513.5 vs. 1170.9 ng/mL, following once daily doses of 400 and 1000 mg tideglusib, respectively. In addition, the time of food intake post-dose or the type of meal appeared to affect the overall exposure to tideglusib. No accumulation, metabolic inhibition, or induction was observed during the treatment period. Conclusions: Even though clearance was constant over the dose range between 400 and 1000 mg, a less than proportional increase in systemic exposure appears to be caused by the dose-dependent bioavailability, which reflects the solubility properties of tideglusib. Despite large interindividual variability in the tideglusib concentration vs. time profiles, body weight was the only explanatory covariate for the observed differences. This finding suggests that the use of weight-banded or weight-normalised doses should be considered to ensure comparable exposure across the paediatric population, regardless of age or body weight. Full article

Pilomatricomas are benign tumors originating from hair follicle matrix cells and represent the most common skin tumors in pediatric patients. Pilomatricomas may be associated with genetic syndromes such as myotonic dystrophy, familial adenomatous polyposis (FAP), Turner syndrome, Rubinstein–Taybi syndrome, Kabuki syndrome, and Sotos syndrome. This study reviews the literature on pilomatricomas occurring in syndromic contexts and presents a novel case linked to Apert syndrome. A systematic review was conducted using PubMed and Cochrane databases, focusing on case reports, case series, and reviews describing pilomatricomas associated with syndromes. A total of 1272 articles were initially screened; after removing duplicates and excluding articles without syndromic diagnoses or lacking sufficient data, 81 full-text articles were reviewed. Overall, 96 cases of pilomatricomas associated with genetic syndromes were identified. Reports of patients with Apert syndrome who do not develop pilomatricomas are absent in the literature. Pilomatricomas predominantly affect pediatric patients, with a slight female predominance, and are often the first manifestation of underlying genetic syndromes. Our study highlights previously unreported associations of pilomatricoma with Apert syndrome, providing molecular insights. This study contributes to understanding the clinical and molecular features of pilomatricomas in syndromic contexts and underscores the importance of genetic analysis for accurate diagnosis and management. Full article

Introduction: Myotonia is a rare neuromuscular condition characterized by impaired muscle relaxation. In this study, we provide normative values for clinical tests related to myotonia in the Hungarian population and compare them to patients with myotonic dystrophy type 1 (DM1). Methods: Relaxation tests (10 eye openings, tongue extension, and palm openings), handgrip strength, and the nine-hole peg test were conducted on 139 healthy individuals and 31 patients with DM1. Results: We observed non-significant declines in handgrip strength and relaxation tests with age (p < 0.05). Significant differences were found between controls (n:139) and patients with DM1 (n = 31) in all tests (p < 0.05). Sex differences were noted in the healthy population: men (n:68/139) had stronger handgrip (mean of men 42.45 ± 1.15 vs. women 24.3 ± 0.9) and slower relaxation tests (mean of eye openings in men 3.6 ± 0.2 vs. in women 4.2 ± 0.2, tongue extensions in men 3.7 ± 0.2 vs. in women 4.2 ± 0.2, palm openings in men 4 ± 0.2 vs. in women 4.9 ± 0.2 However, these differences were not present among patients with DM1. Discussion: Normal values for relaxation tests across different age groups were established. These results might be useful for further clinical investigations. Our study supports the usage of averages of healthy population instead of age groups of relaxation tests and their clinical relevance in the evaluation of patients with myotonia. Full article

Myotonic dystrophy type 1 (DM1) is a complex, multisystemic neuromuscular disorder with several pathological phenotypes, disease severities and ages of onset. DM1 presents significant challenges in clinical management due to its multisystemic nature, affecting multiple organs and systems beyond skeletal muscle. Tackling this condition requires a comprehensive approach that goes beyond symptom management, particularly considering the complexity of its manifestations and in the delayed diagnosis. In this review we will discuss the multisystem symptoms of DM1 and how this understanding is guiding the development of potential therapies for the improvement of patient outcomes and quality of life. This review aims to explore the available treatments and potential novel disease-modifying therapies targeting DM1 molecular mechanisms to address the broad multisystem symptoms of DM1. Effective strategies to manage symptoms remain crucial, such as physical therapy, medications for myotonia and diligent cardiac care. Metabolic management and hormonal therapies play crucial roles in addressing endocrine and metabolic abnormalities. Nevertheless, promising targeted therapies that include antisense oligonucleotides (ASOs) for RNA degradation, small molecules to disrupt protein-RNA interactions and gene editing offer a prospective approach to the underlying mechanisms of DM1 and improve patient outcomes across the different organ systems. Full article

Background/Objectives: MBNL1 is an RNA-binding protein involved in RNA metabolism, including splicing. It colocalizes with RNA foci, a pathological hallmark of myotonic dystrophy, and plays a central role in its disease mechanism. Moreover, MBNL1 has been implicated in other neuromuscular disorders and cancers. In these pathological and biochemical studies, the detection of MBNL1 using antibodies is essential. Given that MBNL1 has multiple splicing-derived isoforms, different antibodies may recognize distinct isoforms. This study aims to compare six commercially available antibodies regarding their specificity in Western blotting, colocalization with RNA foci, and suitability for immunoprecipitation. Methods: Western blot analysis was performed using MBNL1 isoforms and deletion mutants expressed in HEK293 cells, as well as endogenous MBNL1 from various cell lines. RNA fluorescence in situ hybridization (FISH) and immunofluorescence (IF) were conducted in DM1 model cells and patient-derived fibroblasts to assess MBNL1 colocalization with RNA foci. Immunoprecipitation experiments were performed in HEK293 cells to evaluate antibody suitability for protein isolation. Results: Western blot analysis revealed that different antibodies target distinct regions of MBNL1, with three recognizing exon 3 and the remaining antibodies recognizing exon 4, exon 5, and exon 6, respectively. In the FISH-IF experiments, the clarity of RNA foci colocalization varied depending on the antibody used, with some antibodies failing to detect colocalization. The immunoprecipitation analysis showed that four antibodies were able to isolate endogenous MBNL1. Conclusions: This study clarifies the recognition properties and application suitability of MBNL1 antibodies, providing a valuable resource for research on MBNL1-related diseases and RNA metabolism. Full article

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. Full article

Neuromuscular diseases (NMDs) encompass various hereditary conditions affecting motor neurons, the neuromuscular junction, and skeletal muscles. These disorders are characterized by progressive muscle weakness and can manifest at different stages of life, from birth to adulthood. NMDs, such as Duchenne and Becker muscular dystrophies, myotonic dystrophy, and limb–girdle muscular dystrophies, often involve cardiac complications, including cardiomyopathies and arrhythmias. Underlying genetic mutations contribute to skeletal and cardiac muscle dysfunction, particularly in the DMD, EMD, and LMNA genes. The progressive nature of muscle deterioration significantly reduces life expectancy, mainly due to respiratory and cardiac failure. The early detection of cardiac involvement through electrocardiography (ECG) and cardiac imaging is crucial for timely intervention. Pharmacological treatment focuses on managing cardiomyopathies and arrhythmias, with an emerging interest in gene therapies aimed at correcting underlying genetic defects. Heart transplantation, though historically controversial in patients with muscular dystrophies, is increasingly recognized as a viable option for individuals with advanced heart failure and moderate muscle impairment, leading to improved survival rates. Careful patient selection and management are critical to optimizing outcomes in these complex cases. Full article

Background/Objectives: Missplicing caused by toxic DMPK-mRNA is described as a hallmark of myotonic dystrophy type 1 (DM1). Yet, there is an expressional misregulation of additional splicing factors described in DM1, and missplicing has been observed in other myopathies. Here, we compare the expressional misregulation of splicing factors and the resulting splicing profiles between three different hereditary myopathies. Methods: We used publicly available RNA-sequencing datasets for the three muscular dystrophies—DM1, facioscapulohumeral muscular dystrophy (FSHD) and Emery–Dreifuss muscular dystrophy (EDMD)—to compare the splicing factor expression and missplicing genome-wide using DESeq2 and MAJIQ. Results: Upregulation of alternative splicing factors and downregulation of constitutive splicing factors were detected for all three myopathies, but to different degrees. Correspondingly, the missplicing events were mostly alternative exon usage and skipping events. In DM1, most events were alternative exon usage and intron retention, while exon skipping was prevalent in FSHD, with EDMD being in between the two other myopathies in terms of splice factor regulation as well as missplicing. Accordingly, the missplicing events were only partially shared between these three myopathies, sometimes with the same locus being spliced differently. Conclusions: This indicates a combination of primary (toxic RNA) and more downstream effects (splicing factor expression) resulting in the DM1 missplicing phenotype. Furthermore, this analysis allows the distinction between disease-specific missplicing and general myopathic splicing alteration to be used as biomarkers. Full article

The toxic gain-of-function of RNA-CUG_(exp) in DM1 has been largely studied in skeletal muscle, with little focus on its effects on the central nervous system (CNS). This study aimed to study if oxidative stress is present in DM1, its relationship with the toxic RNA gain-of-function and if natural antioxidants can revert some of the RNA-CUG_(exp) toxic effects. Using an inducible glial DM1 model (MIO-M1 cells), we compared OS in expanded vs. unexpanded cells and investigated whether antioxidants can mitigate OS and RNA-CUG_(exp) toxicity. OS was measured via superoxide anion and lipid peroxidation assays. RNA foci were identified using FISH, and the mis-splicing of selected exons was analyzed using semi-quantitative RT-PCR. Cells were treated with natural antioxidants, and the effects on OS, foci formation, and mis-splicing were compared between treated and untreated cells. The results showed significantly higher superoxide anion and lipid peroxidation levels in untreated DM1 cells, which decreased after antioxidant treatment (ANOVA, p < 0.001). Foci were present in 51% of the untreated cells but were reduced in a dose-dependent manner following treatment (ANOVA, p < 0.001). Antioxidants also improved the splicing of selected exons (ANOVA, p < 0.001), suggesting OS plays a role in DM1, and antioxidants may offer therapeutic potential. Full article

Fragile X, Huntington disease, and myotonic dystrophy type 1 are prototypical examples of human disorders caused by short tandem repeat variation, repetitive nucleotide stretches that are highly mutable both in the germline and somatic tissue. As short tandem repeats are unstable, they can expand, contract, and acquire and lose epigenetic marks in somatic tissue. This means within an individual, the genotype and epigenetic state at these loci can vary considerably from cell to cell. This somatic mosaicism may play a key role in clinical pathogenesis, and yet, our understanding of mosaicism in driving clinical phenotypes in short tandem repeat disorders is only just emerging. This review focuses on these three relatively well-studied examples where, given the advent of new technologies and bioinformatic approaches, a critical role for mosaicism is coming into focus both with respect to cellular physiology and clinical phenotypes. Full article

Background/Objectives: Short tandem repeat expansions are the most common cause of inherited neurological diseases. These disorders are clinically and genetically heterogeneous, such as in myotonic dystrophy and spinocerebellar ataxia, and they are caused by different repeat motifs in different genomic locations. Major advances in bioinformatic tools used to detect repeat expansions from short read sequencing data in the last few years have led to the implementation of these workflows into next generation sequencing pipelines in healthcare. Here, we aimed to evaluate the clinical utility of analysing repeat expansions through exome sequencing in a large cohort of genetically undiagnosed patients with neurological disorders. Methods: We here analyse 27 disease-causing DNA repeats found in the coding, intronic and untranslated regions in 12,496 exomes in patients with a range of neurogenetic conditions. Results: We identified—and validated by polymerase chain reaction—29 repeat expansions across a range of loci, 48% (n = 14) of which were diagnostic. We then analysed the genotyping performance across all repeat loci and found that, despite high coverage in most repeats in coding regions, some loci had low genotyping rates, such as those that cause spinocerebellar ataxia 2 (ATXN2, 0.1–8.4%) and Huntington disease (HTT, 0.2–58.2%), depending on the capture kit. Conversely, while most intronic repeats were not genotyped, we found a high genotyping rate in the intronic locus that causes spinocerebellar ataxia 36 (NOP56, 30.1–98.3%) and in the one that causes myotonic dystrophy type 1 (DMPK, myotonic dystrophy type 1). Conclusions: We show that the key factors that influence the genotyping rate of repeat expansion loci analysis are the sequencing read length and exome capture kit. These results provide important information about the performance of exome sequencing as a genetic test for repeat expansion disorders. Full article

Background: Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder clinically characterized by progressive muscular weakness and multisystem degeneration, which correlates with the size of CTG expansion and MBLN decrease. These changes induce a calcium and redox homeostasis imbalance in several models that recapitulate the features of premature tissue aging. In this study, we characterized the impact of a new family of FKBP12 ligands (generically named MPs or MP compounds) designed to stabilize FKBP12 binding to the ryanodine receptors and normalize calcium dysregulation under oxidative stress. Methods: Human primary fibroblasts from DM1 patients and control donors, treated with MP compounds or not, were used for functional studies of cell viability, proliferation, and metabolism. The gene expression profile in treated cells was determined using RNA sequencing. The impact of MP compounds in vivo was evaluated in a Drosophila model of the disease using locomotor activity and longevity studies. Results: The treatment with different MP compounds reversed oxidative stress and impaired cell viability and proliferation, mitochondrial activity, and metabolic defects in DM1-derived primary fibroblasts. RNA sequencing analysis confirmed the restoration of molecular pathways related to calcium and redox homeostasis and additional pathways, including the cell cycle and metabolism. This analysis also revealed the rescue of alternative splicing events in DM1 fibroblasts treated with MP compounds. Importantly, treatment with MP compounds significantly extended the lifespan and improved the locomotor activity of a Drosophila model of the DM1 disease, and restored molecular defects characteristic of the disease in vivo. Conclusions: Our results revealed that MP compounds rescue multiple premature aging phenotypes described in DM1 models and decipher the benefits of this new family of compounds in the pre-clinical setting of DM1. Full article

Drosophila melanogaster usage has provided substantial insights into the pathogenesis of several nucleotide repeat expansion diseases (NREDs), a group of genetic diseases characterized by the abnormal expansion of DNA repeats. Leveraging the genetic simplicity and manipulability of Drosophila, researchers have successfully modeled close to 15 NREDs such as Huntington’s disease (HD), several spinocerebellar ataxias (SCA), and myotonic dystrophies type 1 and 2 (DM1/DM2). These models have been instrumental in characterizing the principal associated molecular mechanisms: protein aggregation, RNA toxicity, and protein function loss, thus recapitulating key features of human disease. Used in chemical and genetic screenings, they also enable us to identify promising small molecules and genetic modifiers that mitigate the toxic effects of expanded repeats. This review summarizes the close to 150 studies performed in this area during the last seven years. The relevant highlights are the achievement of the first fly-based models for some NREDs, the incorporation of new technologies such as CRISPR for developing or evaluating transgenic flies containing repeat expanded motifs, and the evaluation of less understood toxic mechanisms in NREDs such as RAN translation. Overall, Drosophila melanogaster remains a powerful platform for research in NREDs. Full article

Neuromuscular disorders (NMDs) encompass a broad range of hereditary and acquired conditions that affect motor units, significantly impacting patients’ quality of life and reproductive health. This narrative review aims to explore in detail the reproductive challenges associated with major hereditary NMDs, including Charcot–Marie–Tooth disease (CMT), dystrophinopathies, Myotonic Dystrophy (DM), Facioscapulohumeral Muscular Dystrophy (FSHD), Spinal Muscular Atrophy (SMA), Limb–Girdle Muscular Dystrophy (LGMD), and Amyotrophic Lateral Sclerosis (ALS). Specifically, it discusses the stages of diagnosis and genetic testing, recurrence risk estimation, options for preimplantation genetic testing (PGT) and prenatal diagnosis (PND), the reciprocal influence between pregnancy and disease, potential obstetric complications, and risks to the newborn. Full article

Muscular dystrophies (MDs) are genetically heterogeneous diseases characterized by primary skeletal muscle atrophy. The collapse of muscle structure and irreversible degeneration of tissues promote the occurrence of comorbidities, including cardiomyopathy and respiratory failure. Mitochondrial dysfunction leads to inflammation, fibrosis, and adipogenic cellular infiltrates that exacerbate the symptomatology of MD patients. Gastrointestinal disorders and metabolic anomalies are common in MD patients and may be determined by the interaction between the intestine and its microbiota. Therefore, the gut–muscle axis is one of the actors involved in the spread of inflammatory signals to all muscles. In this review, we aim to examine in depth how intestinal dysbiosis can modulate the metabolic state, the immune response, and mitochondrial biogenesis in the course and progression of the most investigated MDs such as Duchenne Muscular Dystrophy (DMD) and Myotonic Dystrophy (MD1), to better identify gut microbiota metabolites working as therapeutic adjuvants to improve symptoms of MD. Full article