Articoli di riviste: "Myotonic Dystrophy type 1 (DM1)"

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García-Puga, Mikel, Ander Saenz-Antoñanzas, Ander Matheu e Adolfo López de Munain. "Targeting Myotonic Dystrophy Type 1 with Metformin". International Journal of Molecular Sciences 23, n. 5 (7 marzo 2022): 2901. http://dx.doi.org/10.3390/ijms23052901.

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Myotonic dystrophy type 1 (DM1) is a multisystemic disorder of genetic origin. Progressive muscular weakness, atrophy and myotonia are its most prominent neuromuscular features, while additional clinical manifestations in multiple organs are also common. Overall, DM1 features resemble accelerated aging. There is currently no cure or specific treatment for myotonic dystrophy patients. However, in recent years a great effort has been made to identify potential new therapeutic strategies for DM1 patients. Metformin is a biguanide antidiabetic drug, with potential to delay aging at cellular and organismal levels. In DM1, different studies revealed that metformin rescues multiple phenotypes of the disease. This review provides an overview of recent findings describing metformin as a novel therapy to combat DM1 and their link with aging.

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Soltanzadeh, Payam. "Myotonic Dystrophies: A Genetic Overview". Genes 13, n. 2 (17 febbraio 2022): 367. http://dx.doi.org/10.3390/genes13020367.

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Myotonic dystrophies (DM) are the most common muscular dystrophies in adults, which can affect other non-skeletal muscle organs such as the heart, brain and gastrointestinal system. There are two genetically distinct types of myotonic dystrophy: myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2), both dominantly inherited with significant overlap in clinical manifestations. DM1 results from CTG repeat expansions in the 3′-untranslated region (3′UTR) of the DMPK (dystrophia myotonica protein kinase) gene on chromosome 19, while DM2 is caused by CCTG repeat expansions in intron 1 of the CNBP (cellular nucleic acid-binding protein) gene on chromosome 3. Recent advances in genetics and molecular biology, especially in the field of RNA biology, have allowed better understanding of the potential pathomechanisms involved in DM. In this review article, core clinical features and genetics of DM are presented followed by a discussion on the current postulated pathomechanisms and therapeutic approaches used in DM, including the ones currently in human clinical trial phase.

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Romigi, A., M. Albanese, C. Liguori, F. Placidi, M. G. Marciani e R. Massa. "Sleep-Wake Cycle and Daytime Sleepiness in the Myotonic Dystrophies". Journal of Neurodegenerative Diseases 2013 (4 novembre 2013): 1–13. http://dx.doi.org/10.1155/2013/692026.

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Myotonic dystrophy is the most common type of muscular dystrophy in adults and is characterized by progressive myopathy, myotonia, and multiorgan involvement. Two genetically distinct entities have been identified, myotonic dystrophy type 1 (DM1 or Steinert’s Disease) and myotonic dystrophy type 2 (DM2). Myotonic dystrophies are strongly associated with sleep dysfunction. Sleep disturbances in DM1 are common and include sleep-disordered breathing (SDB), periodic limb movements (PLMS), central hypersomnia, and REM sleep dysregulation (high REM density and narcoleptic-like phenotype). Interestingly, drowsiness in DM1 seems to be due to a central dysfunction of sleep-wake regulation more than SDB. To date, little is known regarding the occurrence of sleep disorders in DM2. SDB (obstructive and central apnoea), REM sleep without atonia, and restless legs syndrome have been described. Further polysomnographic, controlled studies are strongly needed, particularly in DM2, in order to clarify the role of sleep disorders in the myotonic dystrophies.

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Kitsis, Elizabeth A., Fabreena Napier, Viral Juthani e Howard L. Geyer. "Association of Sjögren’s syndrome with myotonic dystrophy type 1". BMJ Case Reports 12, n. 8 (agosto 2019): e229611. http://dx.doi.org/10.1136/bcr-2019-229611.

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A 47-year-old woman presented with sicca symptoms, polyarthralgias, polymyalgias and dysphagia. She was found to have positive antinuclear, anti-SSA-Ro and anti-SSB-La antibodies. Slit lamp exam confirmed the presence of keratoconjunctivitis sicca, and the patient was diagnosed with Sjögren’s syndrome. Three years later, she was referred for evaluation of gait instability associated with recent falls. On physical examination, the patient was found to have bilateral ptosis, percussion myotonia, distal upper and lower extremity weakness, and a steppage gait. Electromyography demonstrated electrical myotonia. Genetic testing revealed expanded CTG repeats (733 and 533) in the myotonic dystrophy type 1 (DM1) protein kinase gene, confirming the diagnosis of DM1. Dysphagia, pain and eye discomfort may occur in both Sjögren’s syndrome and DM1, and in this case, may have delayed the diagnosis of muscular dystrophy.

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Souidi, Anissa, Monika Zmojdzian e Krzysztof Jagla. "Dissecting Pathogenetic Mechanisms and Therapeutic Strategies in Drosophila Models of Myotonic Dystrophy Type 1". International Journal of Molecular Sciences 19, n. 12 (18 dicembre 2018): 4104. http://dx.doi.org/10.3390/ijms19124104.

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Myotonic dystrophy type 1 (DM1), the most common cause of adult-onset muscular dystrophy, is autosomal dominant, multisystemic disease with characteristic symptoms including myotonia, heart defects, cataracts and testicular atrophy. DM1 disease is being successfully modelled in Drosophila allowing to identify and validate new pathogenic mechanisms and potential therapeutic strategies. Here we provide an overview of insights gained from fruit fly DM1 models, either: (i) fundamental with particular focus on newly identified gene deregulations and their link with DM1 symptoms; or (ii) applied via genetic modifiers and drug screens to identify promising therapeutic targets.

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Day, J. W., K. Ricker, J. F. Jacobsen, L. J. Rasmussen, K. A. Dick, W. Kress, C. Schneider et al. "Myotonic dystrophy type 2". Neurology 60, n. 4 (25 febbraio 2003): 657–64. http://dx.doi.org/10.1212/01.wnl.0000054481.84978.f9.

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Background: Myotonic dystrophy types 1 (DM1) and 2 (DM2/proximal myotonic myopathy PROMM) are dominantly inherited disorders with unusual multisystemic clinical features. The authors have characterized the clinical and molecular features of DM2/PROMM, which is caused by a CCTG repeat expansion in intron 1 of the zinc finger protein 9 (ZNF9) gene.Methods: Three-hundred and seventy-nine individuals from 133 DM2/PROMM families were evaluated genetically, and in 234 individuals clinical and molecular features were compared.Results: Among affected individuals 90% had electrical myotonia, 82% weakness, 61% cataracts, 23% diabetes, and 19% cardiac involvement. Because of the repeat tract’s unprecedented size (mean ∼5,000 CCTGs) and somatic instability, expansions were detectable by Southern analysis in only 80% of known carriers. The authors developed a repeat assay that increased the molecular detection rate to 99%. Only 30% of the positive samples had single sizeable expansions by Southern analysis, and 70% showed multiple bands or smears. Among the 101 individuals with single expansions, repeat size did not correlate with age at disease onset. Affected offspring had markedly shorter expansions than their affected parents, with a mean size difference of −17 kb (−4,250 CCTGs).Conclusions: DM2 is present in a large number of families of northern European ancestry. Clinically, DM2 resembles adult-onset DM1, with myotonia, muscular dystrophy, cataracts, diabetes, testicular failure, hypogammaglobulinemia, and cardiac conduction defects. An important distinction is the lack of a congenital form of DM2. The clinical and molecular parallels between DM1 and DM2 indicate that the multisystemic features common to both diseases are caused by CUG or CCUG expansions expressed at the RNA level.

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Neault, Nafisa, Aymeric Ravel-Chapuis, Stephen D. Baird, John A. Lunde, Mathieu Poirier, Emiliyan Staykov, Julio Plaza-Diaz et al. "Vorinostat Improves Myotonic Dystrophy Type 1 Splicing Abnormalities in DM1 Muscle Cell Lines and Skeletal Muscle from a DM1 Mouse Model". International Journal of Molecular Sciences 24, n. 4 (14 febbraio 2023): 3794. http://dx.doi.org/10.3390/ijms24043794.

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Myotonic dystrophy type 1 (DM1), the most common form of adult muscular dystrophy, is caused by an abnormal expansion of CTG repeats in the 3′ untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. The expanded repeats of the DMPK mRNA form hairpin structures in vitro, which cause misregulation and/or sequestration of proteins including the splicing regulator muscleblind-like 1 (MBNL1). In turn, misregulation and sequestration of such proteins result in the aberrant alternative splicing of diverse mRNAs and underlie, at least in part, DM1 pathogenesis. It has been previously shown that disaggregating RNA foci repletes free MBNL1, rescues DM1 spliceopathy, and alleviates associated symptoms such as myotonia. Using an FDA-approved drug library, we have screened for a reduction of CUG foci in patient muscle cells and identified the HDAC inhibitor, vorinostat, as an inhibitor of foci formation; SERCA1 (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase) spliceopathy was also improved by vorinostat treatment. Vorinostat treatment in a mouse model of DM1 (human skeletal actin–long repeat; HSALR) improved several spliceopathies, reduced muscle central nucleation, and restored chloride channel levels at the sarcolemma. Our in vitro and in vivo evidence showing amelioration of several DM1 disease markers marks vorinostat as a promising novel DM1 therapy.

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Mahadevan, Mani S., Ramesh S. Yadava e Mahua Mandal. "Cardiac Pathology in Myotonic Dystrophy Type 1". International Journal of Molecular Sciences 22, n. 21 (2 novembre 2021): 11874. http://dx.doi.org/10.3390/ijms222111874.

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Myotonic dystrophy type 1 (DM1), the most common muscular dystrophy affecting adults and children, is a multi-systemic disorder affecting skeletal, cardiac, and smooth muscles as well as neurologic, endocrine and other systems. This review is on the cardiac pathology associated with DM1. The heart is one of the primary organs affected in DM1. Cardiac conduction defects are seen in up to 75% of adult DM1 cases and sudden death due to cardiac arrhythmias is one of the most common causes of death in DM1. Unfortunately, the pathogenesis of cardiac manifestations in DM1 is ill defined. In this review, we provide an overview of the history of cardiac studies in DM1, clinical manifestations, and pathology of the heart in DM1. This is followed by a discussion of emerging data about the utility of cardiac magnetic resonance imaging (CMR) as a biomarker for cardiac disease in DM1, and ends with a discussion on models of cardiac RNA toxicity in DM1 and recent clinical guidelines for cardiologic management of individuals with DM1.

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Ballester-Lopez, Alfonsina, Judit Núñez-Manchón, Emma Koehorst, Ian Linares-Pardo, Miriam Almendrote, Giuseppe Lucente, Nicolau Guanyabens et al. "Three-dimensional imaging in myotonic dystrophy type 1". Neurology Genetics 6, n. 4 (21 luglio 2020): e484. http://dx.doi.org/10.1212/nxg.0000000000000484.

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ObjectiveWe aimed to determine whether 3D imaging reconstruction allows identifying molecular:clinical associations in myotonic dystrophy type 1 (DM1).MethodsWe obtained myoblasts from 6 patients with DM1 and 6 controls. We measured cytosine-thymine-guanine (CTG) expansion and detected RNA foci and muscleblind like 1 (MBNL1) through 3D reconstruction. We studied dystrophia myotonica protein kinase (DMPK) expression and splicing alterations of MBNL1, insulin receptor, and sarcoplasmic reticulum Ca(2+)-ATPase 1.ResultsThree-dimensional analysis showed that RNA foci (nuclear and/or cytoplasmic) were present in 45%–100% of DM1-derived myoblasts we studied (range: 0–6 foci per cell). RNA foci represented <0.6% of the total myoblast nuclear volume. CTG expansion size was associated with the number of RNA foci per myoblast (r = 0.876 [95% confidence interval 0.222–0.986]) as well as with the number of cytoplasmic RNA foci (r = 0.943 [0.559–0.994]). Although MBNL1 colocalized with RNA foci in all DM1 myoblast cell lines, colocalization only accounted for 1% of total MBNL1 expression, with the absence of DM1 alternative splicing patterns. The number of RNA foci was associated with DMPK expression (r = 0.967 [0.079–0.999]). On the other hand, the number of cytoplasmic RNA foci was correlated with the age at disease onset (r = −0.818 [−0.979 to 0.019]).ConclusionsCTG expansion size modulates RNA foci number in myoblasts derived from patients with DM1. MBNL1 sequestration plays only a minor role in the pathobiology of the disease in these cells. Higher number of cytoplasmic RNA foci is related to an early onset of the disease, a finding that should be corroborated in future studies.

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Bérenger-Currias, Noémie, Cécile Martinat e Sandrine Baghdoyan. "Pluripotent Stem Cells in Disease Modeling and Drug Discovery for Myotonic Dystrophy Type 1". Cells 12, n. 4 (10 febbraio 2023): 571. http://dx.doi.org/10.3390/cells12040571.

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Myotonic dystrophy type 1 (DM1) is a progressive multisystemic disease caused by the expansion of a CTG repeat tract within the 3′ untranslated region (3′ UTR) of the dystrophia myotonica protein kinase gene (DMPK). Although DM1 is considered to be the most frequent myopathy of genetic origin in adults, DM1 patients exhibit a vast diversity of symptoms, affecting many different organs. Up until now, different in vitro models from patients’ derived cells have largely contributed to the current understanding of DM1. Most of those studies have focused on muscle physiopathology. However, regarding the multisystemic aspect of DM1, there is still a crucial need for relevant cellular models to cover the whole complexity of the disease and open up options for new therapeutic approaches. This review discusses how human pluripotent stem cell–based models significantly contributed to DM1 mechanism decoding, and how they provided new therapeutic strategies that led to actual phase III clinical trials.

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Nieuwenhuis, Sylvia, Joanna Widomska, Paul Blom, Peter-Bram A. C. ‘t Hoen, Baziel G. M. van Engelen e Jeffrey C. Glennon. "Blood Transcriptome Profiling Links Immunity to Disease Severity in Myotonic Dystrophy Type 1 (DM1)". International Journal of Molecular Sciences 23, n. 6 (12 marzo 2022): 3081. http://dx.doi.org/10.3390/ijms23063081.

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The blood transcriptome was examined in relation to disease severity in type I myotonic dystrophy (DM1) patients who participated in the Observational Prolonged Trial In DM1 to Improve QoL- Standards (OPTIMISTIC) study. This sought to (a) ascertain if transcriptome changes were associated with increasing disease severity, as measured by the muscle impairment rating scale (MIRS), and (b) establish if these changes in mRNA expression and associated biological pathways were also observed in the Dystrophia Myotonica Biomarker Discovery Initiative (DMBDI) microarray dataset in blood (with equivalent MIRS/DMPK repeat length). The changes in gene expression were compared using a number of complementary pathways, gene ontology and upstream regulator analyses, which suggested that symptom severity in DM1 was linked to transcriptomic alterations in innate and adaptive immunity associated with muscle-wasting. Future studies should explore the role of immunity in DM1 in more detail to assess its relevance to DM1.

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Lee, Johanna E., e Thomas A. Cooper. "Pathogenic mechanisms of myotonic dystrophy". Biochemical Society Transactions 37, n. 6 (19 novembre 2009): 1281–86. http://dx.doi.org/10.1042/bst0371281.

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DM (myotonic dystrophy) is a dominantly inherited genetic disorder that is the most common cause of muscular dystrophy in adults affecting 1 in 8500 individuals worldwide. Different microsatellite expansions in two loci cause different forms of the disease that share similar features: DM1 (DM type 1) is caused by a tri- (CTG) nucleotide expansion within the DMPK (dystrophia myotonica protein kinase) 3′-untranslated region and DM2 (DM type 2) is caused by a tetra- (CCTG) nucleotide expansion within intron 1 of the ZNF9 (zinc finger 9) gene. The pathogenic mechanism of this disease involves the RNA transcribed from the expanded allele containing long tracts of (CUG)n or (CCUG)n. The RNA results in a toxic effect through two RNA-binding proteins: MBNL1 (muscleblind-like 1) and CUGBP1 (CUG-binding protein 1). In DM1, MBNL1 is sequestered on CUG repeat-containing RNA resulting in its loss-of-function, while CUGBP1 is up-regulated through a signalling pathway. The downstream effects include disrupted regulation of alternative splicing, mRNA translation and mRNA stability, which contribute to the multiple features of DM1. This review will focus on the RNA gain-of-function disease mechanism, the important roles of MBNL1 and CUGBP1 in DM1, and the relevance to other RNA dominant disorders.

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Alegre-Cortés, Eva, Alberto Giménez-Bejarano, Elisabet Uribe-Carretero, Marta Paredes-Barquero, André R. A. Marques, Mafalda Lopes-da-Silva, Otília V. Vieira et al. "Delay of EGF-Stimulated EGFR Degradation in Myotonic Dystrophy Type 1 (DM1)". Cells 11, n. 19 (27 settembre 2022): 3018. http://dx.doi.org/10.3390/cells11193018.

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Myotonic dystrophy type 1 (DM1) is an autosomal dominant disease caused by a CTG repeat expansion in the 3′ untranslated region of the dystrophia myotonica protein kinase gene. AKT dephosphorylation and autophagy are associated with DM1. Autophagy has been widely studied in DM1, although the endocytic pathway has not. AKT has a critical role in endocytosis, and its phosphorylation is mediated by the activation of tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR). EGF-activated EGFR triggers the internalization and degradation of ligand–receptor complexes that serve as a PI3K/AKT signaling platform. Here, we used primary fibroblasts from healthy subjects and DM1 patients. DM1-derived fibroblasts showed increased autophagy flux, with enlarged endosomes and lysosomes. Thereafter, cells were stimulated with a high concentration of EGF to promote EGFR internalization and degradation. Interestingly, EGF binding to EGFR was reduced in DM1 cells and EGFR internalization was also slowed during the early steps of endocytosis. However, EGF-activated EGFR enhanced AKT and ERK1/2 phosphorylation levels in the DM1-derived fibroblasts. Therefore, there was a delay in EGF-stimulated EGFR endocytosis in DM1 cells; this alteration might be due to the decrease in the binding of EGF to EGFR, and not to a decrease in AKT phosphorylation.

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Viegas, Diana, Cátia D. Pereira, Filipa Martins, Tiago Mateus, Odete A. B. da Cruz e Silva, Maria Teresa Herdeiro e Sandra Rebelo. "Nuclear Envelope Alterations in Myotonic Dystrophy Type 1 Patient-Derived Fibroblasts". International Journal of Molecular Sciences 23, n. 1 (4 gennaio 2022): 522. http://dx.doi.org/10.3390/ijms23010522.

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Myotonic dystrophy type 1 (DM1) is a hereditary and multisystemic disease characterized by myotonia, progressive distal muscle weakness and atrophy. The molecular mechanisms underlying this disease are still poorly characterized, although there are some hypotheses that envisage to explain the multisystemic features observed in DM1. An emergent hypothesis is that nuclear envelope (NE) dysfunction may contribute to muscular dystrophies, particularly to DM1. Therefore, the main objective of the present study was to evaluate the nuclear profile of DM1 patient-derived and control fibroblasts and to determine the protein levels and subcellular distribution of relevant NE proteins in these cell lines. Our results demonstrated that DM1 patient-derived fibroblasts exhibited altered intracellular protein levels of lamin A/C, LAP1, SUN1, nesprin-1 and nesprin-2 when compared with the control fibroblasts. In addition, the results showed an altered location of these NE proteins accompanied by the presence of nuclear deformations (blebs, lobes and/or invaginations) and an increased number of nuclear inclusions. Regarding the nuclear profile, DM1 patient-derived fibroblasts had a larger nuclear area and a higher number of deformed nuclei and micronuclei than control-derived fibroblasts. These results reinforce the evidence that NE dysfunction is a highly relevant pathological characteristic observed in DM1.

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Koehorst, Emma, Alfonsina Ballester-Lopez, Virginia Arechavala-Gomeza, Alicia Martínez-Piñeiro e Gisela Nogales-Gadea. "The Biomarker Potential of miRNAs in Myotonic Dystrophy Type I". Journal of Clinical Medicine 9, n. 12 (4 dicembre 2020): 3939. http://dx.doi.org/10.3390/jcm9123939.

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MicroRNAs (miRNAs) are mostly known for their gene regulation properties, but they also play an important role in intercellular signaling. This means that they can be found in bodily fluids, giving them excellent biomarker potential. Myotonic Dystrophy type I (DM1) is the most frequent autosomal dominant muscle dystrophy in adults, with an estimated prevalence of 1:8000. DM1 symptoms include muscle weakness, myotonia, respiratory failure, cardiac conduction defects, cataracts, and endocrine disturbances. Patients display heterogeneity in both age of onset and disease manifestation. No treatment or cure currently exists for DM1, which shows the necessity for a biomarker that can predict disease progression, providing the opportunity to implement preventative measures before symptoms arise. In the past two decades, extensive research has been conducted in the miRNA expression profiles of DM1 patients and their biomarker potential. Here we review the current state of the field with a tissue-specific focus, given the multi-systemic nature of DM1 and the intracellular signaling role of miRNAs.

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Mateus, Tiago, Filipa Martins, Alexandra Nunes, Maria Teresa Herdeiro e Sandra Rebelo. "Metabolic Alterations in Myotonic Dystrophy Type 1 and Their Correlation with Lipin". International Journal of Environmental Research and Public Health 18, n. 4 (12 febbraio 2021): 1794. http://dx.doi.org/10.3390/ijerph18041794.

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Myotonic dystrophy type 1 (DM1) is an autosomal dominant hereditary and multisystemic disease, characterized by progressive distal muscle weakness and myotonia. Despite huge efforts, the pathophysiological mechanisms underlying DM1 remain elusive. In this review, the metabolic alterations observed in patients with DM1 and their connection with lipin proteins are discussed. We start by briefly describing the epidemiology, the physiopathological and systemic features of DM1. The molecular mechanisms proposed for DM1 are explored and summarized. An overview of metabolic syndrome, dyslipidemia, and the summary of metabolic alterations observed in patients with DM1 are presented. Patients with DM1 present clinical evidence of metabolic alterations, namely increased levels of triacylglycerol and low-density lipoprotein, increased insulin and glucose levels, increased abdominal obesity, and low levels of high-density lipoprotein. These metabolic alterations may be associated with lipins, which are phosphatidate phosphatase enzymes that regulates the triacylglycerol levels, phospholipids, lipid signaling pathways, and are transcriptional co-activators. Furthermore, lipins are also important for autophagy, inflammasome activation and lipoproteins synthesis. We demonstrate the association of lipin with the metabolic alterations in patients with DM1, which supports further clinical studies and a proper exploration of lipin proteins as therapeutic targets for metabolic syndrome, which is important for controlling many diseases including DM1.

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Okkersen, Kees, Darren G. Monckton, Nhu Le, Anil M. Tuladhar, Joost Raaphorst e Baziel G. M. van Engelen. "Brain imaging in myotonic dystrophy type 1". Neurology 89, n. 9 (2 agosto 2017): 960–69. http://dx.doi.org/10.1212/wnl.0000000000004300.

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Objective:To systematically review brain imaging studies in myotonic dystrophy type 1 (DM1).Methods:We searched Embase (index period 1974–2016) and MEDLINE (index period 1946–2016) for studies in patients with DM1 using MRI, magnetic resonance spectroscopy (MRS), functional MRI (fMRI), CT, ultrasound, PET, or SPECT. From 81 studies, we extracted clinical characteristics, primary outcomes, clinical-genetic correlations, and information on potential risk of bias. Results were summarized and pooled prevalence of imaging abnormalities was calculated, where possible.Results:In DM1, various imaging changes are widely dispersed throughout the brain, with apparently little anatomical specificity. We found general atrophy and widespread gray matter volume reductions in all 4 cortical lobes, the basal ganglia, and cerebellum. The pooled prevalence of white matter hyperintensities is 70% (95% CI 64–77), compared with 6% (95% CI 3–12) in unaffected controls. DTI shows increased mean diffusivity in all 4 lobes and reduced fractional anisotropy in virtually all major association, projection, and commissural white matter tracts. Functional studies demonstrate reduced glucose uptake and cerebral perfusion in frontal, parietal, and temporal lobes, and abnormal fMRI connectivity patterns that correlate with personality traits. There is significant between-study heterogeneity in terms of imaging methods, which together with the established clinical variability of DM1 may explain divergent results. Longitudinal studies are remarkably scarce.Conclusions:DM1 brains show widespread white and gray matter involvement throughout the brain, which is supported by abnormal resting-state network, PET/SPECT, and MRS parameters. Longitudinal studies evaluating spatiotemporal imaging changes are essential.

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Costa, Adriana, Ana C. Cruz, Filipa Martins e Sandra Rebelo. "Protein Phosphorylation Alterations in Myotonic Dystrophy Type 1: A Systematic Review". International Journal of Molecular Sciences 24, n. 4 (4 febbraio 2023): 3091. http://dx.doi.org/10.3390/ijms24043091.

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Among the most common muscular dystrophies in adults is Myotonic Dystrophy type 1 (DM1), an autosomal dominant disorder characterized by myotonia, muscle wasting and weakness, and multisystemic dysfunctions. This disorder is caused by an abnormal expansion of the CTG triplet at the DMPK gene that, when transcribed to expanded mRNA, can lead to RNA toxic gain of function, alternative splicing impairments, and dysfunction of different signaling pathways, many regulated by protein phosphorylation. In order to deeply characterize the protein phosphorylation alterations in DM1, a systematic review was conducted through PubMed and Web of Science databases. From a total of 962 articles screened, 41 were included for qualitative analysis, where we retrieved information about total and phosphorylated levels of protein kinases, protein phosphatases, and phosphoproteins in DM1 human samples and animal and cell models. Twenty-nine kinases, 3 phosphatases, and 17 phosphoproteins were reported altered in DM1. Signaling pathways that regulate cell functions such as glucose metabolism, cell cycle, myogenesis, and apoptosis were impaired, as seen by significant alterations to pathways such as AKT/mTOR, MEK/ERK, PKC/CUGBP1, AMPK, and others in DM1 samples. This explains the complexity of DM1 and its different manifestations and symptoms, such as increased insulin resistance and cancer risk. Further studies can be done to complement and explore in detail specific pathways and how their regulation is altered in DM1, to find what key phosphorylation alterations are responsible for these manifestations, and ultimately to find therapeutic targets for future treatments.

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Ketley, Ami, Marzena Wojciechowska, Sonja Ghidelli-Disse, Paul Bamborough, Tushar K. Ghosh, Marta Lopez Morato, Saam Sedehizadeh et al. "CDK12 inhibition reduces abnormalities in cells from patients with myotonic dystrophy and in a mouse model". Science Translational Medicine 12, n. 541 (29 aprile 2020): eaaz2415. http://dx.doi.org/10.1126/scitranslmed.aaz2415.

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Myotonic dystrophy type 1 (DM1) is an RNA-based disease with no current treatment. It is caused by a transcribed CTG repeat expansion within the 3′ untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. Mutant repeat expansion transcripts remain in the nuclei of patients’ cells, forming distinct microscopically detectable foci that contribute substantially to the pathophysiology of the condition. Here, we report small-molecule inhibitors that remove nuclear foci and have beneficial effects in the HSALR mouse model, reducing transgene expression, leading to improvements in myotonia, splicing, and centralized nuclei. Using chemoproteomics in combination with cell-based assays, we identify cyclin-dependent kinase 12 (CDK12) as a druggable target for this condition. CDK12 is a protein elevated in DM1 cell lines and patient muscle biopsies, and our results showed that its inhibition led to reduced expression of repeat expansion RNA. Some of the inhibitors identified in this study are currently the subject of clinical trials for other indications and provide valuable starting points for a drug development program in DM1.

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Yadava, Ramesh S., Qing Yu, Mahua Mandal, Frank Rigo, C. Frank Bennett e Mani S. Mahadevan. "Systemic therapy in an RNA toxicity mouse model with an antisense oligonucleotide therapy targeting a non-CUG sequence within the DMPK 3′UTR RNA". Human Molecular Genetics 29, n. 9 (2 aprile 2020): 1440–53. http://dx.doi.org/10.1093/hmg/ddaa060.

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Abstract Myotonic dystrophy type 1 (DM1), the most common adult muscular dystrophy, is an autosomal dominant disorder caused by an expansion of a (CTG)n tract within the 3′ untranslated region (3′UTR) of the dystrophia myotonica protein kinase (DMPK) gene. Mutant DMPK mRNAs are toxic, present in nuclear RNA foci and correlated with a plethora of RNA splicing defects. Cardinal features of DM1 are myotonia and cardiac conduction abnormalities. Using transgenic mice, we have demonstrated that expression of the mutant DMPK 3′UTR is sufficient to elicit these features of DM1. Here, using these mice, we present a study of systemic treatment with an antisense oligonucleotide (ASO) (ISIS 486178) targeted to a non-CUG sequence within the 3′UTR of DMPK. RNA foci and DMPK 3′UTR mRNA levels were reduced in both the heart and skeletal muscles. This correlated with improvements in several splicing defects in skeletal and cardiac muscles. The treatment reduced myotonia and this correlated with increased Clcn1 expression. Furthermore, functional testing showed improvements in treadmill running. Of note, we demonstrate that the ASO treatment reversed the cardiac conduction abnormalities, and this correlated with restoration of Gja5 (connexin 40) expression in the heart. This is the first time that an ASO targeting a non-CUG sequence within the DMPK 3′UTR has demonstrated benefit on the key DM1 phenotypes of myotonia and cardiac conduction defects. Our data also shows for the first time that ASOs may be a viable option for treating cardiac pathology in DM1.

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Dhand, Upinder K., Faisal Raja e Kul Aggarwal. "Structural myocardial involvement in adult patients with type 1 myotonic dystrophy". Neurology International 5, n. 1 (21 marzo 2013): 5. http://dx.doi.org/10.4081/ni.2013.e5.

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Myotonic dystrophy type 1 (DM1) is the commonest muscular dystrophy in adults, affecting multiple organs in addition to skeletal muscles. Cardiac conduction system abnormalities are well recognized as an important component of DM1 phenotype; however, primary structural myocardial abnormalities, which may predispose these patients to congestive heart failure, are not as well characterized. We reviewed the retrospective analysis of the clinical and echocardiographic findings in adult patients with DM1. Among 27 patients (16 male; age 19-61 years) with DM1, the echocardiogram (ECHO) was abnormal in 10 (37%) including one of 6 patients (16%) with congenital myotonic dystrophy. Reduced left ventricular ejection fraction (LVEF ≤50%) was noted in 5, diastolic dysfunction in 4, left atrial dilatation in 3, left ventricular hypertrophy in 2, apical hypokinesia in 1 and mitral valve prolapse in 3 patients. One patient had paradoxical septal movement in the setting of left bundle branch block. Echocardiographic abnormalities significantly correlated with older age; however, patients with systolic dysfunction on echocardiogram ranged in age from 27 to 52 years including 2 patients aged 27 and 34 years. We can conclude that echocardiographic abnormalities are frequent in adult patients with DM1. The incidence is similar in the classical and congenital type of DM1. Overall, echocardiographic abnormalities in DM1 correlate with increasing age; however, reduced LVEF is observed even at young age. Cardiac assessment and monitoring in adult patients with DM1 should include evaluation for primary myocardial involvement.

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Karamlou, Milad, Iman Asaria, Jaime Barron, Petra Boutros, Vincent Fisher, Rachel Grandinetti, Julian Johnson et al. "Complications After Dental Sedation: A Myotonic Mystery Case Report". Anesthesia Progress 69, n. 4 (1 dicembre 2022): 26–31. http://dx.doi.org/10.2344/anpr-69-02-09.

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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.

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Voellenkle, Perfetti, Carrara, Fuschi, Renna, Longo, Sain et al. "Dysregulation of Circular RNAs in Myotonic Dystrophy Type 1". International Journal of Molecular Sciences 20, n. 8 (19 aprile 2019): 1938. http://dx.doi.org/10.3390/ijms20081938.

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Circular RNAs (circRNAs) constitute a recently re-discovered class of non-coding RNAs functioning as sponges for miRNAs and proteins, affecting RNA splicing and regulating transcription. CircRNAs are generated by “back-splicing”, which is the linking covalently of 3′- and 5′-ends of exons. Thus, circRNA levels might be deregulated in conditions associated with altered RNA-splicing. Significantly, growing evidence indicates their role in human diseases. Specifically, myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by expanded CTG repeats in the DMPK gene which results in abnormal mRNA-splicing. In this investigation, circRNAs expressed in DM1 skeletal muscles were identified by analyzing RNA-sequencing data-sets followed by qPCR validation. In muscle biopsies, out of nine tested, four transcripts showed an increased circular fraction: CDYL, HIPK3, RTN4_03, and ZNF609. Their circular fraction values correlated with skeletal muscle strength and with splicing biomarkers of disease severity, and displayed higher values in more severely affected patients. Moreover, Receiver-Operating-Characteristics curves of these four circRNAs discriminated DM1 patients from controls. The identified circRNAs were also detectable in peripheral-blood-mononuclear-cells (PBMCs) and the plasma of DM1 patients, but they were not regulated significantly. Finally, increased circular fractions of RTN4_03 and ZNF609 were also observed in differentiated myogenic cell lines derived from DM1 patients. In conclusion, this pilot study identified circRNA dysregulation in DM1 patients.

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Scarano, Stefano, Antonio Caronni, Elena Carraro, Carola Rita Ferrari Aggradi, Viviana Rota, Chiara Malloggi, Luigi Tesio e Valeria Ada Sansone. "In Myotonic Dystrophy Type 1 Head Repositioning Errors Suggest Impaired Cervical Proprioception". Journal of Clinical Medicine 13, n. 16 (9 agosto 2024): 4685. http://dx.doi.org/10.3390/jcm13164685.

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Background: Myotonic dystrophy type 1 (DM1) is a rare multisystemic genetic disorder with motor hallmarks of myotonia, muscle weakness and wasting. DM1 patients have an increased risk of falling of multifactorial origin, and proprioceptive and vestibular deficits can contribute to this risk. Abnormalities of muscle spindles in DM1 have been known for years. This observational cross-sectional study was based on the hypothesis of impaired cervical proprioception caused by alterations in the neck spindles. Methods: Head position sense was measured in 16 DM1 patients and 16 age- and gender-matched controls. A head-to-target repositioning test was requested from blindfolded participants. Their head was passively rotated approximately 30° leftward or rightward and flexed or extended approximately 25°. Participants had to replicate the imposed positions. An optoelectronic system was adopted to measure the angular differences between the reproduced and the imposed positions (joint position error, JPE, °) concerning the intended (sagittal, horizontal) and unintended (including the frontal) planar projections. In DM1 patients, JPEs were correlated with clinical and balance measures. Static balance in DM1 patients was assessed through dynamic posturography. Results: The accuracy and precision of head repositioning in the intended sagittal and horizontal error components did not differ between DM1 and controls. On the contrary, DM1 patients showed unintended side-bending to the left and the right: the mean [95%CI] of frontal JPE was −1.29° [−1.99°, −0.60°] for left rotation and 0.98° [0.28°, 1.67°] for right rotation. The frontal JPE of controls did not differ significantly from 0° (left rotation: 0.17° [−0.53°, 0.87°]; right rotation: −0.22° [−0.91°, 0.48°]). Frontal JPE differed between left and right rotation trials (p < 0.001) only in DM1 patients. No correlation was found between JPEs and measures from dynamic posturography and clinical scales. Conclusions: Lateral head bending associated with head rotation may reflect a latent impairment of neck proprioception in DM1 patients.

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Parent, Audrey, Laurent Ballaz, Bahare Samadi, Maria Vocos, Alain Steve Comtois e Annie Pouliot-Laforte. "Static Postural Control Deficits in Adults with Myotonic Dystrophy Type 1, Steinert Disease". Journal of Neuromuscular Diseases 9, n. 2 (1 marzo 2022): 311–20. http://dx.doi.org/10.3233/jnd-210639.

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Background: Myotonic dystrophy type 1 (DM1) is characterized by progressive and predominantly distal muscle atrophy and myotonia. Gait and balance impairments, resulting in falls, are frequently reported in this population. However, the extent to which individuals with DM1 rely more on a specific sensory system for balance than asymptomatic individuals (AI) is unknown. Objective: Evaluate postural control performance in individuals with DM1 and its dependence on vision compared to AI. Methods: 20 participants with DM1, divided into two groups based on their diagnosis, i.e. adult and congenital phenotype, and 12 AI participants were recruited. Quiet standing postural control was assessed in two visual conditions: eyes-open and eyes-closed. The outcomes measures were: center of pressure (CoP), mean velocity, CoP range of displacement in anteroposterior and mediolateral axis, and the 95% confidence ellipse’s surface. Friedman and Kruskal-Wallis analysis of variance were used to compare outcomes between conditions and groups, respectively. Results: Significant group effect and condition effect were observed on postural control performance. No significant difference was observed between the two DM1 groups. The significant differences observed between the AI group and the two DM1 groups in the eyes-open condition were also observed in the eyes-closed condition. Conclusions: The result revealed poorer postural control performance in people with DM1 compared to AI. The DM1 group also showed similar decrease in performance than AI in eyes-closed condition, suggesting no excessive visual dependency.

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Álvarez-Abril, Mari Carmen, Irma García-Alcover, Jordi Colonques-Bellmunt, Raquel Garijo, Manuel Pérez-Alonso, Rubén Artero e Arturo López-Castel. "Natural Compound Boldine Lessens Myotonic Dystrophy Type 1 Phenotypes in DM1 Drosophila Models, Patient-Derived Cell Lines, and HSALR Mice". International Journal of Molecular Sciences 24, n. 12 (6 giugno 2023): 9820. http://dx.doi.org/10.3390/ijms24129820.

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Myotonic dystrophy type 1 (DM1) is a complex rare disorder characterized by progressive muscle dysfunction, involving weakness, myotonia, and wasting, but also exhibiting additional clinical signs in multiple organs and systems. Central dysregulation, caused by an expansion of a CTG trinucleotide repeat in the DMPK gene’s 3’ UTR, has led to exploring various therapeutic approaches in recent years, a few of which are currently under clinical trial. However, no effective disease-modifying treatments are available yet. In this study, we demonstrate that treatments with boldine, a natural alkaloid identified in a large-scale Drosophila-based pharmacological screening, was able to modify disease phenotypes in several DM1 models. The most significant effects include consistent reduction in nuclear RNA foci, a dynamic molecular hallmark of the disease, and noteworthy anti-myotonic activity. These results position boldine as an attractive new candidate for therapy development in DM1.

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Savić Pavićević, Dušanka, Jelena Miladinović, Miloš Brkušanin, Saša Šviković, Svetlana Djurica, Goran Brajušković e Stanka Romac. "Molecular Genetics and Genetic Testing in Myotonic Dystrophy Type 1". BioMed Research International 2013 (2013): 1–13. http://dx.doi.org/10.1155/2013/391821.

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Myotonic dystrophy type 1 (DM1) is the most common adult onset muscular dystrophy, presenting as a multisystemic disorder with extremely variable clinical manifestation, from asymptomatic adults to severely affected neonates. A striking anticipation and parental-gender effect upon transmission are distinguishing genetic features in DM1 pedigrees. It is an autosomal dominant hereditary disease associated with an unstable expansion of CTG repeats in the 3′-UTR of theDMPKgene, with the number of repeats ranging from 50 to several thousand. The number of CTG repeats broadly correlates with both the age-at-onset and overall severity of the disease. Expanded DM1 alleles are characterized by a remarkable expansion-biased and gender-specific germline instability, and tissue-specific, expansion-biased, age-dependent, and individual-specific somatic instability. Mutational dynamics in male and female germline account for observed anticipation and parental-gender effect in DM1 pedigrees, while mutational dynamics in somatic tissues contribute toward the tissue-specificity and progressive nature of the disease. Genetic test is routinely used in diagnostic procedure for DM1 for symptomatic, asymptomatic, and prenatal testing, accompanied with appropriate genetic counseling and, as recommended, without predictive information about the disease course. We review molecular genetics of DM1 with focus on those issues important for genetic testing and counseling.

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Thornton, C. "Strategies for treating myotonic dystrophy type 1 (DM1)". Neuromuscular Disorders 28 (aprile 2018): S1. http://dx.doi.org/10.1016/s0960-8966(18)30291-8.

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Modoni, A., G. Silvestri, M. Gabriella Vita, D. Quaranta, P. A. Tonali e C. Marra. "Cognitive impairment in myotonic dystrophy type 1 (DM1)". Journal of Neurology 255, n. 11 (24 settembre 2008): 1737–42. http://dx.doi.org/10.1007/s00415-008-0017-5.

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Antonini, Giovanni, Alessandro Clemenzi, Elisabetta Bucci, Stefania Morino, Matteo Garibaldi, Micaela Sepe-Monti, Franco Giubilei e Giuseppe Novelli. "Erectile dysfunction in myotonic dystrophy type 1 (DM1)". Journal of Neurology 256, n. 4 (aprile 2009): 657–59. http://dx.doi.org/10.1007/s00415-009-0912-4.

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Ho, Genevieve, Kate A. Carey, Michael Cardamone e Michelle A. Farrar. "Myotonic dystrophy type 1: clinical manifestations in children and adolescents". Archives of Disease in Childhood 104, n. 1 (5 giugno 2018): 48–52. http://dx.doi.org/10.1136/archdischild-2018-314837.

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Abstract (sommario):

ObjectiveMyotonic dystrophy type 1 (DM1) is an autosomal-dominant neuromuscular disease with variable severity affecting all ages; however, current care guidelines are adult-focused. The objective of the present study was to profile DM1 in childhood and propose a framework to guide paediatric-focused management.Design, setting and patients40 children with DM1 (mean age 12.8 years; range 2–19) were studied retrospectively for a total of 513 follow-up years at Sydney Children’s Hospital. 143 clinical parameters were recorded.ResultsThe clinical spectrum of disease in childhood differs from adults, with congenital myotonic dystrophy (CDM1) having more severe health issues than childhood-onset/juvenile patients (JDM1). Substantial difficulties with intellectual (CDM1 25/26 96.2%; JDM1 9/10, 90.0%), fine motor (CDM1 23/30, 76.6%; JDM1 6/10, 60.0%), gastrointestinal (CDM1 17/30, 70.0%; JDM1 3/10, 30.0%) and neuromuscular function (CDM1 30/30, 100.0%; JDM1 25/30, 83.3%) were evident.ConclusionThe health consequences of DM1 in childhood are diverse, highlighting the need for paediatric multidisciplinary management approaches that encompass key areas of cognition, musculoskeletal, gastrointestinal, respiratory, cardiac and sleep issues.

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Xing, Xiaomeng, Anjani Kumari, Jake Brown e John David Brook. "Disrupting the Molecular Pathway in Myotonic Dystrophy". International Journal of Molecular Sciences 22, n. 24 (8 dicembre 2021): 13225. http://dx.doi.org/10.3390/ijms222413225.

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Myotonic dystrophy is the most common muscular dystrophy in adults. It consists of two forms: type 1 (DM1) and type 2 (DM2). DM1 is associated with a trinucleotide repeat expansion mutation, which is transcribed but not translated into protein. The mutant RNA remains in the nucleus, which leads to a series of downstream abnormalities. DM1 is widely considered to be an RNA-based disorder. Thus, we consider three areas of the RNA pathway that may offer targeting opportunities to disrupt the production, stability, and degradation of the mutant RNA.

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Lueck, John D., Ami Mankodi, Maurice S. Swanson, Charles A. Thornton e Robert T. Dirksen. "Muscle Chloride Channel Dysfunction in Two Mouse Models of Myotonic Dystrophy". Journal of General Physiology 129, n. 1 (11 dicembre 2006): 79–94. http://dx.doi.org/10.1085/jgp.200609635.

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Muscle degeneration and myotonia are clinical hallmarks of myotonic dystrophy type 1 (DM1), a multisystemic disorder caused by a CTG repeat expansion in the 3′ untranslated region of the myotonic dystrophy protein kinase (DMPK) gene. Transgenic mice engineered to express mRNA with expanded (CUG)250 repeats (HSALR mice) exhibit prominent myotonia and altered splicing of muscle chloride channel gene (Clcn1) transcripts. We used whole-cell patch clamp recordings and nonstationary noise analysis to compare and biophysically characterize the magnitude, kinetics, voltage dependence, and single channel properties of the skeletal muscle chloride channel (ClC-1) in individual flexor digitorum brevis (FDB) muscle fibers isolated from 1–3-wk-old wild-type and HSALR mice. The results indicate that peak ClC-1 current density at −140 mV is reduced >70% (−48.5 ± 3.6 and −14.0 ± 1.6 pA/pF, respectively) and the kinetics of channel deactivation increased in FDB fibers obtained from 18–20- d-old HSALR mice. Nonstationary noise analysis revealed that the reduction in ClC-1 current density in HSALR FDB fibers results from a large reduction in ClC-1 channel density (170 ± 21 and 58 ± 11 channels/pF in control and HSALR fibers, respectively) and a modest decrease in maximal channel open probability(0.91 ± 0.01 and 0.75 ± 0.03, respectively). Qualitatively similar results were observed for ClC-1 channel activity in knockout mice for muscleblind-like 1 (Mbnl1ΔE3/ΔE3), a second murine model of DM1 that exhibits prominent myotonia and altered Clcn1 splicing (Kanadia et al., 2003). These results support a molecular mechanism for myotonia in DM1 in which a reduction in both the number of functional sarcolemmal ClC-1 and maximal channel open probability, as well as an acceleration in the kinetics of channel deactivation, results from CUG repeat–containing mRNA molecules sequestering Mbnl1 proteins required for proper CLCN1 pre-mRNA splicing and chloride channel function.

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Hilbert, James E., Richard J. Barohn, Paula R. Clemens, Elizabeth A. Luebbe, William B. Martens, Michael P. McDermott, Amy L. Parkhill, Rabi Tawil, Charles A. Thornton e Richard T. Moxley. "High frequency of gastrointestinal manifestations in myotonic dystrophy type 1 and type 2". Neurology 89, n. 13 (30 agosto 2017): 1348–54. http://dx.doi.org/10.1212/wnl.0000000000004420.

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Objective:To analyze gastrointestinal (GI) manifestations, their progression over time, and medications being used to treat GI symptoms in a large cohort of patients with myotonic dystrophy types 1 (DM1) and 2 (DM2).Methods:We analyzed patient-reported data and medical records in a national registry cohort at baseline and 5 years.Results:At baseline, the majority of patients reported trouble swallowing in DM1 (55%; n = 499 of 913) and constipation in DM2 (53%; n = 96 of 180). Cholecystectomy occurred in 16.5% of patients with DM1 and 12.8% of patients with DM2, on average before 45 years of age. The use of medications indicated for gastroesophageal reflux disease was reported by 22.5% of DM1 and 18.9% of patients with DM2. Greater risk of a GI manifestation was associated with higher body mass index and longer disease duration in DM1 and female sex in DM2. At the 5-year follow-up, the most common new manifestations were trouble swallowing in patients with DM1 and constipation in patients with DM2.Conclusions:GI manifestations were common in both DM1 and DM2, with a relatively high frequency of gallbladder removal in DM1 and DM2 occurring at a younger age compared to normative data in the literature. Studies are needed to determine the pathomechanism of how sex, weight gain, and duration of disease contribute to GI manifestations and how these manifestations affect quality of life and clinical care for patients with DM1 and DM2.

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Vihola, A., G. Bassez, G. Meola, S. Zhang, H. Haapasalo, A. Paetau, E. Mancinelli et al. "Histopathological differences of myotonic dystrophy type 1 (DM1) and PROMM/DM2". Neurology 60, n. 11 (10 giugno 2003): 1854–57. http://dx.doi.org/10.1212/01.wnl.0000065898.61358.09.

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Li, Mao, Zhanjun Wang, Fang Cui, Fei Yang, Zhaohui Chen, Li Ling, Chuanqiang Pu e Xusheng Huang. "Investigation of molecular diagnosis in Chinese patients with myotonic dystrophy type 1". Chinese Medical Journal 127, n. 6 (20 marzo 2014): 1084–88. http://dx.doi.org/10.3760/cma.j.issn.0366-6999.20132731.

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Abstract (sommario):

Background Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystem disease caused by abnormal expansion of cytosine-thymine-guanine (CTG) repeats in the myotonic dystrophy protein kinase gene. The clinical manifestations of DM1 are multisystemic and highly variable, and the unstable nature of CTG expansion causes wide genotypic and phenotypic presentations, which make molecular methods essential for the diagnosis. So far, very few studies about molecular diagnosis in Chinese patients with DM1 have been reported. Therefore, we carried out a study using two different methods in molecular diagnosis to verify the validity in detecting CTG expansion in Chinese patients showing DM signs. Methods A total of 97 Chinese individuals were referred for molecular diagnosis of DM1 using conventional polymerase chain reaction (PCR) accompanied by Southern blotting and triplet primed PCR (TP-PCR). We evaluated the sensitivity and limitation of each method using percentage. Results By conventional PCR 65 samples showed only one fragment corresponding to the normal allele and 62 out of them were correctly diagnosed as DM1 by TP-PCR and three homologous non-DM1 samples were ruled out; Southern blotting analysis successfully made 13 out of 16 correct diagnoses with a more sensitivity using α-32P-labeled probes than dig-labeled probes. Conclusion Molecular analysis is necessary for the diagnosis of DM1 and TP-PCR is a reliable, sensitive, and easily performed method in molecular diagnosis which is worthy to be popularized.

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Ballester-Lopez, Alfonsina, Ian Linares-Pardo, Emma Koehorst, Judit Núñez-Manchón, Guillem Pintos-Morell, Jaume Coll-Cantí, Miriam Almendrote et al. "The Need for Establishing a Universal CTG Sizing Method in Myotonic Dystrophy Type 1". Genes 11, n. 7 (7 luglio 2020): 757. http://dx.doi.org/10.3390/genes11070757.

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Abstract (sommario):

The number of cytosine-thymine-guanine (CTG) repeats (‘CTG expansion size’) in the 3′untranslated region (UTR) region of the dystrophia myotonica-protein kinase (DMPK) gene is a hallmark of myotonic dystrophy type 1 (DM1), which has been related to age of disease onset and clinical severity. However, accurate determination of CTG expansion size is challenging due to its characteristic instability. We compared five different approaches (heat pulse extension polymerase chain reaction [PCR], long PCR-Southern blot [with three different primers sets—1, 2 and 3] and small pool [SP]-PCR) to estimate CTG expansion size in the progenitor allele as well as the most abundant CTG expansion size, in 15 patients with DM1. Our results indicated variability between the methods (although we found no overall differences between long PCR 1 and 2 and SP-PCR, respectively). While keeping in mind the limited sample size of our patient cohort, SP-PCR appeared as the most suitable technique, with an inverse significant correlation found between CTG expansion size of the progenitor allele, as determined by this method, and age of disease onset (r = −0.734, p = 0.016). Yet, in light of the variability of the results obtained with the different methods, we propose that an international agreement is needed to determine which is the most suitable method for assessing CTG expansion size in DM1.

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Timchenko, Lubov. "Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics". International Journal of Molecular Sciences 23, n. 19 (8 ottobre 2022): 11954. http://dx.doi.org/10.3390/ijms231911954.

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Ikeda, Karin Suzete, Cristina Iwabe-Marchese, Marcondes Cavalcante França Jr, Anamarli Nucci e Keila Monteiro de Carvalho. "Myotonic dystrophy type 1: frequency of ophthalmologic findings". Arquivos de Neuro-Psiquiatria 74, n. 3 (marzo 2016): 183–88. http://dx.doi.org/10.1590/0004-282x20150218.

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ABSTRACT The purpose of the study was to evaluate the frequency of ophthalmologic abnormalities in a cohort of myotonic dystrophy type 1 (DM1) patients and to correlate them with motor function. We reviewed the pathophysiology of cataract and low intraocular pressure (IOP). Method Patients were included after clinical and laboratory diagnosis and after signed informed consent. They were evaluated by Motor Function Measure scale, Portuguese version (MFM-P) and ophthalmic protocol. Results We evaluated 42 patients aged 17 to 64 years (mean 40.7 ± 12.5), 22 of which were men. IOP (n = 41) was reduced in all but one. We found cataract or positivity for surgery in 38 (90.48%) and ptosis in 23 (54.76%). These signs but not IOP were significantly correlated with severity of motor dysfunction. Abnormalities in ocular motility and stereopsis were observed. Conclusion Cataract and ptosis are frequent in DM1 and associated to motor dysfunction. Reduced IOP is also common, but appears not to be related with motor impairment.

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Lutz, Maggie, Miranda Levanti, Rebekah Karns, Genevieve Gourdon, Diana Lindquist, Nikolai A. Timchenko e Lubov Timchenko. "Therapeutic Targeting of the GSK3β-CUGBP1 Pathway in Myotonic Dystrophy". International Journal of Molecular Sciences 24, n. 13 (26 giugno 2023): 10650. http://dx.doi.org/10.3390/ijms241310650.

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Myotonic Dystrophy type 1 (DM1) is a neuromuscular disease associated with toxic RNA containing expanded CUG repeats. The developing therapeutic approaches to DM1 target mutant RNA or correct early toxic events downstream of the mutant RNA. We have previously described the benefits of the correction of the GSK3β-CUGBP1 pathway in DM1 mice (HSALR model) expressing 250 CUG repeats using the GSK3 inhibitor tideglusib (TG). Here, we show that TG treatments corrected the expression of ~17% of genes misregulated in DM1 mice, including genes involved in cell transport, development and differentiation. The expression of chloride channel 1 (Clcn1), the key trigger of myotonia in DM1, was also corrected by TG. We found that correction of the GSK3β-CUGBP1 pathway in mice expressing long CUG repeats (DMSXL model) is beneficial not only at the prenatal and postnatal stages, but also during adulthood. Using a mouse model with dysregulated CUGBP1, which mimics alterations in DM1, we showed that the dysregulated CUGBP1 contributes to the toxicity of expanded CUG repeats by changing gene expression and causing CNS abnormalities. These data show the critical role of the GSK3β-CUGBP1 pathway in DM1 muscle and in CNS pathologies, suggesting the benefits of GSK3 inhibitors in patients with different forms of DM1.

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Russo, Vincenzo, Antonio Capolongo, Roberta Bottino, Andreina Carbone, Alberto Palladino, Biagio Liccardo, Gerardo Nigro, Michał Marchel, Paolo Golino e Antonello D’Andrea. "Echocardiographic Features of Cardiac Involvement in Myotonic Dystrophy 1: Prevalence and Prognostic Value". Journal of Clinical Medicine 12, n. 5 (1 marzo 2023): 1947. http://dx.doi.org/10.3390/jcm12051947.

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Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults. Cardiac involvement is reported in 80% of cases and includes conduction disturbances, arrhythmias, subclinical diastolic and systolic dysfunction in the early stage of the disease; in contrast, severe ventricular systolic dysfunction occurs in the late stage of the disease. Echocardiography is recommended at the time of diagnosis with periodic revaluation in DM1 patients, regardless of the presence or absence of symptoms. Data regarding the echocardiographic findings in DM1 patients are few and conflicting. This narrative review aimed to describe the echocardiographic features of DM1 patients and their prognostic role as predictors of cardiac arrhythmias and sudden death.

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Gagnon, Cynthia, Maud-Christine Chouinard, Luc Laberge, Diane Brisson, Daniel Gaudet, Mélissa Lavoie, Nadine Leclerc e Jean Mathieu. "Prevalence of Lifestyle Risk Factors in Myotonic Dystrophy Type 1". Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 40, n. 1 (gennaio 2013): 42–47. http://dx.doi.org/10.1017/s0317167100012932.

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Abstract:Background:The prevalence of unhealthy lifestyle habits such as smoking has seldom been described in neuromuscular disorders, including myotonic dystrophy type 1 (DM1). However, it is essential to document the unhealthy lifestyle habits as they can exacerbate existing impairments and disabilities. The objectives are: 1) To determine the prevalence of risk factors among individuals with DM1; 2) To compare the prevalence among classic and mild phenotypes.Method:A survey was done on a sample of two-hundred (200) patients with DM1 as part of a larger study. Lifestyle risk factors included being overweight or obese, tobacco smoking, illicit drug use, excessive alcohol consumption and physical inactivity. A registered nurse administered the validated public health survey. Categorization of risk factors were based on national standards and compared with provincial and regional prevalences.Results:50% of DM1 patients were overweight or obese, 23.6% were regular smokers, and 76% were physically inactive. Except for overweight and obesity, significant differences were observed between patients with classic and mild phenotypes for all the other lifestyle risk factors: those with the classic phenotype being more often regular smokers, consuming more often illicit drugs and being less physically active.Conclusions:The results of this study will provide guidance for the development of better adapted and focussed health promotion interventions in the future.

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Kuntawala, Dhvani H., Filipa Martins, Rui Vitorino e Sandra Rebelo. "Automatic Text-Mining Approach to Identify Molecular Target Candidates Associated with Metabolic Processes for Myotonic Dystrophy Type 1". International Journal of Environmental Research and Public Health 20, n. 3 (27 gennaio 2023): 2283. http://dx.doi.org/10.3390/ijerph20032283.

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Myotonic dystrophy type 1 (DM1) is an autosomal dominant hereditary disease caused by abnormal expansion of unstable CTG repeats in the 3′ untranslated region of the myotonic dystrophy protein kinase (DMPK) gene. This disease mainly affects skeletal muscle, resulting in myotonia, progressive distal muscle weakness, and atrophy, but also affects other tissues and systems, such as the heart and central nervous system. Despite some studies reporting therapeutic strategies for DM1, many issues remain unsolved, such as the contribution of metabolic and mitochondrial dysfunctions to DM1 pathogenesis. Therefore, it is crucial to identify molecular target candidates associated with metabolic processes for DM1. In this study, resorting to a bibliometric analysis, articles combining DM1, and metabolic/metabolism terms were identified and further analyzed using an unbiased strategy of automatic text mining with VOSviewer software. A list of candidate molecular targets for DM1 associated with metabolic/metabolism was generated and compared with genes previously associated with DM1 in the DisGeNET database. Furthermore, g:Profiler was used to perform a functional enrichment analysis using the Gene Ontology (GO) and REAC databases. Enriched signaling pathways were identified using integrated bioinformatics enrichment analyses. The results revealed that only 15 of the genes identified in the bibliometric analysis were previously associated with DM1 in the DisGeNET database. Of note, we identified 71 genes not previously associated with DM1, which are of particular interest and should be further explored. The functional enrichment analysis of these genes revealed that regulation of cellular metabolic and metabolic processes were the most associated biological processes. Additionally, a number of signaling pathways were found to be enriched, e.g., signaling by receptor tyrosine kinases, signaling by NRTK1 (TRKA), TRKA activation by NGF, PI3K-AKT activation, prolonged ERK activation events, and axon guidance. Overall, several valuable target candidates related to metabolic processes for DM1 were identified, such as NGF, NTRK1, RhoA, ROCK1, ROCK2, DAG, ACTA, ID1, ID2 MYOD, and MYOG. Therefore, our study strengthens the hypothesis that metabolic dysfunctions contribute to DM1 pathogenesis, and the exploitation of metabolic dysfunction targets is crucial for the development of future therapeutic interventions for DM1.

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Mateus, Tiago, Idália Almeida, Adriana Costa, Diana Viegas, Sandra Magalhães, Filipa Martins, Maria Teresa Herdeiro et al. "Fourier-Transform Infrared Spectroscopy as a Discriminatory Tool for Myotonic Dystrophy Type 1 Metabolism: A Pilot Study". International Journal of Environmental Research and Public Health 18, n. 7 (6 aprile 2021): 3800. http://dx.doi.org/10.3390/ijerph18073800.

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Myotonic dystrophy type 1 (DM1) is a hereditary disease characterized by progressive distal muscle weakness and myotonia. Patients with DM1 have abnormal lipid metabolism and a high propensity to develop a metabolic syndrome in comparison to the general population. It follows that metabolome evaluation in these patients is crucial and may contribute to a better characterization and discrimination between DM1 disease phenotypes and severities. Several experimental approaches are possible to carry out such an analysis; among them is Fourier-transform infrared spectroscopy (FTIR) which evaluates metabolic profiles by categorizing samples through their biochemical composition. In this study, FTIR spectra were acquired and analyzed using multivariate analysis (Principal Component Analysis) using skin DM1 patient-derived fibroblasts and controls. The results obtained showed a clear discrimination between both DM1-derived fibroblasts with different CTG repeat length and with the age of disease onset; this was evident given the distinct metabolic profiles obtained for the two groups. Discrimination could be attributed mainly to the altered lipid metabolism and proteins in the 1800–1500 cm−1 region. These results suggest that FTIR spectroscopy is a valuable tool to discriminate both DM1-derived fibroblasts with different CTG length and age of onset and to study the metabolomic profile of patients with DM1.

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Grande, Valentina, Denisa Hathazi, Emily O’Connor, Theo Marteau, Ulrike Schara-Schmidt, Andreas Hentschel, Genevieve Gourdon, Nikoletta Nikolenko, Hanns Lochmüller e Andreas Roos. "Dysregulation of GSK3β-Target Proteins in Skin Fibroblasts of Myotonic Dystrophy Type 1 (DM1) Patients". Journal of Neuromuscular Diseases 8, n. 4 (30 luglio 2021): 603–19. http://dx.doi.org/10.3233/jnd-200558.

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Myotonic dystrophy type 1 (DM1) is the most common monogenetic muscular disorder of adulthood. This multisystemic disease is caused by CTG repeat expansion in the 3′-untranslated region of the DM1 protein kinase gene called DMPK. DMPK encodes a myosin kinase expressed in skeletal muscle cells and other cellular populations such as smooth muscle cells, neurons and fibroblasts. The resultant expanded (CUG)n RNA transcripts sequester RNA binding factors leading to ubiquitous and persistent splicing deregulation. The accumulation of mutant CUG repeats is linked to increased activity of glycogen synthase kinase 3 beta (GSK3β), a highly conserved and ubiquitous serine/threonine kinase with functions in pathways regulating inflammation, metabolism, oncogenesis, neurogenesis and myogenesis. As GSK3β-inhibition ameliorates defects in myogenesis, muscle strength and myotonia in a DM1 mouse model, this kinase represents a key player of DM1 pathobiochemistry and constitutes a promising therapeutic target. To better characterise DM1 patients, and monitor treatment responses, we aimed to define a set of robust disease and severity markers linked to GSK3βby unbiased proteomic profiling utilizing fibroblasts derived from DM1 patients with low (80– 150) and high (2600– 3600) CTG-repeats. Apart from GSK3β increase, we identified dysregulation of nine proteins (CAPN1, CTNNB1, CTPS1, DNMT1, HDAC2, HNRNPH3, MAP2K2, NR3C1, VDAC2) modulated by GSK3β. In silico-based expression studies confirmed expression in neuronal and skeletal muscle cells and revealed a relatively elevated abundance in fibroblasts. The potential impact of each marker in the myopathology of DM1 is discussed based on respective function to inform potential uses as severity markers or for monitoring GSK3β inhibitor treatment responses.

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Wansink, D. G., e B. Wieringa. "Transgenic mouse models for myotonic dystrophy type 1 (DM1)". Cytogenetic and Genome Research 100, n. 1-4 (2003): 230–42. http://dx.doi.org/10.1159/000072859.

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Izzo, Mariapaola, Jonathan Battistini, Claudia Provenzano, Fabio Martelli, Beatrice Cardinali e Germana Falcone. "Molecular Therapies for Myotonic Dystrophy Type 1: From Small Drugs to Gene Editing". International Journal of Molecular Sciences 23, n. 9 (21 aprile 2022): 4622. http://dx.doi.org/10.3390/ijms23094622.

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Abstract (sommario):

Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy affecting many different body tissues, predominantly skeletal and cardiac muscles and the central nervous system. The expansion of CTG repeats in the DM1 protein-kinase (DMPK) gene is the genetic cause of the disease. The pathogenetic mechanisms are mainly mediated by the production of a toxic expanded CUG transcript from the DMPK gene. With the availability of new knowledge, disease models, and technical tools, much progress has been made in the discovery of altered pathways and in the potential of therapeutic intervention, making the path to the clinic a closer reality. In this review, we describe and discuss the molecular therapeutic strategies for DM1, which are designed to directly target the CTG genomic tract, the expanded CUG transcript or downstream signaling molecules.

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Ionova, Sofya A., Aysylu F. Murtazina, Andrey A. Marakhonov, Olga A. Shchagina, Nina V. Ryadninskaya, Inna S. Tebieva, Vitaly V. Kadyshev et al. "The Study of the Inheritance Mechanisms of Myotonic Dystrophy Type 1 (DM1) in Families from the Republic of North Ossetia-Alania". International Journal of Molecular Sciences 25, n. 17 (9 settembre 2024): 9734. http://dx.doi.org/10.3390/ijms25179734.

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Abstract (sommario):

Myotonic dystrophy type 1 (DM1) is a multisystem disorder with progressive myopathy and myotonia. The clinical study was conducted in the Republic of North Ossetia-Alania (RNOA), and in it 39 individuals from 17 unrelated families were identified with DM1. Clinical presentations varied, including muscle weakness, fatigue, intellectual disability, hypersomnia, ophthalmological abnormalities, and alopecia. Using clinical and genotyping data, we confirmed the diagnosis and enabled the study of CTG-repeat anticipation and DM1 prevalence in the Ossetian and Ingush populations. CTG expansion correlated with age of onset, with clinical severity, and with offspring showing more severe symptoms than parents. In many families, the youngest child had a more severe DM1 phenotype than older siblings. The prevalence was 14.17 per 100,000 in Ossetians and 18.74 per 100,000 in Ingush people, aligning with global data. Segregation analysis showed a higher frequency of maternal transmission. The study highlights the clinical and genetic heterogeneity of DM1 and its dependence on repeat expansion and paternal and maternal age.

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Herrendorff, Ruben, Maria Teresa Faleschini, Adeline Stiefvater, Beat Erne, Tatiana Wiktorowicz, Frances Kern, Matthias Hamburger, Olivier Potterat, Jochen Kinter e Michael Sinnreich. "Identification of Plant-derived Alkaloids with Therapeutic Potential for Myotonic Dystrophy Type I". Journal of Biological Chemistry 291, n. 33 (13 giugno 2016): 17165–77. http://dx.doi.org/10.1074/jbc.m115.710616.

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Abstract (sommario):

Myotonic dystrophy type I (DM1) is a disabling neuromuscular disease with no causal treatment available. This disease is caused by expanded CTG trinucleotide repeats in the 3′ UTR of the dystrophia myotonica protein kinase gene. On the RNA level, expanded (CUG)n repeats form hairpin structures that sequester splicing factors such as muscleblind-like 1 (MBNL1). Lack of available MBNL1 leads to misregulated alternative splicing of many target pre-mRNAs, leading to the multisystemic symptoms in DM1. Many studies aiming to identify small molecules that target the (CUG)n-MBNL1 complex focused on synthetic molecules. In an effort to identify new small molecules that liberate sequestered MBNL1 from (CUG)n RNA, we focused specifically on small molecules of natural origin. Natural products remain an important source for drugs and play a significant role in providing novel leads and pharmacophores for medicinal chemistry. In a new DM1 mechanism-based biochemical assay, we screened a collection of isolated natural compounds and a library of over 2100 extracts from plants and fungal strains. HPLC-based activity profiling in combination with spectroscopic methods were used to identify the active principles in the extracts. The bioactivity of the identified compounds was investigated in a human cell model and in a mouse model of DM1. We identified several alkaloids, including the β-carboline harmine and the isoquinoline berberine, that ameliorated certain aspects of the DM1 pathology in these models. Alkaloids as a compound class may have potential for drug discovery in other RNA-mediated diseases.

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Espinosa-Espinosa, Jorge, Anchel González-Barriga, Arturo López-Castel e Rubén Artero. "Deciphering the Complex Molecular Pathogenesis of Myotonic Dystrophy Type 1 through Omics Studies". International Journal of Molecular Sciences 23, n. 3 (27 gennaio 2022): 1441. http://dx.doi.org/10.3390/ijms23031441.

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Abstract (sommario):

Omics studies are crucial to improve our understanding of myotonic dystrophy type 1 (DM1), the most common muscular dystrophy in adults. Employing tissue samples and cell lines derived from patients and animal models, omics approaches have revealed the myriad alterations in gene and microRNA expression, alternative splicing, 3′ polyadenylation, CpG methylation, and proteins levels, among others, that contribute to this complex multisystem disease. In addition, omics characterization of drug candidate treatment experiments provides crucial insight into the degree of therapeutic rescue and off-target effects that can be achieved. Finally, several innovative technologies such as single-cell sequencing and artificial intelligence will have a significant impact on future DM1 research.

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