scholarly journals Advances in Genetic Characterization and Genotype–Phenotype Correlation of Duchenne and Becker Muscular Dystrophy in the Personalized Medicine Era

2020 ◽  
Vol 10 (3) ◽  
pp. 111 ◽  
Author(s):  
Omar Sheikh ◽  
Toshifumi Yokota
Keyword(s):  
Muscular Dystrophy ◽  
Personalized Medicine ◽  
Genetic Diagnosis ◽  
Exon Skipping ◽  
Dystrophin Gene ◽  
Becker Muscular Dystrophy ◽  
Phenotype Correlation ◽  
Related Condition ◽  
Genotype Phenotype Correlation ◽  
Dystrophin Protein

Currently, Duchenne muscular dystrophy (DMD) and the related condition Becker muscular dystrophy (BMD) can be usually diagnosed using physical examination and genetic testing. While BMD features partially functional dystrophin protein due to in-frame mutations, DMD largely features no dystrophin production because of out-of-frame mutations. However, BMD can feature a range of phenotypes from mild to borderline DMD, indicating a complex genotype–phenotype relationship. Despite two mutational hot spots in dystrophin, mutations can arise across the gene. The use of multiplex ligation amplification (MLPA) can easily assess the copy number of all exons, while next-generation sequencing (NGS) can uncover novel or confirm hard-to-detect mutations. Exon-skipping therapy, which targets specific regions of the dystrophin gene based on a patient’s mutation, is an especially prominent example of personalized medicine for DMD. To maximize the benefit of exon-skipping therapies, accurate genetic diagnosis and characterization including genotype–phenotype correlation studies are becoming increasingly important. In this article, we present the recent progress in the collection of mutational data and optimization of exon-skipping therapy for DMD/BMD.

scholarly journals The Interplay of Mitophagy and Inflammation in Duchenne Muscular Dystrophy

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 648
Author(s):  
Andrea L. Reid ◽  
Matthew S. Alexander
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mitochondrial Dysfunction ◽  
Disease Onset ◽  
Exon Skipping ◽  
Dystrophin Gene ◽  
Muscle Disease ◽  
Mitochondrial Morphology ◽  
Gene Therapies ◽  
Dystrophin Protein

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease caused by a pathogenic disruption of the DYSTROPHIN gene that results in non-functional dystrophin protein. DMD patients experience loss of ambulation, cardiac arrhythmia, metabolic syndrome, and respiratory failure. At the molecular level, the lack of dystrophin in the muscle results in myofiber death, fibrotic infiltration, and mitochondrial dysfunction. There is no cure for DMD, although dystrophin-replacement gene therapies and exon-skipping approaches are being pursued in clinical trials. Mitochondrial dysfunction is one of the first cellular changes seen in DMD myofibers, occurring prior to muscle disease onset and progresses with disease severity. This is seen by reduced mitochondrial function, abnormal mitochondrial morphology and impaired mitophagy (degradation of damaged mitochondria). Dysfunctional mitochondria release high levels of reactive oxygen species (ROS), which can activate pro-inflammatory pathways such as IL-1β and IL-6. Impaired mitophagy in DMD results in increased inflammation and further aggravates disease pathology, evidenced by increased muscle damage and increased fibrosis. This review will focus on the critical interplay between mitophagy and inflammation in Duchenne muscular dystrophy as a pathological mechanism, as well as describe both candidate and established therapeutic targets that regulate these pathways.

Genotype–phenotype correlation in Becker muscular dystrophy in Chinese patients

2018 ◽  
Vol 63 (10) ◽  
pp. 1041-1048 ◽  
Author(s):  
Ruiyi Yuan ◽  
Junfei Yi ◽  
Zhiying Xie ◽  
Yimeng Zheng ◽  
Miao Han ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Becker Muscular Dystrophy ◽  
Chinese Patients ◽  
Phenotype Correlation ◽  
Genotype Phenotype Correlation

scholarly journals Renadirsen, a Novel 2′OMeRNA/ENA® Chimera Antisense Oligonucleotide, Induces Robust Exon 45 Skipping for Dystrophin In Vivo

2021 ◽  
Vol 43 (3) ◽  
pp. 1267-1281
Author(s):  
Kentaro Ito ◽  
Hideo Takakusa ◽  
Masayo Kakuta ◽  
Akira Kanda ◽  
Nana Takagi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Cardiac Dysfunction ◽  
Exon Skipping ◽  
Dystrophin Gene ◽  
Becker Muscular Dystrophy ◽  
Systemic Delivery ◽  
Nuclease Resistance ◽  
Muscle Wasting Disease

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease caused by out-of-frame or nonsense mutation in the dystrophin gene. It begins with a loss of ambulation between 9 and 14 years of age, followed by various other symptoms including cardiac dysfunction. Exon skipping of patients’ DMD pre-mRNA induced by antisense oligonucleotides (AOs) is expected to produce shorter but partly functional dystrophin proteins, such as those possessed by patients with the less severe Becker muscular dystrophy. We are working on developing modified nucleotides, such as 2′-O,4′-C-ethylene-bridged nucleic acids (ENAs), possessing high nuclease resistance and high affinity for complementary RNA strands. Here, we demonstrate the preclinical characteristics (exon-skipping activity in vivo, stability in blood, pharmacokinetics, and tissue distribution) of renadirsen, a novel AO modified with 2′-O-methyl RNA/ENA chimera phosphorothioate designed for dystrophin exon 45 skipping and currently under clinical trials. Notably, systemic delivery of renadirsen sodium promoted dystrophin exon skipping in cardiac muscle, skeletal muscle, and diaphragm, compared with AOs with the same sequence as renadirsen but conventionally modified by PMO and 2′OMePS. These findings suggest the promise of renadirsen sodium as a therapeutic agent that improves not only skeletal muscle symptoms but also other symptoms in DMD patients, such as cardiac dysfunction.

scholarly journals The lncRNA 44s2 Study Applicability to the Design of 45-55 Exon Skipping Therapeutic Strategy for DMD

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 219
Author(s):  
Elena Gargaun ◽  
Sestina Falcone ◽  
Guilhem Solé ◽  
Julien Durigneux ◽  
Andoni Urtizberea ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Gene Mutations ◽  
Exon Skipping ◽  
Becker Muscular Dystrophy ◽  
Protein Stabilization ◽  
Progressive Muscular Dystrophy ◽  
Dilatative Cardiomyopathy ◽  
Proliferation And Differentiation ◽  
Dmd Gene ◽  
Dystrophin Protein

In skeletal muscle, long noncoding RNAs (lncRNAs) are involved in dystrophin protein stabilization but also in the regulation of myocytes proliferation and differentiation. Hence, they could represent promising therapeutic targets and/or biomarkers for Duchenne and Becker muscular dystrophy (DMD/BMD). DMD and BMD are X-linked myopathies characterized by a progressive muscular dystrophy with or without dilatative cardiomyopathy. Two-thirds of DMD gene mutations are represented by deletions, and 63% of patients carrying DMD deletions are eligible for 45 to 55 multi-exons skipping (MES), becoming BMD patients (BMDΔ45-55). We analyzed the genomic lncRNA presence in 38 BMDΔ45-55 patients and characterized the lncRNA localized in introns 44 and 55 of the DMD gene. We highlighted that all four lncRNA are differentially expressed during myogenesis in immortalized and primary human myoblasts. In addition, the lncRNA44s2 was pointed out as a possible accelerator of differentiation. Interestingly, lncRNA44s expression was associated with a favorable clinical phenotype. These findings suggest that lncRNA44s2 could be involved in muscle differentiation process and become a potential disease progression biomarker. Based on these results, we support MES45-55 therapy and propose that the design of the CRISPR/Cas9 MES45-55 assay consider the lncRNA sequences bordering the exonic 45 to 55 deletion.

scholarly journals Duchene Muscular Dystrophy: Pathogenesis, Pathophysiology, Diagnosis Management to Therapy.

1970 ◽  
Vol 8 (3) ◽  
pp. 130-134
Author(s):  
Bharti Sharma ◽  
Savita Devi ◽  
Kamaldeep Singh
Keyword(s):  
Muscular Dystrophy ◽  
Exon Skipping ◽  
Dystrophin Gene ◽  
The Body ◽  
Confirmatory Test ◽  
Inherited Disease ◽  
Progressive Muscle Weakness ◽  
Duchene Muscular Dystrophy ◽  
Cardiac Gene ◽  
Dystrophin Protein

Duchene muscular dystrophy (DMD) is a neuromuscular inherited disease which deal with X-linked occurs due to mutations in the dystrophin gene. The characterisation achieved by progressive muscle weakness in all our the body specially in legs and arms and wasting due to the absence of dystrophin protein which further causes degeneration of different types of muscules such as skeletal and cardiac. Gene mutation is one of the major causes for Duchenne muscular dystrophy located in cytoskeletal protein dystrophin. The diagnosis can be start up with careful review of the physical condition, history and examination of body organs and developmental delay, proximal weakness in muscules, and elevated biochemical compound serum creatine kinase, plus other confirmatory test like muscle biopsy or genetic testing. To improve the life expectancy of patient the early use of exercises, diet & nutrition management and other supportive strategies has been implemented. Moreover, uncontrolled condition can be treated with gene therapy with the use of plasmids or viruses, mutations and short DNA fragments can be corrected, oligonucleotides are first line treatment for exon skipping of mutations. Myoblasts or stem cells replacement therapy can be apply to reproduction of muscules.  

scholarly journals A Genotype-Phenotype Correlation Study of Exon Skip-Equivalent In-Frame Deletions and Exon Skip-Amenable Out-of-Frame Deletions across the DMD Gene to Simulate the Effects of Exon-Skipping Therapies: A Meta-Analysis

2021 ◽  
Vol 11 (1) ◽  
pp. 46
Author(s):  
Saeed Anwar ◽  
Merry He ◽  
Kenji Rowel Q. Lim ◽  
Rika Maruyama ◽  
Toshifumi Yokota
Keyword(s):  
Muscular Dystrophy ◽  
Rational Design ◽  
Meta Analysis ◽  
Exon Skipping ◽  
Correlation Study ◽  
Phenotype Correlation ◽  
Patient Registries ◽  
Genotype Phenotype Correlation ◽  
Exon Skip ◽  
Dmd Gene

Dystrophinopathies are caused by mutations in the DMD gene. Out-of-frame deletions represent most mutational events in severe Duchenne muscular dystrophy (DMD), while in-frame deletions typically lead to milder Becker muscular dystrophy (BMD). Antisense oligonucleotide-mediated exon skipping converts an out-of-frame transcript to an in-frame one, inducing a truncated but partially functional dystrophin protein. The reading frame rule, however, has many exceptions. We thus sought to simulate clinical outcomes of exon-skipping therapies for DMD exons from clinical data of exon skip-equivalent in-frame deletions, in which the expressed quasi-dystrophins are comparable to those resulting from exon-skipping therapies. We identified a total of 1298 unique patients with exon skip-equivalent mutations in patient registries and the existing literature. We classified them into skip-equivalent deletions of each exon and statistically compared the ratio of DMD/BMD and asymptomatic individuals across the DMD gene. Our analysis identified that five exons are associated with significantly milder phenotypes than all other exons when corresponding exon skip-equivalent in-frame deletion mutations occur. Most exon skip-equivalent in-frame deletions were associated with a significantly milder phenotype compared to corresponding exon skip-amenable out-of-frame mutations. This study indicates the importance of genotype-phenotype correlation studies in the rational design of exon-skipping therapies.

scholarly journals Mutation-Based Therapeutic Strategies for Duchenne Muscular Dystrophy: From Genetic Diagnosis to Therapy

2019 ◽  
Vol 9 (1) ◽  
pp. 16 ◽  
Author(s):  
Akinori Nakamura
Keyword(s):  
Muscular Dystrophy ◽  
Single Gene ◽  
Genetic Diagnosis ◽  
Exon Skipping ◽  
Becker Muscular Dystrophy ◽  
Therapeutic Strategies ◽  
Severe Phenotype ◽  
Reading Frame ◽  
Dystrophin Expression ◽  
Dmd Gene

Duchenne and Becker muscular dystrophy (DMD/BMD) are X-linked muscle disorders caused by mutations of the DMD gene, which encodes the subsarcolemmal protein dystrophin. In DMD, dystrophin is not expressed due to a disruption in the reading frame of the DMD gene, resulting in a severe phenotype. Becker muscular dystrophy exhibits a milder phenotype, having mutations that maintain the reading frame and allow for the production of truncated dystrophin. To date, various therapeutic approaches for DMD have been extensively developed. However, the pathomechanism is quite complex despite it being a single gene disorder, and dystrophin is expressed not only in a large amount of skeletal muscle but also in cardiac, vascular, intestinal smooth muscle, and nervous system tissue. Thus, the most appropriate therapy would be complementation or restoration of dystrophin expression, such as gene therapy using viral vectors, readthrough therapy, or exon skipping therapy. Among them, exon skipping therapy with antisense oligonucleotides can restore the reading frame and yield the conversion of a severe phenotype to one that is mild. In this paper, I present the significance of molecular diagnosis and the development of mutation-based therapeutic strategies to complement or restore dystrophin expression.

scholarly journals The Neurocognitive and Behavioral Profiles of 3 Brothers With Becker Muscular Dystrophy

2020 ◽  
Vol 7 ◽  
pp. 2329048X2095721
Author(s):  
Danique M. J. Hellebrekers ◽  
Johan S. H. Vles ◽  
Sylvia Klinkenberg ◽  
Jos G. M. Hendriksen
Keyword(s):  
Muscular Dystrophy ◽  
Processing Speed ◽  
Dystrophin Gene ◽  
Becker Muscular Dystrophy ◽  
Behavioral Profiles ◽  
Reading Abilities ◽  
Intellectual Abilities ◽  
Neuropsychological Assessments ◽  
Age Range ◽  
Dystrophin Protein

Becker muscular dystrophy patients generally carry in-frame mutations in the dystrophin gene, allowing the production of partially functional dystrophin protein. The presence of cognitive and behavioral comorbidities and the relation with the location of mutations has been scarcely investigated in Becker. This case report describes the neurocognitive and behavioral profiles of 3 brothers with Becker carrying an in-frame deletion of exons 45-48. The 3 cases underwent 2 consecutive neuropsychological assessments of which one assessment took place when they completed their primary education (age range of the cases: 11.2 -12.1 years). Intellectual abilities were normal to high and all cases had difficulties with processing speed and math. The brothers differed in intellectual abilities, executive functions, working memory, attention and reading abilities. Variability in cognitive development was noted as well. This report suggests that cognitive and behavioral functions in Becker vary regardless of gene mutation and exposer to similar environmental factors.

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