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Neuromuscular Disorders : NMD Jun 2024Duchenne muscular dystrophy is a neuromuscular disease caused by DMD gene mutations that result in an absence of functional dystrophin protein. Patients with Duchenne...
Duchenne muscular dystrophy is a neuromuscular disease caused by DMD gene mutations that result in an absence of functional dystrophin protein. Patients with Duchenne experience progressive muscle weakness, are typically wheelchair dependent by their early teens, and develop respiratory and cardiac complications that lead to death in their twenties or thirties. Becker muscular dystrophy is also caused by DMD gene mutations, but symptoms are less severe and progression is slower compared with Duchenne. We describe a case study of a patient with Becker muscular dystrophy who was still ambulant at age 61 years and had a milder phenotype than Duchenne, despite 46% of his DMD gene being missing. His affected relatives had similarly mild phenotypes and clinical courses. These data guided the understanding of the criticality of various regions of dystrophin and informed the development of micro-dystrophin constructs to compensate for the absence of functional dystrophin in Duchenne.
Topics: Humans; Muscular Dystrophy, Duchenne; Dystrophin; Male; Middle Aged; Phenotype; Follow-Up Studies; Pedigree
PubMed: 38653179
DOI: 10.1016/j.nmd.2024.04.004 -
Neurogastroenterology and Motility Apr 2024Duchenne's muscular dystrophy (DMD) is a severe type of hereditary, neuromuscular disorder caused by a mutation in the dystrophin gene resulting in the absence or... (Review)
Review
BACKGROUND
Duchenne's muscular dystrophy (DMD) is a severe type of hereditary, neuromuscular disorder caused by a mutation in the dystrophin gene resulting in the absence or production of truncated dystrophin protein. Conventionally, clinical descriptions of the disorder focus principally on striated muscle defects; however, DMD manifestations involving gastrointestinal (GI) smooth muscle have been reported, even if not rigorously studied.
PURPOSE
The objective of the present review is to offer a comprehensive perspective on the existing knowledge concerning GI manifestations in DMD, focusing the attention on evidence in DMD patients and mdx mice. This includes an assessment of symptomatology, etiological pathways, and potential corrective approaches. This paper could provide helpful information about DMD gastrointestinal implications that could serve as a valuable orientation for prospective research endeavors in this field. This manuscript emphasizes the effectiveness of mdx mice, a DMD animal model, in unraveling mechanistic insights and exploring the pathological alterations in the GI tract. The gastrointestinal consequences evident in patients with DMD and the mdx mice models are a significant area of focus for researchers. The exploration of this area in depth could facilitate the development of more efficient therapeutic approaches and improve the well-being of individuals impacted by the condition.
PubMed: 38651673
DOI: 10.1111/nmo.14804 -
American Journal of Physiology. Cell... Jul 2024The dystrophin gene () is recognized for its significance in Duchenne muscular dystrophy (DMD), a lethal and progressive skeletal muscle disease. Some patients with DMD...
The dystrophin gene () is recognized for its significance in Duchenne muscular dystrophy (DMD), a lethal and progressive skeletal muscle disease. Some patients with DMD and model mice with muscular dystrophy (mdx) spontaneously develop various types of tumors, among which rhabdomyosarcoma (RMS) is the most prominent. By contrast, spindle cell sarcoma (SCS) has rarely been reported in patients or mdx mice. In this study, we aimed to use metabolomics to better understand the rarity of SCS development in mdx mice. Gas chromatography-mass spectrometry was used to compare the metabolic profiles of spontaneously developed SCS and RMS tumors from mdx mice, and metabolite supplementation assays and silencing experiments were used to assess the effects of metabolic differences in SCS tumor-derived cells. The levels of 75 metabolites exhibited differences between RMS and SCS, 25 of which were significantly altered. Further characterization revealed downregulation of nonessential amino acids, including alanine, in SCS tumors. Alanine supplementation enhanced the growth, epithelial mesenchymal transition, and invasion of SCS cells. Reduction of intracellular alanine via knockdown of the alanine transporter Slc1a5 reduced the growth of SCS cells. Lower metabolite secretion and reduced proliferation of SCS tumors may explain the lower detection rate of SCS in mdx mice. Targeting of alanine depletion pathways may have potential as a novel treatment strategy. To the best of our knowledge, SCS has rarely been identified in patients with DMD or mdx mice. We observed that RMS and SCS tumors that spontaneously developed from mdx mice with the same genetic background exhibited differences in metabolic secretion. We proposed that, in addition to dystrophin deficiency, the levels of secreted metabolites may play a role in the determination of tumor-type development in a deficient background.
Topics: Animals; Mice, Inbred mdx; Rhabdomyosarcoma; Mice; Sarcoma; Metabolomics; Cell Line, Tumor; Mice, Inbred C57BL; Disease Models, Animal; Cell Proliferation; Male; Muscular Dystrophy, Duchenne; Epithelial-Mesenchymal Transition; Amino Acid Transport System ASC
PubMed: 38646787
DOI: 10.1152/ajpcell.00523.2023 -
Zhonghua Fu Chan Ke Za Zhi Apr 2024To evaluate the diagnostic efficiency of copy number variation sequencing (CNV-seq) to detect the deletion or duplication of DMD gene in prenatal diagnosis. A...
To evaluate the diagnostic efficiency of copy number variation sequencing (CNV-seq) to detect the deletion or duplication of DMD gene in prenatal diagnosis. A retrospective analysis was carried out on the CNV-seq results of 34 544 fetuses diagnosed in the First People's Hospital of Yunnan Province from January 2018 to July 2023. A total of 156 cases of fetuses were collected, including Group 1:125 cases with family history of Duchenne muscular dystrophy or Becker muscular dystrophy (DMD/BMD), and Group 2:31 cases with no family history but a DMD gene deletion or duplication was detected unexpectedly by CNV-seq. Multiplex ligation-dependent probe amplification (MLPA) was used as a standard method to detect the deletion or duplication. Consistency test was carried out basing on the results of CNV-seq and MLPA of all 156 cases. Comparing to MLPA, CNV-seq had a coincidence rate of 92.3% (144/156) for DMD gene deletion or duplication, with a sensitivity and positive predictive value of 88.2%, with a specificity and negative predictive value of 94.3%, a missed detection rate of 3.8%, and a Kappa value of 0.839. CNV-seq missed 4 cases with deletions and 2 with duplications due to involved fragments less than 100 Kb, among 20 cases of deletions and 6 cases of duplications detected by MLPA in Group 1. In Group 2, the deletions and duplications detected by CNV-seq were 42% (13/31) and 58% (18/31), respectively, in which the percentage of duplication was higher than that in Group 1. Among those 18 cases with duplications, 3 cases with duplication locating in exon 42~67 were likely pathogenic; while 9 cases with duplication covering the 5' or 3' end of the DMD gene, containing exon 1 or 79 and with only one breakpoint within the gene, along with the last 6 cases with duplications locating at chrX: 32650635_32910000 detected only by CNV-seq, which might be judged as variants of uncertain significance. CNV-seq has a good efficiency to detect fetal DMD gene deletion or duplication in prenatal diagnosis, while a further verification test by MLPA is recommended. The duplications on chrX: 32650635_32910000, 5' or 3' end of DMD gene detected by CNV-seq should be carefully verified and assessed because those variants appear to be nonpathogenic polymorphisms.
Topics: Humans; DNA Copy Number Variations; Prenatal Diagnosis; Pregnancy; Female; Muscular Dystrophy, Duchenne; Retrospective Studies; Gene Duplication; Gene Deletion; Sensitivity and Specificity; Dystrophin; Fetus; Multiplex Polymerase Chain Reaction
PubMed: 38644274
DOI: 10.3760/cma.j.cn112141-20230919-00107 -
Case Reports in Ophthalmology 2024Duchenne muscular dystrophy (DMD) is an X-linked disorder due to a dystrophin mutation and is the leading cause of muscular dystrophy. DMD presents with characteristic...
Duchenne muscular dystrophy (DMD) is an X-linked disorder due to a dystrophin mutation and is the leading cause of muscular dystrophy. DMD presents with characteristic systemic effects, including severe muscular atrophy, cardiomyopathy, and ocular manifestations. Performing corneal refractive surgeries in patients with DMD raises concerns regarding patient positioning, risk of cataracts, and other comorbid conditions. Published reports of photorefractive keratectomy, laser-assisted in situ keratomileuses, and small incision lenticule extraction are lacking in this population. Here, we discuss a patient being evaluated for a corneal refractive surgery. This article also discusses the current understanding of DMD, known ocular manifestations, and factors to consider when evaluating a patient for potential corrective vision laser surgery.
PubMed: 38638871
DOI: 10.1159/000533579 -
Cureus Mar 2024This case report provides insights into the physiotherapy management of a 12-year-old male with Duchenne muscular dystrophy (DMD). DMD is a devastating genetic disorder...
This case report provides insights into the physiotherapy management of a 12-year-old male with Duchenne muscular dystrophy (DMD). DMD is a devastating genetic disorder characterized by progressive muscle degeneration and weakness. Skeletal muscle degeneration is induced by a genetic disorder. It is a common X-linked condition that causes hypertrophy of the calves and proximal muscular weakness in children. It frequently results in early mortality, wheelchair confinement, and delays in motor development. Physiotherapy interventions aim to optimize functional abilities and quality of life in individuals with DMD. This case report highlights the effectiveness of physiotherapy in managing DMD progression. This study presents a case exhibiting notable clinical symptoms, highlighting the urgency for advanced treatments to combat this debilitating disease. Outcome measures such as body mass index, spirometry, manual muscle testing, and the World Health Organization Quality-of-Life scale are used to report patient progress. The treatment plan was carried out for six weeks, five times a week. Physiotherapy strategies include diet management, stretching and splinting techniques, and pulmonary training. While current treatments focus on symptom management, ongoing research holds promise for the development of more effective therapies to improve outcomes and quality of life for affected individuals. Multidisciplinary care, including neurophysiotherapy rehabilitation, plays a crucial role in managing the symptoms and complications of DMD, emphasizing the importance of comprehensive support for patients and their families. At the end of our rehabilitation, the patient showed significant improvement in the outcome measures.
PubMed: 38629006
DOI: 10.7759/cureus.56315 -
Journal of Veterinary Internal Medicine 2024X-linked dystrophin-deficient muscular dystrophy (MD) is a form of MD caused by variants in the DMD gene. It is a fatal disease characterized by progressive weakness and...
BACKGROUND
X-linked dystrophin-deficient muscular dystrophy (MD) is a form of MD caused by variants in the DMD gene. It is a fatal disease characterized by progressive weakness and degeneration of skeletal muscles.
HYPOTHESIS/OBJECTIVES
Identify deleterious genetic variants in DMD by whole-genome sequencing (WGS) using a next-generation sequencer.
ANIMALS
One MD-affected cat, its parents, and 354 cats from a breeding colony.
METHODS
We compared the WGS data of the affected cat with data available in the National Center for Biotechnology Information database and searched for candidate high-impact variants by in silico analyses. Next, we confirmed the candidate variants by Sanger sequencing using samples from the parents and cats from the breeding colony. We used 2 genome assemblies, the standard felCat9 (from an Abyssinian cat) and the novel AnAms1.0 (from an American Shorthair cat), to evaluate genome assembly differences.
RESULTS
We found 2 novel high-impact variants: a 1-bp deletion in felCat9 and an identical nonsense variant in felCat9 and AnAms1.0. Whole genome and Sanger sequencing validation showed that the deletion in felCat9 was a false positive because of misassembly. Among the 357 cats, the nonsense variant was only found in the affected cat, which indicated it was a de novo variant.
CONCLUSION AND CLINICAL IMPORTANCE
We identified a de novo variant in the affected cat and next-generation sequencing-based genotyping of the whole DMD gene was determined to be necessary for affected cats because the parents of the affected cat did not have the risk variant.
Topics: Cats; Animals; Cat Diseases; Codon, Nonsense; Dystrophin; Male; Muscular Dystrophy, Duchenne; Whole Genome Sequencing; Female; Muscular Dystrophy, Animal
PubMed: 38613437
DOI: 10.1111/jvim.17078 -
Journal of Neuromuscular Diseases 2024Duchenne muscular dystrophy (DMD) is a rare, degenerative, recessive X-linked neuromuscular disease. Mutations in the gene encoding dystrophin lead to the absence of...
BACKGROUND
Duchenne muscular dystrophy (DMD) is a rare, degenerative, recessive X-linked neuromuscular disease. Mutations in the gene encoding dystrophin lead to the absence of functional dystrophin protein. Individuals living with DMD exhibit progressive muscle weakness resulting in loss of ambulation and limb function, respiratory insufficiency, and cardiomyopathy, with multiorgan involvement. Adeno-associated virus vector-mediated gene therapy designed to enable production of functional dystrophin protein is a new therapeutic strategy. Delandistrogene moxeparvovec (Sarepta Therapeutics, Cambridge, MA) is indicated for treatment of ambulatory pediatric patients aged 4 through 5 years with DMD who have an indicated mutation in the DMD gene.
OBJECTIVE
Evidence-based considerations for management of potential adverse events following gene therapy treatment for DMD are lacking in clinical literature. Our goal was to provide interdisciplinary consensus considerations for selected treatment-related adverse events (TRAEs) (vomiting, acute liver injury, myocarditis, and immune-mediated myositis) that may arise following gene therapy dosing with delandistrogene moxeparvovec.
METHODS
An interdisciplinary panel of 12 specialists utilized a modified Delphi process to develop consensus considerations for the evaluation and management of TRAEs reported in delandistrogene moxeparvovec clinical studies. Panelists completed 2 Questionnaires prior to gathering for an in-person discussion. Consensus was defined as a majority (≥58% ; 7/12) of panelists either agreeing or disagreeing.
RESULTS
Panelists agreed that the choice of baseline assessments should be informed by individual clinical indications, the treating provider's judgment, and prescribing information. Corticosteroid dosing for treatment of TRAEs should be optimized by considering individual risk versus benefit for each indication. In all cases involving patients with a confirmed TRAE, consultations with appropriate specialists were suggested.
CONCLUSIONS
The Delphi Panel established consensus considerations for the evaluation and management of potential TRAEs for patients receiving delandistrogene moxeparvovec, including vomiting, acute liver injury, myocarditis, and immune-mediated myositis.
Topics: Humans; Muscular Dystrophy, Duchenne; Genetic Therapy; Delphi Technique; Myocarditis; Child, Preschool; Biological Products; Recombinant Fusion Proteins
PubMed: 38607761
DOI: 10.3233/JND-230185 -
Cells Mar 2024Duchenne muscular dystrophy (DMD) is a genetic progressive muscle-wasting disorder that leads to rapid loss of mobility and premature death. The absence of functional... (Review)
Review
Duchenne muscular dystrophy (DMD) is a genetic progressive muscle-wasting disorder that leads to rapid loss of mobility and premature death. The absence of functional dystrophin in DMD patients reduces sarcolemma stiffness and increases contraction damage, triggering a cascade of events leading to muscle cell degeneration, chronic inflammation, and deposition of fibrotic and adipose tissue. Efforts in the last decade have led to the clinical approval of novel drugs for DMD that aim to restore dystrophin function. However, combination therapies able to restore dystrophin expression and target the myriad of cellular events found impaired in dystrophic muscle are desirable. Muscles are higher energy consumers susceptible to mitochondrial defects. Mitochondria generate a significant source of reactive oxygen species (ROS), and they are, in turn, sensitive to proper redox balance. In both DMD patients and animal models there is compelling evidence that mitochondrial impairments have a key role in the failure of energy homeostasis. Here, we highlighted the main aspects of mitochondrial dysfunction and oxidative stress in DMD and discussed the recent findings linked to mitochondria/ROS-targeted molecules as a therapeutic approach. In this respect, dual targeting of both mitochondria and redox homeostasis emerges as a potential clinical option in DMD.
Topics: Animals; Humans; Muscular Dystrophy, Duchenne; Dystrophin; Reactive Oxygen Species; Muscle, Skeletal; Mitochondria
PubMed: 38607013
DOI: 10.3390/cells13070574 -
Disease Models & Mechanisms Apr 2024Duchenne muscular dystrophy (DMD) is a devastating monogenic skeletal muscle-wasting disorder. Although many pharmacological and genetic interventions have been reported...
Duchenne muscular dystrophy (DMD) is a devastating monogenic skeletal muscle-wasting disorder. Although many pharmacological and genetic interventions have been reported in preclinical studies, few have progressed to clinical trials with meaningful benefit. Identifying therapeutic potential can be limited by availability of suitable preclinical mouse models. More rigorous testing across models with varied background strains and mutations can identify treatments for clinical success. Here, we report the generation of a DMD mouse model with a CRISPR-induced deletion within exon 62 of the dystrophin gene (Dmd) and the first generated in BALB/c mice. Analysis of mice at 3, 6 and 12 months of age confirmed loss of expression of the dystrophin protein isoform Dp427 and resultant dystrophic pathology in limb muscles and the diaphragm, with evidence of centrally nucleated fibers, increased inflammatory markers and fibrosis, progressive decline in muscle function, and compromised trabecular bone development. The BALB/c.mdx62 mouse is a novel model of DMD with associated variations in the immune response and muscle phenotype, compared with those of existing models. It represents an important addition to the preclinical model toolbox for developing therapeutic strategies.
Topics: Animals; Muscular Dystrophy, Duchenne; Disease Models, Animal; Mice, Inbred BALB C; Dystrophin; Muscle, Skeletal; Mice, Inbred mdx; Mice; Exons; Male; Fibrosis; Phenotype
PubMed: 38602028
DOI: 10.1242/dmm.050502