-
Acta Myologica : Myopathies and... Dec 2007Mutations in the genes for nuclear envelope proteins of emerin (EMD) and lamin A/C (LMNA) are known to cause Emery-Dreifuss muscular dystrophy (EDMD) and limb girdle... (Review)
Review
Mutations in the genes for nuclear envelope proteins of emerin (EMD) and lamin A/C (LMNA) are known to cause Emery-Dreifuss muscular dystrophy (EDMD) and limb girdle muscular dystrophy (LGMD). We compared clinical features of the muscular dystrophy patients associated with mutations in EMD (emerinopathy) and LMNA (laminopathy) in our series. The incidence of laminopathy was slightly higher than that of emerinopathy. The age at onset of the disease in emerinopathy was variable and significantly older than in laminopathy. The initial symptom of emerinopathy was also variable, whereas nearly all laminopathy patients presented initially with muscle weakness. Calf hypertrophy was often seen in laminopathy, underscoring the importance of mutation screening for LMNA in childhood muscular dystrophy with calf hypertrophy. The clinical spectrum of emerinopathy is actually wider than previously known including EDMD, LGMD, conduction defects with minimal muscle/joint involvement, and their intermittent forms. Pathologically, no marked difference was observed between emerinopathy and laminopathy. Increased number and variation in size of myonuclei were detected. More precise observations using electron microscopy is warranted to characterize the detailed nuclear changes in nuclear envelopathy.
Topics: DNA; Humans; Japan; Lamin Type A; Lipodystrophy; Membrane Proteins; Muscular Dystrophies; Mutation; Nuclear Envelope; Nuclear Proteins; Polymerase Chain Reaction; Prevalence
PubMed: 18646565
DOI: No ID Found -
Biochimica Et Biophysica Acta Apr 2015Muscular dystrophies are heterogeneous genetic disorders that share progressive muscle wasting. This may generate partial impairment of motility as well as a dramatic... (Review)
Review
Muscular dystrophies are heterogeneous genetic disorders that share progressive muscle wasting. This may generate partial impairment of motility as well as a dramatic and fatal course. Less than 30 years ago, the identification of the genetic basis of Duchenne muscular dystrophy opened a new era. An explosion of new information on the mechanisms of disease was witnessed, with many thousands of publications and the characterization of dozens of other genetic forms. Genes mutated in muscular dystrophies encode proteins of the plasma membrane and extracellular matrix, several of which are part of the dystrophin-associated complex. Other gene products localize at the sarcomere and Z band, or are nuclear membrane components. In the present review, we focus on muscular dystrophies caused by defects that affect the sarcolemmal and sub-sarcolemmal proteins. We summarize the nature of each disease, the genetic cause, and the pathogenic pathways that may suggest future treatment options. We examine X-linked Duchenne and Becker muscular dystrophies and the autosomal recessive limb-girdle muscular dystrophies caused by mutations in genes encoding sarcolemmal proteins. The mechanism of muscle damage is reviewed starting from disarray of the shock-absorbing dystrophin-associated complex at the sarcolemma and activation of inflammatory response up to the final stages of fibrosis. We trace only a part of the biochemical, physiopathological and clinical aspects of muscular dystrophy to avoid a lengthy list of different and conflicting observations. We attempt to provide a critical synthesis of what we consider important aspects to better understand the disease. In our opinion, it is becoming ever more important to go back to the bedside to validate and then translate each proposed mechanism. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.
Topics: Animals; Genetic Diseases, Inborn; Humans; Muscle Proteins; Muscular Dystrophies; Sarcolemma
PubMed: 25086336
DOI: 10.1016/j.bbadis.2014.07.023 -
Pediatric Neurology Nov 2014Gene therapy for the muscular dystrophies has evolved as a promising treatment for this progressive group of disorders. Although corticosteroids and/or supportive... (Review)
Review
Gene therapy for the muscular dystrophies has evolved as a promising treatment for this progressive group of disorders. Although corticosteroids and/or supportive treatments remain the standard of care for Duchenne muscular dystrophy, loss of ambulation, respiratory failure, and compromised cardiac function is the inevitable outcome. Recent developments in genetically mediated therapies have allowed for personalized treatments that strategically target individual muscular dystrophy subtypes based on disease pathomechanism and phenotype. In this review, we highlight the therapeutic progress with emphasis on evolving preclinical data and our own experience in completed clinical trials and others currently underway. We also discuss the lessons we have learned along the way and the strategies developed to overcome limitations and obstacles in this field.
Topics: Animals; Genetic Therapy; Humans; Muscular Dystrophies
PubMed: 25439576
DOI: 10.1016/j.pediatrneurol.2014.08.002 -
Nature Medicine Oct 2019The essential product of the Duchenne muscular dystrophy (DMD) gene is dystrophin, a rod-like protein that protects striated myocytes from contraction-induced injury....
The essential product of the Duchenne muscular dystrophy (DMD) gene is dystrophin, a rod-like protein that protects striated myocytes from contraction-induced injury. Dystrophin-related protein (or utrophin) retains most of the structural and protein binding elements of dystrophin. Importantly, normal thymic expression in DMD patients should protect utrophin by central immunologic tolerance. We designed a codon-optimized, synthetic transgene encoding a miniaturized utrophin (µUtro), deliverable by adeno-associated virus (AAV) vectors. Here, we show that µUtro is a highly functional, non-immunogenic substitute for dystrophin, preventing the most deleterious histological and physiological aspects of muscular dystrophy in small and large animal models. Following systemic administration of an AAV-µUtro to neonatal dystrophin-deficient mdx mice, histological and biochemical markers of myonecrosis and regeneration are completely suppressed throughout growth to adult weight. In the dystrophin-deficient golden retriever model, µUtro non-toxically prevented myonecrosis, even in the most powerful muscles. In a stringent test of immunogenicity, focal expression of µUtro in the deletional-null German shorthaired pointer model produced no evidence of cell-mediated immunity, in contrast to the robust T cell response against similarly constructed µDystrophin (µDystro). These findings support a model in which utrophin-derived therapies might be used to treat clinical dystrophin deficiency, with a favorable immunologic profile and preserved function in the face of extreme miniaturization.
Topics: Animals; Dependovirus; Disease Models, Animal; Dogs; Dystrophin; Genetic Therapy; Humans; Mice; Mice, Inbred mdx; Muscle Contraction; Muscle, Skeletal; Muscular Dystrophies; Muscular Dystrophy, Animal; Muscular Dystrophy, Duchenne; Transgenes; Utrophin
PubMed: 31591596
DOI: 10.1038/s41591-019-0594-0 -
Human Gene Therapy Oct 2018In the last few years, significant advances have occurred in the preclinical and clinical work toward gene and cell therapy for muscular dystrophy. At the time of this... (Review)
Review
In the last few years, significant advances have occurred in the preclinical and clinical work toward gene and cell therapy for muscular dystrophy. At the time of this writing, several trials are ongoing and more are expected to start. It is thus a time of expectation, even though many hurdles remain and it is unclear whether they will be overcome with current strategies or if further improvements will be necessary.
Topics: Animals; Cell- and Tissue-Based Therapy; Gene Expression; Gene Expression Regulation; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Muscular Dystrophies; Organ Specificity; Transduction, Genetic; Transgenes
PubMed: 30132372
DOI: 10.1089/hum.2018.151 -
Journal of Neuromuscular Diseases 2017Muscular dystrophy is a group of genetic disorders characterized by progressive muscle weakness. In the early 2000s, a new classification of muscular dystrophy,... (Review)
Review
Muscular dystrophy is a group of genetic disorders characterized by progressive muscle weakness. In the early 2000s, a new classification of muscular dystrophy, dystroglycanopathy, was established. Dystroglycanopathy often associates with abnormalities in the central nervous system. Currently, at least eighteen genes have been identified that are responsible for dystroglycanopathy, and despite its genetic heterogeneity, its common biochemical feature is abnormal glycosylation of alpha-dystroglycan. Abnormal glycosylation of alpha-dystroglycan reduces its binding activities to ligand proteins, including laminins. In just the last few years, remarkable progress has been made in determining the sugar chain structures and gene functions associated with dystroglycanopathy. The normal sugar chain contains tandem structures of ribitol-phosphate, a pentose alcohol that was previously unknown in humans. The dystroglycanopathy genes fukutin, fukutin-related protein (FKRP), and isoprenoid synthase domain-containing protein (ISPD) encode essential enzymes for the synthesis of this structure: fukutin and FKRP transfer ribitol-phosphate onto sugar chains of alpha-dystroglycan, and ISPD synthesizes CDP-ribitol, a donor substrate for fukutin and FKRP. These findings resolved long-standing questions and established a disease subgroup that is ribitol-phosphate deficient, which describes a large population of dystroglycanopathy patients. Here, we review the history of dystroglycanopathy, the properties of the sugar chain structure of alpha-dystroglycan, dystroglycanopathy gene functions, and therapeutic strategies.
Topics: Animals; Dystroglycans; Humans; Muscular Dystrophies; Protein Processing, Post-Translational
PubMed: 29081423
DOI: 10.3233/JND-170255 -
International Journal of Molecular... Apr 2022Although they are considered rare disorders, muscular dystrophies have a strong impact on people's health. Increased disease severity with age, frequently accompanied by... (Review)
Review
Although they are considered rare disorders, muscular dystrophies have a strong impact on people's health. Increased disease severity with age, frequently accompanied by the loss of ability to walk in some people, and the lack of treatment, have directed the researchers towards the development of more effective therapeutic strategies aimed to improve the quality of life and life expectancy, slow down the progression, and delay the onset or convert a severe phenotype into a milder one. Improved understanding of the complex pathology of these diseases together with the tremendous advances in molecular biology technologies has led to personalized therapeutic procedures. Different approaches that are currently under extensive investigation require more efficient, sensitive, and less invasive methods. Due to its remarkable analytical sensitivity, droplet digital PCR has become a promising tool for accurate measurement of biomarkers that monitor disease progression and quantification of various therapeutic efficiency and can be considered a tool for non-invasive prenatal diagnosis and newborn screening. Here, we summarize the recent applications of droplet digital PCR in muscular dystrophy research and discuss the factors that should be considered to get the best performance with this technology.
Topics: Female; Humans; Muscular Dystrophies; Muscular Dystrophy, Duchenne; Polymerase Chain Reaction; Pregnancy; Quality of Life; Technology
PubMed: 35563191
DOI: 10.3390/ijms23094802 -
Journal of Neuromuscular Diseases 2019The recent availability and development of mutant and transgenic zebrafish strains that model human muscular dystrophies has created new research opportunities for... (Review)
Review
The recent availability and development of mutant and transgenic zebrafish strains that model human muscular dystrophies has created new research opportunities for therapeutic development. Not only do these models mimic many pathological aspects of human dystrophies, but their small size, large clutch sizes, rapid ex utero development, body transparency, and genetic tractability enable research approaches that would be inconceivable with mammalian model systems. Here we discuss the use of zebrafish models of muscular dystrophy to rapidly screen hundreds to thousands of bioactive compounds in order to identify novel therapeutic candidates that modulate pathologic phenotypes. We review the justification and rationale behind this unbiased approach, including how zebrafish screens have identified FDA-approved drugs that are candidates for treating Duchenne and limb girdle muscular dystrophies. Not only can these drugs be re-purposed for treating dystrophies in a fraction of the time and cost of new drug development, but their identification has revealed novel, unexpected directions for future therapy development. Phenotype-driven zebrafish drug screens are an important compliment to the more established mammalian, target-based approaches for rapidly developing and validating therapeutics for muscular dystrophies.
Topics: Animals; Disease Models, Animal; Drug Discovery; Drug Evaluation, Preclinical; Muscular Dystrophies; Muscular Dystrophy, Animal; Phenotype; Zebrafish
PubMed: 31282429
DOI: 10.3233/JND-190389 -
The FEBS Journal Sep 2013The muscular dystrophies comprise more than 30 clinical disorders that are characterized by progressive skeletal muscle wasting and degeneration. Although the genetic... (Review)
Review
The muscular dystrophies comprise more than 30 clinical disorders that are characterized by progressive skeletal muscle wasting and degeneration. Although the genetic basis for many of these disorders has been identified, the exact mechanism for pathogenesis generally remains unknown. It is considered that disturbed levels of reactive oxygen species (ROS) contribute to the pathology of many muscular dystrophies. Reactive oxygen species and oxidative stress may cause cellular damage by directly and irreversibly damaging macromolecules such as proteins, membrane lipids and DNA; another major cellular consequence of reactive oxygen species is the reversible modification of protein thiol side chains that may affect many aspects of molecular function. Irreversible oxidative damage of protein and lipids has been widely studied in Duchenne muscular dystrophy, and we have recently identified increased protein thiol oxidation in dystrophic muscles of the mdx mouse model for Duchenne muscular dystrophy. This review evaluates the role of elevated oxidative stress in Duchenne muscular dystrophy and other forms of muscular dystrophies, and presents new data that show significantly increased protein thiol oxidation and high levels of lipofuscin (a measure of cumulative oxidative damage) in dysferlin-deficient muscles of A/J mice at various ages. The significance of this elevated oxidative stress and high levels of reversible thiol oxidation, but minimal myofibre necrosis, is discussed in the context of the disease mechanism for dysferlinopathies, and compared with the situation for dystrophin-deficient mdx mice.
Topics: Animals; Dysferlin; Humans; Membrane Proteins; Mice; Mice, Inbred mdx; Mice, Knockout; Muscular Dystrophies; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; Sulfhydryl Compounds
PubMed: 23332128
DOI: 10.1111/febs.12142 -
Acta Myologica : Myopathies and... Oct 2016Although the presence of cognitive deficits in Duchenne muscular dystrophy or myotonic dystrophy DM1 is well established in view of brain-specific expression of affected... (Review)
Review
Although the presence of cognitive deficits in Duchenne muscular dystrophy or myotonic dystrophy DM1 is well established in view of brain-specific expression of affected muscle proteins, in other neuromuscular disorders, such as congenital myopathies and limb-girdle muscular dystrophies, cognitive profiles are poorly defined. Also, there are limited characterization of the cognitive profile of children with congenital muscular dystrophies, notwithstanding the presence of cerebral abnormality in some forms, and in spinal muscular atrophies, with the exception of distal spinal muscular atrophy (such as the DYN1CH1- associated form). Starting from the Duchenne muscular dystrophy, which may be considered a kind of paradigm for the co-occurrence of learning disabilities in the contest of a progressive muscular involvement, the findings of neuropsychological (or cognitive) dysfunctions in several forms of neuromuscular diseases will be examined and reviewed.
Topics: Humans; Intellectual Disability; Learning Disabilities; Muscular Diseases; Muscular Dystrophies; Muscular Dystrophies, Limb-Girdle; Muscular Dystrophy, Duchenne; Myotonic Dystrophy; Spinal Muscular Atrophies of Childhood
PubMed: 28344438
DOI: No ID Found