A genome-wide association analysis of loss of ambulation in dystrophinopathy patients suggests multiple candidate modifiers of disease severity.

The major determinant of disease severity in Duchenne muscular dystrophy (DMD) or milder Becker muscular dystrophy (BMD) is whether the dystrophin gene (DMD) mutation truncates the mRNA reading frame or allows expression of a partially functional protein. However, even in the complete absence of dystrophin, variability in disease severity is observed, and candidate gene studies have implicated several genes as modifiers. Here we present the largest genome-wide search to date for loci influencing severity in N = 419 DMD patients.

Assessment of Extracellular Volume Fraction in Becker Muscular Dystrophy by Using MR Fingerprinting.

Background Quantitative MRI is increasingly proposed in clinical trials related to dystrophinopathies, including Becker muscular dystrophy (BMD). Purpose To establish the sensitivity of extracellular volume fraction (ECV) quantification using an MR fingerprinting sequence with water and fat separation as a quantitative imaging biomarker of skeletal muscle tissue alterations in BMD compared with fat fraction (FF) and water relaxation time quantification. Materials and Methods In this prospective study, study participants with BMD and healthy volunteers were included from April 2018 until October 2022 ( identifier NCT02020954).

Epilepsy Characteristics in Duchenne and Becker Muscular Dystrophies.

Dystrophinopathies cover a spectrum of X-linked muscle disorders including Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and cardiomyopathy due to pathogenic variants in the gene. Neuropsychiatric manifestations occur approximately in one-third of patients with dystrophinopathy. Epilepsy has been described.

The P2X7 purinoceptor in pathogenesis and treatment of dystrophino- and sarcoglycanopathies.

Dystrophinopathy and sarcoglycanopathies are incurable diseases caused by mutations in the genes encoding dystrophin or members of the dystrophin associated protein complex (DAPC). Restoration of the missing dystrophin or sarcoglycans via genetic approaches is complicated by the downsides of personalised medicines and immune responses against re-expressed proteins. Thus, the targeting of disease mechanisms downstream from the mutant protein has a strong translational potential.

CB2 Receptor as Emerging Anti-Inflammatory Target in Duchenne Muscular Dystrophy.

Duchenne Muscular Dystrophy (DMD) is a very severe X-linked dystrophinopathy. It is due to a mutation in the DMD gene and causes muscular degeneration in conjunction with several secondary co-morbidities, such cardiomyopathy and respiratory failure. DMD is characterized by a chronic inflammatory state, and corticosteroids represent the main therapy for these patients.

Spectrum of Genetic Variants in the Dystrophin Gene: A Single Centre Retrospective Analysis of 750 Duchenne and Becker Patients from Southern Italy.

Dystrophinopathies are X-linked recessive muscle disorders caused by mutations in the dystrophin () gene that include deletions, duplications, and point mutations. Correct diagnosis is important for providing adequate patient care and family planning, especially at this time when mutation-specific therapies are available. We report a large single-centre study on the spectrum of gene variants observed in 750 patients analyzed for suspected Duchenne (DMD) or Becker (BMD) muscular dystrophy, over the past 30 years, at the Cardiomyology and Medical Genetics of the University of Campania.

Phosphorylation alters the mechanical stiffness of a model fragment of the dystrophin homologue utrophin.

Duchenne muscular dystrophy is a lethal muscle wasting disease caused by the absence of the protein dystrophin. Utrophin is a dystrophin homologue currently under investigation as a protein replacement therapy for Duchenne muscular dystrophy. Dystrophin is hypothesized to function as a molecular shock absorber that mechanically stabilizes the sarcolemma.

Protection of dystrophic muscle cells using Idebenone correlates with the interplay between calcium, oxidative stress and inflammation.

There is strong cross-talk between abnormal intracellular calcium concentration, high levels of reactive oxygen species (ROS) and an exacerbated inflammatory process in the dystrophic muscles of mdx mice, the experimental model of Duchenne muscular dystrophy (DMD). In this study, we investigated effects of Idebenone, a potent anti-oxidant, on oxidative stress markers, the anti-oxidant defence system, intracellular calcium concentrations and the inflammatory process in primary dystrophic muscle cells from mdx mice. Dystrophic muscle cells were treated with Idebenone (0.

Dystrophin Genotype and Risk of Neuropsychiatric Disorders in Dystrophinopathies: A Systematic Review and Meta-Analysis.

Background: Dystrophinopathies are associated with neuropsychiatric disorders due to alterations in dystrophin/DMD expression.

Objective: The objective was to estimate the association of developmental disorders, autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), depression, anxiety disorders, and obsessive-compulsive disorder with the dystrophin/DMD genotype in population with dystrophinopathies.

Methods: Systematic searches of Medline, Scopus, Web of Science, and Cochrane Library were performed from inception to September 2022.

Long-term outcomes for females with early-onset dystrophinopathy.

Aim: To study long-term disease course for females with early-onset dystrophinopathy, including common (female) symptoms, challenges in social participation, the need for care, and current healthcare management to support guideline development.

Method: Twelve females with early-onset dystrophinopathy were followed for a median period of more than 17 years (range 1-36).

Results: One patient died owing to end-stage cardiac failure.

Histological Methods to Assess Skeletal Muscle Degeneration and Regeneration in Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a progressive disease caused by the loss of function of the protein dystrophin. This protein contributes to the stabilisation of striated cells during contraction, as it anchors the cytoskeleton with components of the extracellular matrix through the dystrophin-associated protein complex (DAPC). Moreover, absence of the functional protein affects the expression and function of proteins within the DAPC, leading to molecular events responsible for myofibre damage, muscle weakening, disability and, eventually, premature death.

The Dystrophinopathies.

Purpose Of Review: This article reviews the history, epidemiology, genetics, clinical presentation, multidisciplinary management, and established and emerging therapies for the dystrophinopathies.

Recent Findings: The multidisciplinary care of individuals with dystrophinopathies continues to improve in many ways, including early surveillance and implementation of respiratory, cardiac, and orthopedic health management. The era of genetic therapeutics has altered the treatment landscape in neuromuscular disorders, including the dystrophinopathies.

Drug-refractory Heart Failure in Female Carrier of Duchenne Muscular Dystrophy: A Case of X-linked Dilated Cardiomyopathy.

A 56-year-old woman was referred to our hospital for the further evaluation of drug-refractory heart failure with a reduced ejection fraction. A family history interview revealed that men in her family had died of Duchenne muscular dystrophy (DMD), whereas she had no skeletal muscle disorder. Myocardial histopathology revealed a reduced dystrophin expression in the cardiomyocyte membrane, and a dystrophin (DMD) gene analysis identified a duplication in exon 8-9 on Xp21, suggesting that she had a cardiac-specific phenotype of dystrophinopathy, i.

Global prevalence of intellectual developmental disorder in dystrophinopathies: A systematic review and meta-analysis.

Aim: To estimate the global prevalence of intellectual developmental disorder (IDD) and the IDD prevalence-genotype association in Becker muscular dystrophy (BMD) or Duchenne muscular dystrophy (DMD) according to the affected isoforms of the DMD gene: Dp427, Dp140, Dp71.

Method: Systematic searches in MEDLINE, Scopus, Web of Science, and the Cochrane Library were conducted from inception of each database to March 2022. Observational studies that determined the prevalence of IDD in the population with BMD or DMD were included.

Identification of Biallelic dystrophin gene variants during maternal carrier testing for Becker muscular dystrophy and review of the DMD exon 49-51 deletion phenotype.

Background: Dystrophinopathies are X-linked recessive conditions caused by pathogenic variants in the dystrophin (DMD) gene. In a family that included two boys with Becker muscular dystrophy (BMD) due to a DMD deletion of exons 45-47, maternal carrier testing unexpectedly identified biallelic DMD deletions of exons 45-47 and 49-51.

Methods: The patient's mild phenotype in the setting of biallelic DMD variants prompted further investigation of the exon 49-51 deletion in particular, via literature review and retrospective chart review of patients who have been evaluated in our institution's comprehensive neuromuscular center and/or diagnosed in our clinical genetic testing laboratory.

Wechsler Scale Intelligence Testing in Males with Dystrophinopathies: A Review and Meta-Analysis.

Background: Intelligence scores in males with Duchenne Muscular Dystrophy (DMD) and Becker Muscular Dystrophy (BMD) remain a major issue in clinical practice. We performed a literature review and meta-analysis to further delineate the intellectual functioning of dystrophinopathies.

Method: Published, peer-reviewed articles assessing intelligence, using Wechsler Scales, of males with DMD or BMD were searched from 1960 to 2022.

Myalgic Becker Muscular Dystrophy Due to an Exon 15 Point Mutation: Case Series and Literature Review.

Dystrophinopathies result from mutations to the DMD gene. We report 5 boys in 3 families with heterogenous phenotypes due to a point mutation in the DMD gene: a hemizygous tyrosine-to-cysteine change in exon 15 (c.1724T>C) resulting in an amino acid substitution of leucine to proline at codon 575.

Morpholino-Mediated Exons 28-29 Skipping of Dysferlin and Characterization of Multiexon-skipped Dysferlin using RT-PCR, Immunoblotting, and Membrane Wounding Assay.

Dysferlinopathies are a group of disabling muscular dystrophies  that includes limb girdle muscular dystrophy type 2B (LGMD2B), Miyoshi myopathy, and distal myopathy with anterior tibial onset (DMAT) as the main phenotypes. They are associated with molecular defects in DYSF, which encodes dysferlin, a key player in sarcolemmal homeostasis. Previous investigations have suggested that exon skipping may be a promising therapy for many patients with dysferlinopathies.

Overview of Neuromuscular Disorder Molecular Diagnostic Experience for the Population of Latvia.

Background And Objectives: Genetic testing has become an integral part of health care, allowing the confirmation of thousands of hereditary diseases, including neuromuscular disorders (NMDs). The reported average prevalence of individual inherited NMDs is 3.7-4.