Basic genetics and patterns of inheritance
Hung N. Winn, Frank A. Chervenak, Roberto Romero in Clinical Maternal-Fetal Medicine Online, 2021
Finally, methods for manipulating the expression or splicing of mutant genes are being investigated. Drugs that induce read-through of a stop codon during translation of a mutant gene can result in increased expression of full-length protein. This approach has been tried experimentally with cystic fibrosis and Duchenne muscular dystrophy. In other studies, antisense oligonucleotides have been used to induce skipping during mRNA splicing of exons that contain mutations; this approach will produce a smaller protein, but one that might retain some residual function. This method of therapy has been investigated for Duchenne muscular dystrophy. It is anticipated that more such opportunities will become available in the future for targeted therapy of the disease manifestations of genetic disorders.
Neurology and neurosurgery
Jagdish M. Gupta, John Beveridge in MCQs in Paediatrics, 2020
12.22. Which of the following statements is/are correct of neuromuscular diseases?The Duchenne and Becker types of muscular dystrophy exhibit the same mode of inheritance.Visible fasciculations are characteristic of the muscular dystrophies.Distal distribution of weakness and sensory loss is characteristic of peripheral neuropathies.Nerve conduction velocity is slowed in spinal muscular atrophy.The serum creatine kinase level is always elevated in the early stages of Duchenne type muscular dystrophy.
Neuromuscular disorders
Ashley W. Blom, David Warwick, Michael R. Whitehouse in Apley and Solomon’s System of Orthopaedics and Trauma, 2017
The muscular dystrophies are a group of over 50 rare inherited disorders characterized by progressive muscle weakness and wasting. Pathological changes include malformation of muscle fibres, death of musde cells and replacement of muscle by fibrous tissue and fat. Historically, they have been grouped according to their various inheritance patterns, age of onset, distribution of affected musculature and severity of the muscle weakness. The following are those most likely to be encountered in orthopaedic practice: Duchenne muscular dystrophy (DMD) — a severe, generalized sex-linked disorder affecting only boys in early childhood.Becker muscular dystrophy — is similar to DMD but less severe, starts somewhat later and progresses more slowly.Limb girdle dystrophies — a mixed group, usually of autosomal recessive inheritance, with more localized changes, affecting boys and girls in later childhood.Facioscapulohumeral dystrophy — an autosomal dominant condition of variable severity, usually appearing in early adulthood.
Optimizing assays of zebrafish larvae swimming performance for drug discovery
Published in Expert Opinion on Drug Discovery, 2023
Jeffrey J. Widrick, Matthias R. Lambert, Louis M. Kunkel, Alan H. Beggs
The touch-evoked escape response is normally a qualitative method that relies upon human vision and discretion to judge whether larval swimming velocity and/or displacement is impaired. Some investigators have modified the touch-evoked escape response in order to make the approach more quantitative in nature. For example, by placing a transparent plastic sheet printed with concentric rings under the dish holding the larvae, initiating the escape response with the larvae centered in the inner most ring, and recording the response on video, the time required by the larvae to swim to the outermost ring could be determined [69]. This approach was used to evaluate a novel drug treatment for muscular dystrophy. Another method for quantifying escape response swimming is to record the movement using high-speed videography to then calculate maximum acceleration of larvae after the touch stimulus [48]. This approach was able to differentiate a nemaline myopathy model from wild type larvae.
Shaping the future from the small scale: dry powder inhalation of CRISPR-Cas9 lipid nanoparticles for the treatment of lung diseases
Published in Expert Opinion on Drug Delivery, 2023
Simone P. Carneiro, Antonietta Greco, Enrica Chiesa, Ida Genta, Olivia M. Merkel
Cheng and colleagues [105] designed Selective Organ Targeting (SORT) LNPs for CRISPR-Cas9 mRNA and sgRNA delivery aiming to reach the lungs, spleen, and liver and selectively modify therapeutically relevant cells such as T cells, B cells, and hepatocytes. Kenjo and colleagues [54] studied a new therapeutic approach for the treatment of Duchenne muscular dystrophy. They developed pH-dependent ionizable lipids with three hydrophobic tails employed to formulate LNPs for the transient delivery of Cas9 mRNA and sgRNA to the skeletal muscle tissues in vivo. This therapeutic approach allowed the repeated injection of LNPs to cover all skeletal muscle. Moreover, investigating the limb perfusion injection method (interesting for the targeting of multiple skeletal muscle groups), LNPs were administered in smaller volumes, compared to conventional hydrodynamic injection, due to the enhanced release of CRISPR-Cas9 from LNPs. Considering the treatment of patients, the injection of small volumes is a huge advantage to avoid compartment syndrome. In comparison to approved antisense oligonucleotide drugs, the effect of LNP-delivered CRISPR-Cas studied by Kenjo was maintained over months. Interestingly, the treated cells did not show mutagenesis overcoming the off-target limitation; however, different candidate DNA cleavage sites were identified.
Proteomic profiling of carbonic anhydrase CA3 in skeletal muscle
Published in Expert Review of Proteomics, 2021
Paul Dowling, Stephen Gargan, Margit Zweyer, Hemmen Sabir, Dieter Swandulla, Kay Ohlendieck
The muscular dystrophies are a large group of inherited disorders that primarily affect skeletal muscles [114]. X-linked muscular dystrophies are due to mutations in the DMD gene that encodes a variety of tissue-specific isoforms of the protein named dystrophin. Loss of the full-length dystrophin isoform Dp427-M causes the Duchenne type of muscular dystrophy, which is a highly progressive muscle wasting disorder of early childhood [115]. Dystrophin exists in skeletal muscles in a tight linkage with several sarcolemmal glycoproteins [116]. The core dystrophin-glycoprotein complex interacts with the basal lamina on the outside of muscle fibers and the actin membrane cytoskeleton on the inside of contractile cells forming a supramolecular membrane assembly. The dystrophin complex was shown to be involved in the integration of fiber stability, the transmission of lateral force to the extracellular matrix, the organization of the cytoskeletal network and cellular signaling events in the peripheral membrane system of skeletal muscle fibers [116].
Related Knowledge Centers
- Becker Muscular Dystrophy
- Mutation
- Neuromuscular Disease
- Skeletal Muscle
- Duchenne Muscular Dystrophy
- Body
- Facioscapulohumeral Muscular Dystrophy
- Myotonic Dystrophy
- Limb–Girdle Muscular Dystrophy
- Congenital Muscular Dystrophy