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Muscular Dystrophy Presentation - Neuroscience Class.pptx
- 1. MUSCULAR DYSTROPHY Intan Dwikarlina Principle of Neuroscience Class
- 3. Contractile-soft tissue Muscle Dystrophy Disorder in which an organ or tissue of the body wastes away.
- 4. What is Muscular Dystrophy? Muscular Dystrophy (MD) is a a group of inherited genetic conditions that gradually cause muscle wasting and leading to muscle weakness and motoric disability. Definition Muscular Dystrophy is a progressive condition. This condition often begins by only affecting a particular group of muscles, before affecting the muscles more widely. NHS. Muscular Dystrophy. Cited on September 29th 2023 [https://www.nhs.uk/conditions/muscular-dystrophy]
- 5. The cause of Muscular Dystrophy Etiology Genes inherited from a person's parents Changes of genes structures (Genes mutation) Changes in the muscle fibres interfere with the muscles' ability to function and increase disability. NHS. Muscular Dystrophy. Cited on September 29th 2023 [https://www.nhs.uk/conditions/muscular-dystrophy]
- 6. TYPES OF MUSCULAR DYSTROPHY Duchenne MD Becker MD Fascioscapulahumeral MD Emery-Dreifuss MD Limb-girdle MD Distal MD Oculopharyngeal MD A B C D E F Emery AE. The muscular dystrophies. The Lancet. 2002 Feb 23;359(9307):687-95. Types
- 8. Duchenne MD is an X-Linked Disorder, caused by mutations in DMD gene that eliminate the production of dystrophin in muscle. DMD prevent the production of the muscle isoform of dystrophin (Dp427m). Mutations in DMD can also cause Becker MD – a milder disease with later onset and slower progression than Duchenne. ABOUT Duchenne MD Duan D, Goemans N, Takeda SI, Mercuri E, Aartsma-Rus A. Duchenne muscular dystrophy. Nature Reviews Disease Primers. 2021 Feb 18;7(1):13.
- 9. Mutations in DMD can also cause Becker MD – a milder disease with later onset and slower progression than Duchenne. Duan D, Goemans N, Takeda SI, Mercuri E, Aartsma-Rus A. Duchenne muscular dystrophy. Nature Reviews Disease Primers. 2021 Feb 18;7(1):13.
- 10. Overview: Muscle ● Myofiber: functional unit of muscle ● Sarcolemma: muscle cell membrane ● Sarcoplasm: cytoplasm of myofiber ● Sarcomere: contracting unit (actin- containing thin filaments & myosin- containing thick filaments) ● Costamere: sub-membranous, Z-line associated structures found in striated muscle ● Myofibril: protein to connect to the sarcolemma along the Z-disks Sarcolemma should firmly attached to the basal lamina, which consists of ECM proteins. Failure to attach properly results in sarcolemmal disruption, which is the predominant underlying cause of several forms of muscular dystrophies. Rahimov F, Kunkel LM. Cellular and molecular mechanisms underlying muscular dystrophy. Journal of Cell Biology. 2013 May 13;201(4):499-510.
- 11. CONCEPTS Dystrophin is an intracellular, rod-shaped protein localized to the inner surface of the sarcolemma with a high abundance at costameres. 1 Recessive, frameshifting deletions and duplications OR nonsense mutations 2 Complete loss of OR Expression of nonfunctional dystrophin in Myofibers Duan D, Goemans N, Takeda SI, Mercuri E, Aartsma-Rus A. Duchenne muscular dystrophy. Nature Reviews Disease Primers. 2021 Feb 18;7(1):13.
- 12. CONCEPTS The N terminal and a portion of the middle rod domain interact with the cytoskeletal filamentous actin (F-actin) The C-terminal domain interacts with multiple proteins to assemble the dystrophin-associated protein complex (DAPC) Duan D, Goemans N, Takeda SI, Mercuri E, Aartsma-Rus A. Duchenne muscular dystrophy. Nature Reviews Disease Primers. 2021 Feb 18;7(1):13.
- 13. CONCEPTS The integrity of DAPC is crucial for the contracting myofiber to withstand the mechanical stress and to prevent its fragile sarcolemma. Duan D, Goemans N, Takeda SI, Mercuri E, Aartsma-Rus A. Duchenne muscular dystrophy. Nature Reviews Disease Primers. 2021 Feb 18;7(1):13.
- 14. CONCEPTS Muscle cells that lack of dystrophin become FRAGILE and EASILY DAMAGE, resulting in muscle atrophies and leading to muscle weakness Duan D, Goemans N, Takeda SI, Mercuri E, Aartsma-Rus A. Duchenne muscular dystrophy. Nature Reviews Disease Primers. 2021 Feb 18;7(1):13.
- 15. Pathophysiology of Duchenne MD The France Foundation: Genes, Exons, and Pathophysiology of Duchenne Muscular Dystrophy. Cited on September 29th 2023 [https://www.youtube.com/watch?v=-9H9syJXU4s]
- 16. Symptoms of Duchenne MD Muscle weakness Delayed motor milestones Young males (aged 2–4 years old) the Gowers sign Cognitive impairment and speech delay Duan D, Goemans N, Takeda SI, Mercuri E, Aartsma-Rus A. Duchenne muscular dystrophy. Nature Reviews Disease Primers. 2021 Feb 18;7(1):13.
- 17. How to Diagnose DUCHENNE MD Screening for CK level in plasma Accurate genetic diagnosis Evaluating 79 DMD exons using MLPA or array CGH Prenatal screening Non-invasive prenatal screening (based on the analysis of cell-free DNA in the maternal serum) Newborn screening 01 02 03 Duan D, Goemans N, Takeda SI, Mercuri E, Aartsma-Rus A. Duchenne muscular dystrophy. Nature Reviews Disease Primers. 2021 Feb 18;7(1):13. Diagnose
- 18. Duchenne MD Treatment Multidisciplinary approach Respiratory Care Cardiac Care Orthopaedic Management Endocrinological Neurodevelopmental and Neuropsychological Gastroenterological Duan D, Goemans N, Takeda SI, Mercuri E, Aartsma-Rus A. Duchenne muscular dystrophy. Nature Reviews Disease Primers. 2021 Feb 18;7(1):13. Treatment
- 19. Thank you for your attention!
Editor's Notes
- Dys = "bad" or "difficult
- Not all types of MD cause severe disability and many don't affect life expectancy.
- Mutations in DMD can also cause Becker MD – a milder disease with later onset and slower progression than Duchenne.
- In muscle, dystrophin links cytoskeletal F-actin with the extracellular matrix via its N-terminal and C-terminal domains. In DMD, frameshifting mutations (deletions or duplications that involve a number of nucleotides not divisible by three) or nonsense mutations (a point mutation where the code for a codon for an amino acid is changed into a stop codon) cause premature truncation of protein translation, leading to non-functional and unstable dystrophin. Nonsense-mediated decay does not seem to affect these dystrophin transcripts but epigenetic changes cause a reduction in transcript production4. By contrast, in BMD, mutations in the middle of the gene maintain the reading frame (deletions or duplications containing a number of nucleotides divisible by three) and allow the production of dystrophins with fewer spectrin-like repeats but that have both F-actin and extracellular matrix binding domains and are therefore partially functional (Fig. 1).
- In muscle, dystrophin links cytoskeletal F-actin with the extracellular matrix via its N-terminal and C-terminal domains. In DMD, frameshifting mutations (deletions or duplications that involve a number of nucleotides not divisible by three) or nonsense mutations (a point mutation where the code for a codon for an amino acid is changed into a stop codon) cause premature truncation of protein translation, leading to non-functional and unstable dystrophin. Nonsense-mediated decay does not seem to affect these dystrophin transcripts but epigenetic changes cause a reduction in transcript production4. By contrast, in BMD, mutations in the middle of the gene maintain the reading frame (deletions or duplications containing a number of nucleotides divisible by three) and allow the production of dystrophins with fewer spectrin-like repeats but that have both F-actin and extracellular matrix binding domains and are therefore partially functional (Fig. 1).
- DAPS is a group of proteins that span the sarcolemma of the skeletal and cardiac muscle. DAPC encompasses: (1) dystrophin, (2) intracellular (α1- and β1-syntrophin, α-dystrobrevin, and nNOS), (3) transmembrane (β-dystroglycan, α-, β-, γ-, and δ-sarcoglycan, and sarcospan), and (4) extracellular proteins (α-dystroglycan and laminin-2)
- The integrity of DAPC is crucial for the contracting myofiber to withstand the mechanical stress (generated by sarcomeres) and to prevent its fragile sarcolemma (from contraction-induced injuries).
- Gowers Sign (patients use their hands to ‘walk’ on their lower limbs when getting up from the floor to compensate for weakness in the upper leg and hip muscles)
- Specific attention should be paid to the management of neurodevelopmental and neuropsychological disorders in patients with DMD34,146. Patients with DMD have a higher incidence of cognitive impairment, attention deficit/hyperactivity disorder, autism spectrum disorder, anxiety and obsessive-compulsive disorder compared with the general population146. A referral for neuropsychological evaluations should be considered at diagnosis of DMD but is essential when concerns about developmental progress arise. Educational support may be required and will be driven by the results of neuropsychological tests, which are increasingly performed as part of routine care. The treatment of attention deficit/hyperactivity disorder or other behavioural or psychiatric problems is based on the symptoms and follows guidelines for the treatment of these disorders in the general population. Further research to improve the knowledge of these manifestations of DMD and to provide guidelines to identify, monitor and treat these manifestations is crucial as they have a major effect on functioning and QOL of both patients and their families. Corticosteroid Over 6 to 18 months of treatment, indicating that prednisone has a beneficial effect on muscle strength and function in patients with Duchenne muscular dystrophy and recommended that corticosteroids be offered (prednisone 0.75 mg/kg/d and deflazacort 0.9 mg/kg/d) as treatment. indicates that long-term corticosteroid therapy (1) prolongs ambulation by 2 to 5 years, (2) reduces the need for spinal stabilization surgery, (3) improves cardiopulmonary function, (4) delays the need for noninvasive nasal ventilation, and (5) increases survival and the quality of life of patients with Duchenne muscular dystrophy.