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Early signs of gait deviation in Duchenne muscular dystrophy

Discussion in 'Pediatrics' started by NewsBot, Sep 15, 2011.

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  1. NewsBot

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    Early signs of gait deviation in Duchenne muscular dystrophy.
    Doglio L, Pavan E, Pernigotti I, Petralia P, Frigo C, Minetti C.
    Eur J Phys Rehabil Med. 2011 Sep 13. [Epub ahead of print]
     
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    Another muscular dystrophy mystery solved; MU scientists inch closer to a therapy for patients
     
  4. Admin2

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    Duchenne muscular dystrophy

    Duchenne muscular dystrophy (DMD) is a severe type of muscular dystrophy that primarily affects boys.[3] Muscle weakness usually begins around the age of four, and worsens quickly.[2] Muscle loss typically occurs first in the thighs and pelvis followed by the arms.[3] This can result in trouble standing up.[3] Most are unable to walk by the age of 12.[2] Affected muscles may look larger due to increased fat content.[3] Scoliosis is also common.[3] Some may have intellectual disability.[3] Females with a single copy of the defective gene may show mild symptoms.[3]

    The disorder is X-linked recessive.[3] About two thirds of cases are inherited from a person's mother, while one third of cases are due to a new mutation.[3] It is caused by a mutation in the gene for the protein dystrophin.[3] Dystrophin is important to maintain the muscle fiber's cell membrane.[3] Genetic testing can often make the diagnosis at birth.[3] Those affected also have a high level of creatine kinase in their blood.[3]

    Although there is no known cure, physical therapy, braces, and corrective surgery may help with some symptoms.[2] Assisted ventilation may be required in those with weakness of breathing muscles.[3] Medications used include steroids to slow muscle degeneration, anticonvulsants to control seizures and some muscle activity, and immunosuppressants to delay damage to dying muscle cells.[2] Gene therapy, as a treatment, is in the early stages of study in humans.[3] A small initial study using gene therapy has given some children improved muscle strength, but long term effects are unknown as of 2020.[5]

    Various figures of the occurrence of DMD are reported. One source reports that it affects about one in 3,500 to 6,000 males at birth.[3] Another source reports DMD being a rare disease and having an occurrence of 7.1 per 100,000 male births.[6] A number of sources referenced in this article indicate an occurrence of 6 per 100,000.[7]

    It is the most common type of muscular dystrophy.[3] The median life expectancy is 28–30;[8][9] however, with excellent care, some may live up to their 30s or 40s.[3] The disease is much more rare in girls, occurring approximately once in 50,000,000 live female births.[4]

    1. ^ "Duchenne". Merriam-Webster.com Dictionary.
    2. ^ a b c d e f g "NINDS Muscular Dystrophy Information Page". NINDS. 4 March 2016. Archived from the original on 30 July 2016. Retrieved 12 September 2016.
    3. ^ a b c d e f g h i j k l m n o p q r s t u v w "Muscular Dystrophy: Hope Through Research". NINDS. 4 March 2016. Archived from the original on 30 September 2016. Retrieved 12 September 2016.
    4. ^ a b Nozoe KT, Akamine RT, Mazzotti DR, Polesel DN, Grossklauss LF, Tufik S, et al. (2016). "Phenotypic contrasts of Duchenne Muscular Dystrophy in women: Two case reports". Sleep Science. 9 (3): 129–133. doi:10.1016/j.slsci.2016.07.004. PMC 5241604. PMID 28123647.
    5. ^ Hamilton J (27 July 2020). "A Boy with Muscular Dystrophy Was Headed for a Wheelchair. Then Gene Therapy Arrived". NPR.
    6. ^ Crisafulli S, Sultana J, Fontana A, Salvo F, Messina S, Trifirò G (June 2020). "Global epidemiology of Duchenne muscular dystrophy: an updated systematic review and meta-analysis". Orphanet Journal of Rare Diseases. 15 (1): 141. doi:10.1186/s13023-020-01430-8. PMC 7275323. PMID 32503598.
    7. ^ "Duchenne Muscular Dystrophy (DMD) - Diseases". Muscular Dystrophy Association. 17 November 2017. Retrieved 15 November 2022.
    8. ^ Cite error: The named reference :1 was invoked but never defined (see the help page).
    9. ^ Cite error: The named reference :2 was invoked but never defined (see the help page).
     
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    Scientists find drug that may help in fight against Duchenne muscular dystrophy
     
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    Stem-cell approach shows promise for Duchenne muscular dystrophy
     
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    A quantum leap in gene therapy of Duchenne muscular dystrophy
     
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    Combined therapy could repair and prevent damage in Duchenne muscular dystrophy
     
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    New Muscular Dystrophy Treatment Shows Promise in Early Study Led by Children’s National
    September 17, 2013

     
  10. Craig Payne

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    It took him 16hrs, but he completed the Chicago marathon:



    http://running.competitor.com/2013/...lar-dystrophy-finishes-chicago-marathon_86454
     
    Last edited by a moderator: Sep 22, 2016
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    Nanoparticles treat muscular dystrophy in mice
     
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    Recent advances in Duchenne muscular dystrophy
    Perkins KJ, Davies KE
    Degenerative Neurological and Neuromuscular Disease

     
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    Effects of AFO Use on Walking in Boys With Duchenne Muscular Dystrophy: A Pilot Study.
    Townsend EL, Tamhane H, Gross KD.
    Pediatr Phys Ther. 2014 Nov 14.
     
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    Gait propulsion in patients with facioscapulohumeral muscular dystrophy and ankle plantarflexor weakness
    N.H.M. Rijken, MSc, B.G.M. van Engelen, MD PhD, J.W.J. de Rooy, MD, V. Weerdesteyn, PhD, A.C.H. Geurts, MD PhD
    Gait & Posture; Articles in Press
     
  15. Admin2

    Admin2 Administrator Staff Member

    Facioscapulohumeral muscular dystrophy

    Facioscapulohumeral muscular dystrophy (FSHD) is a type of muscular dystrophy, a group of heritable diseases that cause degeneration of muscle and progressive weakness. Per the name, FSHD tends to sequentially weaken the muscles of the face, those that position the scapula, and those overlying the humerus bone of the upper arm.[2][3] These areas can be spared, and muscles of other areas usually are affected, especially those of the chest, abdomen, spine, and shin. Almost any skeletal muscle can be affected in advanced disease. Abnormally positioned, termed 'winged', scapulas are common, as is the inability to lift the foot, known as foot drop. The two sides of the body are often affected unequally. Weakness typically manifests at ages 15 – 30 years.[4] FSHD can also cause hearing loss and blood vessel abnormalities at the back of the eye.

    FSHD is caused by a genetic mutation leading to deregulation of the DUX4 gene.[5] Normally, DUX4 is expressed (i.e., turned on) in cells of the ovary and in very early human development, becoming repressed (i.e., turned off) by the time an embryo is several days old.[6][7] In FSHD, DUX4 is inadequately repressed, allowing sporadic expression throughout life. Deletion of DNA in the region surrounding DUX4 is the causative mutation in 95% of cases, termed "D4Z4 contraction" and defining FSHD type 1 (FSHD1).[8] FSHD caused by other mutations is FSHD type 2 (FSHD2). For disease to develop, also required is a 4qA allele, which is a common variation in the DNA next to DUX4. The chances of a D4Z4 contraction with a 4qA allele being passed on to a child is 50% (autosomal dominant);[2] in 30% of cases, the mutation arose spontaneously.[4] Mutations of FSHD cause inadequate DUX4 repression by unpacking the DNA around DUX4, making it accessible to be copied into messenger RNA (mRNA). The 4qA allele stabilizes this DUX4 mRNA, allowing it to be used for production of DUX4 protein.[9] DUX4 protein is a modulator of hundreds of other genes, many of which are involved in muscle function.[2][5] How this genetic modulation causes muscle damage remains unclear.[2]

    Signs, symptoms, and diagnostic tests can suggest FSHD; genetic testing usually provides definitive diagnosis.[2] FSHD can be presumptively diagnosed in an individual with signs/symptoms and an established family history. No intervention has proven effective for slowing progression of weakness.[10] Screening allows for early detection and intervention for various disease complications. Symptoms can be addressed with physical therapy, bracing, and reconstructive surgery such as surgical fixation of the scapula to the thorax.[11] FSHD affects up to 1 in 8,333 people,[2] putting it in the three most common muscular dystrophies with myotonic dystrophy and Duchenne muscular dystrophy.[12][13] Prognosis is variable. Many are not significantly limited in daily activity, whereas a wheel chair or scooter is required in 20% of cases.[14] Life expectancy is not affected, although death can rarely be attributed to respiratory insufficiency due to FSHD.[15]

    FSHD was first distinguished as a disease in the 1870s and 1880s when French physicians Louis Théophile Joseph Landouzy and Joseph Jules Dejerine followed a family affected by it, thus the initial name Landouzy–Dejerine muscular dystrophy. Their work is predated by descriptions of probable individual FSHD cases.[16][17][18] The significance of D4Z4 contraction on chromosome 4 was established in the 1990s. The DUX4 gene was discovered in 1999, found to be expressed and toxic in 2007, and in 2010 the genetic mechanism causing its expression was elucidated. In 2012, the gene most frequently mutated in FSHD2 was identified. In 2019, the first drug designed to counteract DUX4 expression entered clinical trials.[19]

    1. ^ The sources listed below differ on pronunciation of the 'u' in 'scapulo'. A 'long u' sound in an unstressed nonfinal syllable is often reduced to a schwa and varies by speaker.
      • "Facioscapulohumeral". Merriam-Webster.com Dictionary.
      • "Facioscapulohumeral". Medical Dictionary, Farlex and Partners, 2009.
    2. ^ a b c d e f g h Wagner, Kathryn R. (December 2019). "Facioscapulohumeral Muscular Dystrophies". CONTINUUM: Lifelong Learning in Neurology. 25 (6): 1662–1681. doi:10.1212/CON.0000000000000801. PMID 31794465. S2CID 208531681.
    3. ^ Stedman, Thomas (1987). Webster's New World/Stedman's Concise Medical Dictionary (1 ed.). Baltimore: Williams & Wilkins. p. 230. ISBN 0139481427.
    4. ^ a b Cite error: The named reference Mul2016ClinicalFeatures was invoked but never defined (see the help page).
    5. ^ a b Kumar, Vinay; Abbas, Abul; Aster, Jon, eds. (2018). Robbins Basic Pathology (Tenth ed.). Philadelphia, Pennsylvania: Elsevier. p. 844. ISBN 978-0-323-35317-5.
    6. ^ De Iaco, A; Planet, E; Coluccio, A; Verp, S; Duc, J; Trono, D (June 2017). "DUX-family transcription factors regulate zygotic genome activation in placental mammals". Nature Genetics. 49 (6): 941–945. doi:10.1038/ng.3858. PMC 5446900. PMID 28459456.
    7. ^ Snider, L; Geng, LN; Lemmers, RJ; Kyba, M; Ware, CB; Nelson, AM; Tawil, R; Filippova, GN; van der Maarel, SM; Tapscott, SJ; Miller, DG (28 October 2010). "Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene". PLOS Genetics. 6 (10): e1001181. doi:10.1371/journal.pgen.1001181. PMC 2965761. PMID 21060811.
    8. ^ Lemmers RJ, van der Vliet PJ, Klooster R, Sacconi S, Camaño P, Dauwerse JG, Snider L, Straasheijm KR, van Ommen GJ, Padberg GW, Miller DG, Tapscott SJ, Tawil R, Frants RR, van der Maarel SM (19 August 2010). "A Unifying Genetic Model for Facioscapulohumeral Muscular Dystrophy" (PDF). Science. 329 (5999): 1650–3. Bibcode:2010Sci...329.1650L. doi:10.1126/science.1189044. hdl:1887/117104. PMC 4677822. PMID 20724583. Archived from the original (PDF) on 2014-06-05.
    9. ^ Lemmers RJ, Wohlgemuth M, van der Gaag KJ, et al. (November 2007). "Specific sequence variations within the 4q35 region are associated with facioscapulohumeral muscular dystrophy". Am. J. Hum. Genet. 81 (5): 884–94. doi:10.1086/521986. PMC 2265642. PMID 17924332.
    10. ^ Cite error: The named reference Mul2022Review was invoked but never defined (see the help page).
    11. ^ Cite error: The named reference Eren2020ScapFusionStaging was invoked but never defined (see the help page).
    12. ^ Theadom, A; Rodrigues, M; Roxburgh, R; Balalla, S; Higgins, C; Bhattacharjee, R; Jones, K; Krishnamurthi, R; Feigin, V (2014). "Prevalence of muscular dystrophies: a systematic literature review". Neuroepidemiology. 43 (3–4): 259–68. doi:10.1159/000369343. hdl:10292/13206. PMID 25532075. S2CID 2426923.
    13. ^ Mah, JK; Korngut, L; Fiest, KM; Dykeman, J; Day, LJ; Pringsheim, T; Jette, N (January 2016). "A Systematic Review and Meta-analysis on the Epidemiology of the Muscular Dystrophies". The Canadian Journal of Neurological Sciences. Le Journal Canadien des Sciences Neurologiques. 43 (1): 163–77. doi:10.1017/cjn.2015.311. PMID 26786644. S2CID 24936950.
    14. ^ Cite error: The named reference Tawil2006Review was invoked but never defined (see the help page).
    15. ^ Statland, JM; Tawil, R (December 2016). "Facioscapulohumeral Muscular Dystrophy". Continuum (Minneapolis, Minn.). 22 (6, Muscle and Neuromuscular Junction Disorders): 1916–1931. doi:10.1212/CON.0000000000000399. PMC 5898965. PMID 27922500.
    16. ^ Cite error: The named reference Cruveilhier1852Firstdescription was invoked but never defined (see the help page).
    17. ^ Cite error: The named reference Rogers2004TextbookHistory was invoked but never defined (see the help page).
    18. ^ Cite error: The named reference Landouzy1885Review was invoked but never defined (see the help page).
    19. ^ Cite error: The named reference Cohen2020Therapeutics was invoked but never defined (see the help page).
     
  16. NewsBot

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    Press Release:
    Bacterial defense mechanism targets duchenne muscular dystrophy
    Gene therapy approach could treat 60 percent of Duchenne Muscular Dystrophy patients.

     
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    Effects of AFO Use on Walking in Boys With Duchenne Muscular Dystrophy: A Pilot Study: A Pilot Study
    Townsend, Elise L. PT, DPT, PhD, PCS; Tamhane, Himani PT, DPT, MS; Gross, K. Douglas PT, DPT, ScD, FAAOMPT, CPed
    Pediatric Physical Therapy: Spring 2015 - Volume 27 - Issue 1 - p 24–29
     
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    Press Release:
    Ottawa researchers discover that Duchenne muscular dystrophy is a stem cell disease
    November 16, 2015

     
  19. NewsBot

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    PUBLIC RELEASE: 31-DEC-2015
    Gene-editing technique successfully stops progression of Duchenne muscular dystrophy
     
  20. NewsBot

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    PUBLIC RELEASE: 12-FEB-2016
    Stem cell gene therapy could be key to treating Duchenne muscular dystrophy
    Approach developed at UCLA holds promise for 60 percent of patients with the deadly disease
     
  21. NewsBot

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    Rehabilitative technology use among individuals with Duchenne/Becker muscular dystrophy.
    Pandya S et al
    J Pediatr Rehabil Med. 2016 Feb 27;9(1):45-53.
     
  22. NewsBot

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  23. NewsBot

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    Beneficial effects of ankle-foot orthosis daytime use on the gait of Duchenne muscular dystrophy patients
    Mariana Angelica de Souza, Marisa Maia Leonardi Figueiredo, Cyntia Rogean de Jesus Alves de Baptista, Robson Devanir Aldaves, Ana Claudia Mattiello-Sverzut
    Clinical Biomechanics; Article in Press
     
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    Press Release:
    Sarepta Issues Statement on Advisory Committee Outcome for Use of Eteplirsen in the Treatment of Duchenne Muscular Dystrophy
     
  25. NewsBot

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    Hip kinetics during gait are clinically meaningful outcomes in young boys with Duchenne muscular dystrophy
    Kent Hebererl, Eileen Fowler, Loretta Staudt, Susan Sienko, Cathleen E. Buckon, Anita Bagley, Mitell Sison-Williamson, Craig M. McDonald, Michael D. Sussman
    Gait and Posture; Article in Press
     
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    FDA Approves Exondys 51 (eteplirsen) for Duchenne Muscular Dystrophy
     
  27. NewsBot

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    Muscle activations during gait in children with Duchenne muscular dystrophy.
    Ropars J et al
    Ann Phys Rehabil Med. 2016 Sep;59S:e82-e83. doi: 10.1016/j.rehab.2016.07.190.
     
  28. NewsBot

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    PUBLIC RELEASE: 3-JAN-2017
    Not all Europeans receive the same care for Duchenne muscular dystrophy
    Researchers report significant regional and age-dependent differences, in the Journal of Neuromuscular Diseases

     
  29. NewsBot

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    PUBLIC RELEASE: 3-JAN-2017
    Not all Europeans receive the same care for Duchenne muscular dystrophy
    Researchers report significant regional and age-dependent differences, in the Journal of Neuromuscular Diseases

     
  30. NewsBot

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    Long-Term Outcome of Interdisciplinary Management of Patients with Duchenne Muscular Dystrophy Receiving Daily Glucocorticoid Treatment.
    Wong BL et al
    J Pediatr. 2016 Dec 30. pii: S0022-3476(16)31386-5.
     
  31. NewsBot

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    FDA News Release
    FDA approves drug to treat Duchenne muscular dystrophy
    For Immediate Release
    February 9, 2017
     
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    Not all is what it seems:
    Source: https://www.wsj.com/articles/marath...89-000-for-muscular-dystrophy-drug-1486738267
     
  33. NewsBot

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    Diagnosis of duchenne muscular dystrophy in italy in the last decade: critical issues and areas for improvements
    Adele D'Amico et al
    Neuromuscular Disorders; Article in Press
     
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    Gait deviations in Duchenne muscular dystrophy—Part 1. A systematic review
    Marije Goudriaan et al
    Gait and Posture; Article in Press
     
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    Press Release:
    Sarepta Therapeutics Announces Plan to Submit a New Drug Application (NDA) for Accelerated Approval of Golodirsen (SRP-4053) in Patients with Duchenne Muscular Dystrophy (DMD) Amenable to Skipping Exon 53
    CAMBRIDGE, Mass., March 12, 2018 (GLOBE NEWSWIRE) -- Sarepta Therapeutics, Inc. (NASDAQ:SRPT), a commercial-stage biopharmaceutical company focused on the discovery and development of precision genetic medicine to treat rare neuromuscular diseases, announced today that it recently received final minutes from a February 2018 Type C meeting held with the Division of Neurology Products, United States Food and Drug Administration (the Division), to solicit the Division's guidance on the development pathway for Sarepta's therapeutic candidate, golodirsen, a phosphordiamidate morpholino oligimer engineered to treat those patients with Duchenne muscular dystrophy (DMD) who have genetic mutations subject to skipping exon 53 of the DMD gene.

    "Sarepta is thankful for the FDA Neurology Division’s thoughtful and direct guidance regarding golodirsen," said Doug Ingram, Sarepta's president and chief executive officer. "Obviously, whether golodirsen will obtain accelerated approval is a review decision that will come after the submission and review of our NDA. But we greatly appreciate the willingness of the Neurology Division to engage and provide clear direction to us on the steps necessary to support an NDA submission for accelerated approval."

    As previously announced in the third quarter of 2017, Sarepta’s 4053-101 study – a Phase 1/2 study to assess the safety, tolerability, pharmacokinetics and efficacy of golodirsen in 25 boys with confirmed deletions of the DMD gene amenable to exon 53 skipping – demonstrated statistically significant results in favor of golodirsen on all biological endpoints, including properly exon-skipped RNA transcript using reverse transcription polymerase chain reaction, quantity of dystrophin expression using Western blot and dystrophin intensity pursuant to immunohistochemistry.

    Based on the results of Study 4053-101 and informed now by FDA's feedback, Sarepta intends to complete a rolling submission of a golodirsen NDA by year-end 2018, seeking accelerated approval of golodirsen based on an increase in dystrophin protein as a surrogate endpoint.

    Among other guidance:
    The Division reported that in light of the precedent of eteplirsen’s approval, based on an increase in dystrophin protein as a surrogate endpoint reasonably likely to predict clinical benefit, a statistically significant increase in de novo, truncated dystrophin protein in Study 4053-101, based on a scientifically sound experimental design and rigorous analytical methods, may serve as a basis for accelerated approval of golodirsen for the treatment of Duchenne muscular dystrophy, assuming that Sarepta provides substantial evidence of the effect of golodirsen on dystrophin from a single study.

    Sarepta proposed that its Study 4045-301 (ESSENCE), a Phase 3 ongoing placebo-controlled clinical trial assessing the efficacy of golodirsen and casimersen, serve as the post-marketing confirmatory study. The Division confirmed that ESSENCE could possibly serve as a confirmatory study if golodirsen is granted accelerated approval, with the understanding that it is incumbent upon Sarepta to describe how it will successfully enroll and complete the ESSENCE study in light of an accelerated approval.

    The Division indicated that it is willing to accept a rolling submission of the NDA. The complete submission must include long-term animal toxicology studies, which will be completed in the fourth quarter of 2018. Hence, Sarepta anticipates the NDA submission will be complete in late 2018.
     
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    Development and evaluation of a passive trunk support system for Duchenne muscular dystrophy patients.
    Mahmood MN et al
    J Neuroeng Rehabil. 2018 Mar 14;15(1):22. doi: 10.1186/s12984-018-0353-3.
     
  37. NewsBot

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    Surface EMG signals in very late-stage of Duchenne muscular dystrophy: a case study.
    Lobo-Prat J et al
    J Neuroeng Rehabil. 2017 Aug 29;14(1):86. doi: 10.1186/s12984-017-0292-4.
     
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    Consensus statement
    Consensus on the diagnosis, treatment and follow-up of patients with Duchenne muscular dystrophy ☆

    A. Nascimento Osorioa, J. Medina Cantillob, A. Camacho Salasc, M. Madruga Garridod, J.J. Vilchez Padillae, f, ,
    Neurología (English Edition) 30 April 2018
     
  39. NewsBot

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    Gait deviations in Duchenne muscular dystrophy—Part 2. Statistical non-parametric mapping to analyze gait deviations in children with Duchenne muscular dystrophy
    Marije Goudriaan et al
    Gait and Posture; Article in Press
     
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    Press Release:
    Duchenne muscular dystrophy: How muscle cells journey to the dark side

    SEPTEMBER 11, 2018
    Promoting repair of dystrophic muscles is a major goal in the treatment of muscular dystrophies but is complicated by the incomplete knowledge of the cellular and molecular events that drive muscle regeneration.

    Answers could lie in better understanding muscle repair—which resembles a delicate cellular dance choreographed by special cells called fibro-adipogenic progenitors (FAPs). Researchers already know these cells have a dark side—they are also responsible for the muscle wasting and scarring that occurs during Duchenne muscular dystrophy (DMD).

    Now, scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) have revealed that FAPs don’t have just one identity—but several distinct identities that emerge during key stages of muscle regeneration. Importantly, the FAPs that drive the symptoms of DMD have defined markers, meaning they could be targeted for drug development. The study was published in Nature Communications.

    "There is increasing evidence from mouse studies that FAPs may play a critical role in muscle regeneration,” says Grace Pavlath, Ph.D., senior vice president and scientific program director of the Muscular Dystrophy Association (MDA). “This study provides further insight into the mechanisms underpinning impaired regeneration and the development of fibrosis in DMD, and suggests future avenues for therapeutic intervention."

    DMD mostly affects boys and is caused by the absence of a muscle-strengthening protein called dystrophin. Over time, muscle is replaced by scar tissue and fat, a process called fibrosis that ultimately leads to muscle wasting and weakness. Most people with DMD do not survive past their mid-20s.

    “While advances are being made, there is still an urgent need for effective treatments for DMD,” says Pier Lorenzo Puri, M.D., senior author of the study; professor in the Development, Aging and Regeneration Program at SBP; and lab director at Fondazione Santa Lucia IRCCS. “This discovery reveals novel cell targets for selective interventions that may promote regeneration and prevent fibrosis in DMD muscles.”

    Adds Filippo Buccella, founder of the Duchenne Parent Project Italy, part of an international federation created by parents to accelerate the development of new therapies, "This major advancement sheds a new light on the complex process of muscle degeneration/regeneration and may indeed improve the lives of Duchenne patients and their families. This breakthrough comes years after working with skilled physicians and great scientists like Dr. Puri, and it will be invaluable for the many patients and families who as of today are involved worldwide with experimental clinical trials.”

    Mapping FAPs over time

    Puri’s team analyzed the transcriptome of single FAP cells, which shows the genes that are turned on or off, from samples of muscle tissue obtained from mouse models of acute injury and DMD. This work identified cellular markers unique to a subpopulation of FAPs (sub-FAPs).

    The scientists then applied the transcriptome analysis to each of the identified sub-FAPs to track the relative amounts of gene expression and types of genes expressed in three settings of muscle regeneration: following acute injury; during DMD; and immediately after birth, which uses a different regeneration process from adult muscle repair.

    Clear patterns emerged and revealed that the identified sub-FAPs transitioned through different functional states—correlating with key events during the muscle regeneration process. At early stages after acute injury, sub-FAPs expressing the cell surface marker Tie2 appear. They were followed by transient sub-FAPs expressing the cell surface marker Vcam1. Genome-wide transcriptome analysis indicated that Tie2-expressing FAPs promote blood vessel formation and muscle stem cell activation, while Vcam1-expressing sub-FAPs promote fibrosis.

    “Importantly, this analysis revealed an association between these functional states and the inflammatory response of regenerating muscles,” says Puri. “We observed that during acute injury, the inflammatory infiltrate—specifically macrophages—promptly cleared Vcam1-expressing sub-FAPs. This restricts their pro-fibrotic activity to transient collagen deposition, which favors optimal muscle stem cell division. However, in experimental conditions of macrophage depletion or in DMD muscles, in which macrophage activity is altered, an impaired clearance of Vcam1-expressing sub-FAPs resulted in chronic deposition of collagen and muscle fibrosis—one of the most deleterious events in DMD progression.”

    Adds co–first author Barbora Malecova, Ph.D., former postdoctoral researcher in Puri’s lab at SBP and current scientist at Avidity Biosciences, LLC, “This study elucidates the cellular and molecular pathogenesis of muscular dystrophy. These results indicate that removing or modulating the activity of Vcam1-positive sub-FAPs, which promote fibrosis, could be an effective treatment for DMD.”

    Additional co–first authors of the study are Sole Gatto, Ph.D. former postdoctoral researcher in Puri’s lab at SBP and current bioinformatics scientist at Monoceros Biosystems, LLC; and Usue Etxaniz, Ph.D., postdoctoral fellow in Puri’s lab at SBP.

    “This work paves the way for pharmacological manipulation of FAPs, in order to correct their aberrant behavior in muscular diseases,” says Puri. “For instance, the identification of drugs that can target Vcam1-expressing sub-FAPs might inspire therapeutic interventions toward preventing fibrosis in muscular dystrophies. It is also possible that existing drugs have this potential, and we are now exploring the effect of histone deacetylase (HDAC) inhibitors, which have shown beneficial effects (anti-fibrotic) in muscles of mouse models of DMD, in preclinical studies and in DMD boys in recent clinical trial.”

    Research reported in this press release was supported by National Institutes of Health (NIH) grants P30AR061303, R01AR056712, R01AR052779, and P30AR061303; California Institute for Regenerative Medicine (CIRM) grant TG2-01162; the Muscular Dystrophy Association (MDA), the French Muscular Dystrophy Association (AFM); and EPIGEN. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The study’s DOI is 10.1038/s41467-018-06068-6.
     
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