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Posner N, Manjelievskaia J, Talaga AK, Richards M, Lew CR, Merla V, Alvir JMJ, Nelson SF. Real-world treatment and health care utilization among patients with Duchenne muscular dystrophy by race and ethnicity in a Medicaid population. J Manag Care Spec Pharm 2025; 31:205-213. [PMID: 39912815 PMCID: PMC11852792 DOI: 10.18553/jmcp.2025.31.2.205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2025]
Abstract
BACKGROUND Duchenne muscular dystrophy (DMD) is a rare neuromuscular disorder, and data on the impact of patients' race on treatment outcomes and health care resource utilization are lacking. OBJECTIVE To describe the real-world treatment and health care utilization among patients with DMD, by race, in a Medicaid population. METHODS This was a retrospective cohort study of patients with DMD in the Merative Multi-State Medicaid Database between January 2017 and June 2021. Patients with DMD were identified using a validated algorithm and included male patients with at least 2 DMD diagnoses (earliest DMD diagnosis date = index date), aged 40 years or younger, with at least 12 months of continuous enrollment prior to index date, and with at least 12 months (or evidence of death) following the index date were selected. Demographics, clinical characteristics, treatment utilization, and health care utilization and costs were reported by race and ethnicity in the 12-month baseline and 12-month follow-up periods. RESULTS A total of 561 patients were included in the study, of which 360 (64.2%) were White, 50 (8.9%) were Black, 33 (5.9%) were Hispanic, and 118 (21.0%) were of other/unknown race and ethnicity. The median age on the index date was 16, 13, 14, and 15 years among the race and ethnicity categories, respectively. In the follow-up, period clinical characteristics were similar across cohorts. Corticosteroids were the most commonly received treatment, with the highest use among Hispanic patients (73%) and lowest use among Black patients (52%). A third of patients treated with corticosteroids received deflazacort, with similar utilization across groups. Exon-skipping therapy use was rare, with 3% utilization overall, and highest use among White patients (4.2%). In both the baseline and follow-up periods, differences in health care costs were not statistically significant. White patients had the highest total costs in the follow-up period (mean [SD] = $108,895 [$346,934]) compared with $59,501 [$85,758] in the Black cohort, $61,199 [$67,021] in the Hispanic cohort, and $65,247 [$119,733] in the unknown/other cohort. Differences in total health care costs were driven by outpatient pharmacy costs, likely because of the larger proportion of White patients having a prescription for an exon-skipping therapy. CONCLUSIONS Differences were seen across race and ethnicities in select clinical characteristics, DMD treatments, and health care utilization and costs in a Medicaid population.
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Affiliation(s)
| | | | | | | | | | | | | | - Stanley F. Nelson
- David Geffen School of Medicine at University of California, Los Angeles
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Molnar MJ, Szabó L, Vladacenco OA, Cobzaru AM, Dor T, Dori A, Papadimas G, Juříková L, Litvinenko I, Tournev I, Dixon C. Essential components of an effective transition from paediatric to adult neurologist care for adolescents with Duchenne muscular dystrophy; a consensus derived using the Delphi methodology in Eastern Europe, Greece and Israel. Orphanet J Rare Dis 2024; 19:260. [PMID: 38982500 PMCID: PMC11234532 DOI: 10.1186/s13023-024-03270-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 07/01/2024] [Indexed: 07/11/2024] Open
Abstract
PURPOSE An increasing number of patients with Duchenne muscular dystrophy (DMD) now have access to improved standard of care and disease modifying treatments, which improve the clinical course of DMD and extend life expectancy beyond 30 years of age. A key issue for adolescent DMD patients is the transition from paediatric- to adult-oriented healthcare. Adolescents and adults with DMD have unique but highly complex healthcare needs associated with long-term steroid use, orthopaedic, respiratory, cardiac, psychological, and gastrointestinal problems meaning that a comprehensive transition process is required. A sub-optimal transition into adult care can have disruptive and deleterious consequences for a patient's long-term care. This paper details the results of a consensus amongst clinicians on transitioning adolescent DMD patients from paediatric to adult neurologists that can act as a guide to best practice to ensure patients have continuous comprehensive care at every stage of their journey. METHODS The consensus was derived using the Delphi methodology. Fifty-three statements were developed by a Steering Group (the authors of this paper) covering seven topics: Define the goals of transition, Preparing the patient, carers/parents and the adult centre, The transition process at the paediatric centre, The multidisciplinary transition summary - Principles, The multidisciplinary transition summary - Content, First visit in the adult centre, Evaluation of transition. The statements were shared with paediatric and adult neurologists across Central Eastern Europe (CEE) as a survey requesting their level of agreement with each statement. RESULTS Data from 60 responders (54 full responses and six partial responses) were included in the data set analysis. A consensus was agreed across 100% of the statements. CONCLUSIONS It is hoped that the findings of this survey which sets out agreed best practice statements, and the transfer template documents developed, will be widely used and so facilitate an effective transition from paediatric to adult care for adolescents with DMD.
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Affiliation(s)
- Maria Judit Molnar
- Director of Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest, Hungary
| | - Léna Szabó
- Pediatric Center, Semmelweis University, Budapest, Hungary
| | | | | | - Talya Dor
- Pediatric Neurology Unit, Hadassah University Hospital, Jerusalem, Israel
| | - Amir Dori
- Sheba Medical Center at Tel-Hashomer, Neurology Clinic, Ramat-Gan, Israel
| | | | - Lenka Juříková
- Department of Pediatric Neurology, University Hospital Brno, Brno, Czech Republic
| | - Ivan Litvinenko
- Pediatric Neurology Department, SHATPD "Prof. Dr. Ivan Mitev", Sofia, Bulgaria
| | - Ivailo Tournev
- Department of Neurology, University Hospital Aleksandrovska, Medical University, Sofia, Bulgaria
- Department of Cognitive Science and Psychology, New Bulgarian University, Sofia, Bulgaria
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Golli T, Juříková L, Sejersen T, Dixon C. The role of ataluren in the treatment of ambulatory and non-ambulatory children with nonsense mutation duchenne muscular dystrophy - a consensus derived using a modified Delphi methodology in Eastern Europe, Greece, Israel and Sweden. BMC Neurol 2024; 24:73. [PMID: 38383326 PMCID: PMC10880248 DOI: 10.1186/s12883-024-03570-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 02/13/2024] [Indexed: 02/23/2024] Open
Abstract
BACKGROUND This paper details the results of an evaluation of the level of consensus amongst clinicians on the use of ataluren in both ambulatory and non-ambulatory patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). The consensus was derived using a modified Delphi methodology that involved an exploration phase and then an evaluation phase. METHODS The exploration phase involved 90-minute virtual 1:1 interviews of 12 paediatric neurologists who cared for 30-120 DMD patients each and had patient contact every one or two weeks. The respondents managed one to ten nmDMD patients taking ataluren. The Discussion Guide for the interviews can be viewed as Appendix A. Following the exploration phase interviews, the interview transcripts were analysed by an independent party to identify common themes, views and opinions and developed 43 draft statements that the Steering Group (authors) reviewed, refined and endorsed a final list of 42 statements. Details of the recruitment of participants for the exploration and evaluation phases can be found under the Methods section. RESULTS A consensus was agreed (> 66% of respondents agreeing) for 41 of the 42 statements using results from a consensus survey of healthcare professionals (n = 20) experienced in the treatment of nmDMD. CONCLUSIONS The statements with a high consensus suggest that treatment with ataluren should be initiated as soon as possible to delay disease progression and allow patients to remain ambulatory for as long as possible. Ataluren is indicated for the treatment of Duchenne muscular dystrophy that results from a nonsense mutation in the dystrophin gene, in ambulatory patients aged 2 years and older (see Summary of Product Characteristics for each country).
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Affiliation(s)
- Tanja Golli
- Department of Child, Adolescent and Developmental Neurology, Ljubljana University Medical Centre, Ljubljana, Slovenia
| | - Lenka Juříková
- Department of Pediatric Neurology, Faculty of Medicine, University Hospital Brno, Masaryk University in Brno, Brno, Moravia, Czech Republic
| | - Thomas Sejersen
- Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden
| | - Craig Dixon
- MASS Team, Suite 99, 95 Mortimer Street, London, W1W 7GB, UK.
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Akat A, Karaöz E. Cell Therapy Strategies on Duchenne Muscular Dystrophy: A Systematic Review of Clinical Applications. Stem Cell Rev Rep 2024; 20:138-158. [PMID: 37955832 DOI: 10.1007/s12015-023-10653-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/03/2023] [Indexed: 11/14/2023]
Abstract
Duchenne Muscular Dystrophy (DMD) is an inherited genetic disorder characterized by progressive degeneration of muscle tissue, leading to functional disability and premature death. Despite extensive research efforts, the discovery of a cure for DMD continues to be elusive, emphasizing the need to investigate novel treatment approaches. Cellular therapies have emerged as prospective approaches to address the underlying pathophysiology of DMD. This review provides an examination of the present situation regarding cell-based therapies, including CD133 + cells, muscle precursor cells, mesoangioblasts, bone marrow-derived mononuclear cells, mesenchymal stem cells, cardiosphere-derived cells, and dystrophin-expressing chimeric cells. A total of 12 studies were found eligible to be included as they were completed cell therapy clinical trials, clinical applications, or case reports with quantitative results. The evaluation encompassed an examination of limitations and potential advancements in this particular area of research, along with an assessment of the safety and effectiveness of cell-based therapies in the context of DMD. In general, the available data indicates that diverse cell therapy approaches may present a new, safe, and efficacious treatment modality for patients diagnosed with DMD. However, further studies are required to comprehensively understand the most advantageous treatment approach and therapeutic capacity.
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Affiliation(s)
- Ayberk Akat
- Life Park Hospital, Cellular and Biological Products Manufacturing Center, Ragıp Kenan Sok. No:8, Ortakoy, 99010, Nicosia (Lefkosa), Cyprus.
| | - Erdal Karaöz
- Liv Hospital Ulus, Regenerative Medicine and Stem Cell Center, Istanbul, Turkey
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Kioutchoukova IP, Foster DT, Thakkar RN, Foreman MA, Burgess BJ, Toms RM, Molina Valero EE, Lucke-Wold B. Neurologic orphan diseases: Emerging innovations and role for genetic treatments. World J Exp Med 2023; 13:59-74. [PMID: 37767543 PMCID: PMC10520757 DOI: 10.5493/wjem.v13.i4.59] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 07/16/2023] [Accepted: 08/11/2023] [Indexed: 09/15/2023] Open
Abstract
Orphan diseases are rare diseases that affect less than 200000 individuals within the United States. Most orphan diseases are of neurologic and genetic origin. With the current advances in technology, more funding has been devoted to developing therapeutic agents for patients with these conditions. In our review, we highlight emerging options for patients with neurologic orphan diseases, specifically including diseases resulting in muscular deterioration, epilepsy, seizures, neurodegenerative movement disorders, inhibited cognitive development, neuron deterioration, and tumors. After extensive literature review, gene therapy offers a promising route for the treatment of neurologic orphan diseases. The use of clustered regularly interspaced palindromic repeats/Cas9 has demonstrated positive results in experiments investigating its role in several diseases. Additionally, the use of adeno-associated viral vectors has shown improvement in survival, motor function, and developmental milestones, while also demonstrating reversal of sensory ataxia and cardiomyopathy in Friedreich ataxia patients. Antisense oligonucleotides have also been used in some neurologic orphan diseases with positive outcomes. Mammalian target of rapamycin inhibitors are currently being investigated and have reduced abnormal cell growth, proliferation, and angiogenesis. Emerging innovations and the role of genetic treatments open a new window of opportunity for the treatment of neurologic orphan diseases.
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Affiliation(s)
| | - Devon T Foster
- Florida International University Herbert Wertheim College of Medicine, Florida International University Herbert Wertheim College of Medicine, Miami, FL 33199, United States
| | - Rajvi N Thakkar
- College of Medicine, University of Florida, Gainesville, FL 32611, United States
| | - Marco A Foreman
- College of Medicine, University of Florida, Gainesville, FL 32611, United States
| | - Brandon J Burgess
- College of Medicine, University of Florida, Gainesville, FL 32611, United States
| | - Rebecca M Toms
- College of Medicine, University of Florida, Gainesville, FL 32611, United States
| | | | - Brandon Lucke-Wold
- Department of Neurosurgery, University of Florida, Gainesville, FL 32611, United States
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Chrastina J, Haroková M. End of Life in Boys and Young Men With Duchenne Muscular Dystrophy - The Perspective of Dying Men and Their Families: A Systematic Review and Thematic Synthesis of Qualitative Evidence. OMEGA-JOURNAL OF DEATH AND DYING 2023:302228231186358. [PMID: 37408104 DOI: 10.1177/00302228231186358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/07/2023]
Abstract
Understanding the perceptions and experiences related to the end of life (EoL) of boys and men with Duchenne muscular dystrophy from their own and/or family perspective is limited based on the available qualitative empirical studies. This systematic review was done with a thematic synthesis of qualitative evidence according to the PRISMA Statement Guidelines and the SPIDER search tool. The review included empirical, qualitative, and relevant full-text studies published in 2000-2023 in the EBSCO Discovery Service, ISI Web of Science, Scopus, PubMed, and ProQuest databases. From o total of eight included qualitative studies, four main key themes were identified: "Being a parent/caregiver" - psychosocial aspects, needs, and experiences; "Communication about EoL with healthcare and other professionals" - positive experiences and personal shortcomings; "Discussions about…" - the issue of EoL, dying and death; and "End of life" - end-of-life care, planning and the need for palliative care.
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Affiliation(s)
- Jan Chrastina
- Institute of Special Education Studies, Faculty of Education, Palacký University Olomouc, Olomouc, Czech Republic
| | - Martina Haroková
- Institute of Special Education Studies, Faculty of Education, Palacký University Olomouc, Olomouc, Czech Republic
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Tyagi SC, Pushpakumar S, Sen U, Mokshagundam SPL, Kalra DK, Saad MA, Singh M. COVID-19 Mimics Pulmonary Dysfunction in Muscular Dystrophy as a Post-Acute Syndrome in Patients. Int J Mol Sci 2022; 24:ijms24010287. [PMID: 36613731 PMCID: PMC9820572 DOI: 10.3390/ijms24010287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 12/12/2022] [Accepted: 12/21/2022] [Indexed: 12/28/2022] Open
Abstract
Although progressive wasting and weakness of respiratory muscles are the prominent hallmarks of Duchenne muscular dystrophy (DMD) and long-COVID (also referred as the post-acute sequelae of COVID-19 syndrome); however, the underlying mechanism(s) leading to respiratory failure in both conditions remain unclear. We put together the latest relevant literature to further understand the plausible mechanism(s) behind diaphragm malfunctioning in COVID-19 and DMD conditions. Previously, we have shown the role of matrix metalloproteinase-9 (MMP9) in skeletal muscle fibrosis via a substantial increase in the levels of tumor necrosis factor-α (TNF-α) employing a DMD mouse model that was crossed-bred with MMP9-knockout (MMP9-KO or MMP9-/-) strain. Interestingly, recent observations from clinical studies show a robust increase in neopterin (NPT) levels during COVID-19 which is often observed in patients having DMD. What seems to be common in both (DMD and COVID-19) is the involvement of neopterin (NPT). We know that NPT is generated by activated white blood cells (WBCs) especially the M1 macrophages in response to inducible nitric oxide synthase (iNOS), tetrahydrobiopterin (BH4), and tetrahydrofolate (FH4) pathways, i.e., folate one-carbon metabolism (FOCM) in conjunction with epigenetics underpinning as an immune surveillance protection. Studies from our laboratory, and others researching DMD and the genetically engineered humanized (hACE2) mice that were administered with the spike protein (SP) of SARS-CoV-2 revealed an increase in the levels of NPT, TNF-α, HDAC, IL-1β, CD147, and MMP9 in the lung tissue of the animals that were subsequently accompanied by fibrosis of the diaphragm depicting a decreased oscillation phenotype. Therefore, it is of interest to understand how regulatory processes such as epigenetics involvement affect DNMT, HDAC, MTHFS, and iNOS that help generate NPT in the long-COVID patients.
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Affiliation(s)
- Suresh C. Tyagi
- Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40202, USA
| | - Sathnur Pushpakumar
- Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40202, USA
| | - Utpal Sen
- Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40202, USA
| | - Sri Prakash L. Mokshagundam
- Division of Endocrinology, Metabolism and Diabetes and Robley Rex VA Medical Center, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Dinesh K. Kalra
- Division of Cardiovascular Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Mohamed A. Saad
- Division of Pulmonary, Critical Care and Sleep Disorders Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Mahavir Singh
- Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40202, USA
- Correspondence: or
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CRISPR-Based Therapeutic Gene Editing for Duchenne Muscular Dystrophy: Advances, Challenges and Perspectives. Cells 2022; 11:cells11192964. [PMID: 36230926 PMCID: PMC9564082 DOI: 10.3390/cells11192964] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 09/06/2022] [Accepted: 09/09/2022] [Indexed: 11/19/2022] Open
Abstract
Duchenne muscular dystrophy (DMD) is a severe neuromuscular disease arising from loss-of-function mutations in the dystrophin gene and characterized by progressive muscle degeneration, respiratory insufficiency, cardiac failure, and premature death by the age of thirty. Albeit DMD is one of the most common types of fatal genetic diseases, there is no curative treatment for this devastating disorder. In recent years, gene editing via the clustered regularly interspaced short palindromic repeats (CRISPR) system has paved a new path toward correcting pathological mutations at the genetic source, thus enabling the permanent restoration of dystrophin expression and function throughout the musculature. To date, the therapeutic benefits of CRISPR genome-editing systems have been successfully demonstrated in human cells, rodents, canines, and piglets with diverse DMD mutations. Nevertheless, there remain some nonignorable challenges to be solved before the clinical application of CRISPR-based gene therapy. Herein, we provide an overview of therapeutic CRISPR genome-editing systems, summarize recent advancements in their applications in DMD contexts, and discuss several potential obstacles lying ahead of clinical translation.
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Coles CA, Woodcock I, Pellicci DG, Houweling PJ. A Spotlight on T Lymphocytes in Duchenne Muscular Dystrophy-Not Just a Muscle Defect. Biomedicines 2022; 10:535. [PMID: 35327337 PMCID: PMC8945129 DOI: 10.3390/biomedicines10030535] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/25/2022] [Accepted: 02/01/2022] [Indexed: 11/16/2022] Open
Abstract
The lack of dystrophin in Duchenne muscular dystrophy (DMD) results in membrane fragility resulting in contraction-induced muscle damage and subsequent inflammation. The impact of inflammation is profound, resulting in fibrosis of skeletal muscle, the diaphragm and heart, which contributes to muscle weakness, reduced quality of life and premature death. To date, the innate immune system has been the major focus in individuals with DMD, and our understanding of the adaptive immune system, specifically T cells, is limited. Targeting the immune system has been the focus of multiple clinical trials for DMD and is considered a vital step in the development of better treatments. However, we must first have a complete picture of the involvement of the immune systems in dystrophic muscle disease to better understand how inflammation influences disease progression and severity. This review focuses on the role of T cells in DMD, highlighting the importance of looking beyond skeletal muscle when considering how the loss of dystrophin impacts disease progression. Finally, we propose that targeting T cells is a potential novel therapeutic in the treatment of DMD.
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Affiliation(s)
- Chantal A. Coles
- Murdoch Children’s Research Institute (MCRI), Melbourne, VIC 3052, Australia; (I.W.); (D.G.P.); (P.J.H.)
- Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, VIC 3052, Australia
| | - Ian Woodcock
- Murdoch Children’s Research Institute (MCRI), Melbourne, VIC 3052, Australia; (I.W.); (D.G.P.); (P.J.H.)
- Royal Children’s Hospital, Melbourne, VIC 3052, Australia
| | - Daniel G. Pellicci
- Murdoch Children’s Research Institute (MCRI), Melbourne, VIC 3052, Australia; (I.W.); (D.G.P.); (P.J.H.)
- Department of Paediatrics, The University of Melbourne, Melbourne, VIC 3052, Australia
| | - Peter J. Houweling
- Murdoch Children’s Research Institute (MCRI), Melbourne, VIC 3052, Australia; (I.W.); (D.G.P.); (P.J.H.)
- Department of Paediatrics, The University of Melbourne, Melbourne, VIC 3052, Australia
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MUNNO PAULAM, BARROSO POLIANAR, VASCONCELOS BRUNAF, SILVA GEOVANNEBDA, SALGUEIRO THIAGOM, AGUIAR HELOISAH, VITORINO LETÍCIAM, OLIVEIRA MURILOX, MARTINS HELENR, GAIAD THAISP, MACHADO ALEXS. Acute toxicity and regenerative dose finding of an extract of Miconia ferruginata DC. in a mouse model of Duchenne muscular dystrophy. AN ACAD BRAS CIENC 2022; 94:e20210190. [DOI: 10.1590/0001-3765202220210190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 06/02/2021] [Indexed: 12/23/2022] Open
Affiliation(s)
- PAULA M. MUNNO
- Universidade Federal dos Vales do Jequitinhonha e Mucuri, Brazil
| | | | | | | | | | | | | | | | - HELEN R. MARTINS
- Universidade Federal dos Vales do Jequitinhonha e Mucuri, Brazil
| | - THAIS P. GAIAD
- Universidade Federal dos Vales do Jequitinhonha e Mucuri, Brazil
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Podkalicka P, Mucha O, Dulak J, Loboda A. Targeting angiogenesis in Duchenne muscular dystrophy. Cell Mol Life Sci 2019; 76:1507-1528. [PMID: 30770952 PMCID: PMC6439152 DOI: 10.1007/s00018-019-03006-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2018] [Revised: 12/28/2018] [Accepted: 01/07/2019] [Indexed: 02/07/2023]
Abstract
Duchenne muscular dystrophy (DMD) represents one of the most devastating types of muscular dystrophies which affect boys already at early childhood. Despite the fact that the primary cause of the disease, namely the lack of functional dystrophin is known already for more than 30 years, DMD still remains an incurable disease. Thus, an enormous effort has been made during recent years to reveal novel mechanisms that could provide therapeutic targets for DMD, especially because glucocorticoids treatment acts mostly symptomatic and exerts many side effects, whereas the effectiveness of genetic approaches aiming at the restoration of functional dystrophin is under the constant debate. Taking into account that dystrophin expression is not restricted to muscle cells, but is present also in, e.g., endothelial cells, alterations in angiogenesis process have been proposed to have a significant impact on DMD progression. Indeed, already before the discovery of dystrophin, several abnormalities in blood vessels structure and function have been revealed, suggesting that targeting angiogenesis could be beneficial in DMD. In this review, we will summarize current knowledge about the angiogenesis status both in animal models of DMD as well as in DMD patients, focusing on different organs as well as age- and sex-dependent effects. Moreover, we will critically discuss some approaches such as modulation of vascular endothelial growth factor or nitric oxide related pathways, to enhance angiogenesis and attenuate the dystrophic phenotype. Additionally, we will suggest the potential role of other mediators, such as heme oxygenase-1 or statins in those processes.
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Affiliation(s)
- Paulina Podkalicka
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Kraków, Poland
| | - Olga Mucha
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Kraków, Poland
| | - Jozef Dulak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Kraków, Poland
| | - Agnieszka Loboda
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Kraków, Poland.
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Cho MJ, Lee JW, Lee J, Shin YB. Evaluation of Early Left Ventricular Dysfunction in Patients with Duchenne Muscular Dystrophy Using Two-Dimensional Speckle Tracking Echocardiography and Tissue Doppler Imaging. Pediatr Cardiol 2018; 39:1614-1619. [PMID: 30003298 DOI: 10.1007/s00246-018-1938-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 07/05/2018] [Indexed: 11/30/2022]
Abstract
Although progressive cardiac dysfunction is the leading cause of death in patients with Duchenne muscular dystrophy (DMD), their cardiac function measured by conventional echocardiography has been generally interpreted as normal at a young age. We aimed to determine whether two-dimensional speckle tracking echocardiography (STE) or tissue Doppler imaging (TDI) could be used for early identification and detection of cardiac dysfunction in young patients with DMD. Thirteen pediatric patients (mean age, 9.69 ± 2.2 years) with DMD and 26 age-matched healthy children (mean age, 9.65 ± 2.2 years) were included in the study. All patients were examined via conventional echocardiography, TDI, and STE. Standard echocardiographic measurements of left ventricular (LV) systolic and diastolic function were obtained. Myocardial velocities including peak-systolic and early- and late-diastolic myocardial velocities were calculated in longitudinal direction in the interventricular septum, using TDI. Speckle tracking analyses were performed by acquiring apical four-, three-, and two-chamber views with the highest possible frame rates. Conventional parameters were similar between the two groups, but heart rates were higher in patients with DMD than in controls. The results of LV diastolic function evaluated using TDI showed that annular peak velocity during early diastole (e'; 10.9 ± 1.7 vs. 14.6 ± 1.7 cm/s), e'/a' ratio (2.0 ± 0.5 vs. 3.0 ± 0.5), E/e' ratio (9.4 ± 1.4 vs. 7.3 ± 0.8), and myocardial performance index (0.46 ± 0.05 vs. 0.36 ± 0.06) of the mitral septal annulus among patients with DMD differed significantly from those of healthy children. A significant decrease in global longitudinal systolic strain was found in patients with DMD (- 16.6 ± 3.7 vs. - 21.2 ± 2.1), with a marked decrease in the LV basal inferolateral and basal inferior walls. In young patients with DMD who have global normal systolic function, reductions in systolic deformation parameters as well as reduced early diastolic myocardial velocities can be detected particularly in the basal inferolateral LV walls. The prognostic significance of these findings warrants further longitudinal follow-up.
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Affiliation(s)
- Min-Jung Cho
- Department of Pediatrics, Biomedical Research Institute of Pusan National University Hospital, Pusan National University Hospital, Ami-dong, Seo-gu, Busan, 602-739, Republic of Korea.
| | - Ji-Won Lee
- Department of Radiology, Biomedical Research Institute of Pusan National University Hospital, Pusan National University Hospital, Busan, Republic of Korea
| | - JeSang Lee
- Department of Rehabilitation Medicine, Biomedical Research Institute of Pusan National University Hospital, Pusan National University Hospital, Busan, Republic of Korea
| | - Yong Beom Shin
- Department of Rehabilitation Medicine, Biomedical Research Institute of Pusan National University Hospital, Pusan National University Hospital, Busan, Republic of Korea
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Hind D, Parkin J, Whitworth V, Rex S, Young T, Hampson L, Sheehan J, Maguire C, Cantrill H, Scott E, Epps H, Main M, Geary M, McMurchie H, Pallant L, Woods D, Freeman J, Lee E, Eagle M, Willis T, Muntoni F, Baxter P. Aquatic therapy for children with Duchenne muscular dystrophy: a pilot feasibility randomised controlled trial and mixed-methods process evaluation. Health Technol Assess 2018. [PMID: 28627356 DOI: 10.3310/hta21270] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Duchenne muscular dystrophy (DMD) is a rare disease that causes the progressive loss of motor abilities such as walking. Standard treatment includes physiotherapy. No trial has evaluated whether or not adding aquatic therapy (AT) to land-based therapy (LBT) exercises helps to keep muscles strong and children independent. OBJECTIVES To assess the feasibility of recruiting boys with DMD to a randomised trial evaluating AT (primary objective) and to collect data from them; to assess how, and how well, the intervention and trial procedures work. DESIGN Parallel-group, single-blind, randomised pilot trial with nested qualitative research. SETTING Six paediatric neuromuscular units. PARTICIPANTS Children with DMD aged 7-16 years, established on corticosteroids, with a North Star Ambulatory Assessment (NSAA) score of 8-34 and able to complete a 10-m walk without aids/assistance. Exclusions: > 20% variation between baseline screens 4 weeks apart and contraindications. INTERVENTIONS Participants were allocated on a 1 : 1 ratio to (1) optimised, manualised LBT (prescribed by specialist neuromuscular physiotherapists) or (2) the same plus manualised AT (30 minutes, twice weekly for 6 months: active assisted and/or passive stretching regime; simulated or real functional activities; submaximal exercise). Semistructured interviews with participants, parents (n = 8) and professionals (n = 8) were analysed using Framework analysis. An independent rater reviewed patient records to determine the extent to which treatment was optimised. A cost-impact analysis was performed. Quantitative and qualitative data were mixed using a triangulation exercise. MAIN OUTCOME MEASURES Feasibility of recruiting 40 participants in 6 months, participant and therapist views on the acceptability of the intervention and research protocols, clinical outcomes including NSAA, independent assessment of treatment optimisation and intervention costs. RESULTS Over 6 months, 348 children were screened - most lived too far from centres or were enrolled in other trials. Twelve (30% of target) were randomised to AT (n = 8) or control (n = 4). People in the AT (n = 8) and control (n = 2: attrition because of parental report) arms contributed outcome data. The mean change in NSAA score at 6 months was -5.5 [standard deviation (SD) 7.8] for LBT and -2.8 (SD 4.1) in the AT arm. One boy suffered pain and fatigue after AT, which resolved the same day. Physiotherapists and parents valued AT and believed that it should be delivered in community settings. The independent rater considered AT optimised for three out of eight children, with other children given programmes that were too extensive and insufficiently focused. The estimated NHS costs of 6-month service were between £1970 and £2734 per patient. LIMITATIONS The focus on delivery in hospitals limits generalisability. CONCLUSIONS Neither a full-scale frequentist randomised controlled trial (RCT) recruiting in the UK alone nor a twice-weekly open-ended AT course delivered at tertiary centres is feasible. Further intervention development research is needed to identify how community-based pools can be accessed, and how families can link with each other and community physiotherapists to access tailored AT programmes guided by highly specialised physiotherapists. Bayesian RCTs may be feasible; otherwise, time series designs are recommended. TRIAL REGISTRATION Current Controlled Trials ISRCTN41002956. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 27. See the NIHR Journals Library website for further project information.
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Affiliation(s)
- Daniel Hind
- Sheffield Clinical Trials Research Unit, University of Sheffield, Sheffield, UK
| | - James Parkin
- Sheffield Clinical Trials Research Unit, University of Sheffield, Sheffield, UK
| | - Victoria Whitworth
- Sheffield Clinical Trials Research Unit, University of Sheffield, Sheffield, UK
| | - Saleema Rex
- Sheffield Clinical Trials Research Unit, University of Sheffield, Sheffield, UK
| | - Tracey Young
- School of Health and Related Research, University of Sheffield, Sheffield, UK
| | - Lisa Hampson
- Department of Mathematics and Statistics, University of Lancaster, Lancaster, UK
| | - Jennie Sheehan
- Evelina London Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, UK
| | - Chin Maguire
- Sheffield Clinical Trials Research Unit, University of Sheffield, Sheffield, UK
| | - Hannah Cantrill
- Sheffield Clinical Trials Research Unit, University of Sheffield, Sheffield, UK
| | - Elaine Scott
- School of Health and Related Research, University of Sheffield, Sheffield, UK
| | | | - Marion Main
- Dubowitz Neuromuscular Centre (DNC), Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Michelle Geary
- Children's Therapy Department, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Heather McMurchie
- Paediatric Physiotherapy, Heart of England NHS Foundation Trust, Birmingham, UK
| | - Lindsey Pallant
- Regional Paediatric Neuromuscular Team, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | | | - Jennifer Freeman
- Leeds Institute of Health Sciences, University of Leeds, Leeds, UK
| | - Ellen Lee
- Sheffield Clinical Trials Research Unit, University of Sheffield, Sheffield, UK
| | | | - Tracey Willis
- The Oswestry Inherited Neuromuscular Service, The Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Foundation Trust, Oswestry, UK
| | - Francesco Muntoni
- Dubowitz Neuromuscular Centre (DNC), Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Peter Baxter
- Paediatric Neurology, Sheffield Children's Hospital, Sheffield, UK
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Salehi F, Zeinaloo A, Riasi HR, Shamloo AS. Effectiveness of Coenzyme Q10 on echocardiographic parameters of patients with Duchenne muscular dystrophy. Electron Physician 2017; 9:3896-3904. [PMID: 28461862 PMCID: PMC5407220 DOI: 10.19082/3896] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Accepted: 12/23/2016] [Indexed: 02/02/2023] Open
Abstract
Background Myocardial damage is a common complication in patients with Duchenne muscular dystrophy (DMD) that occurs due to myocardial replacement by fat and fibrosis. In recent years, efforts have been made toward finding new pharmacological agents with fewer complications which can be used as prophylactic before the symptoms. Coenzyme Q10 plays a central role in production of bioenergy in heart muscle and antioxidant in reperfusion condition of myocardial damaged muscle and leads to membrane stability and prevents cell death. Objective This study aimed at comparing the Effectiveness of coenzyme Q10 on echocardiographic parameters of pediatric patients with Duchenne muscular dystrophy. Methods This randomized clinical trial study (RCT) was carried out on 25 pediatric patients with pre-diagnosed DMD who attended the Children’s Medical Center (CMC), Tehran, Iran from February 2013 to 2015. The patients were randomly divided into two groups. Group-1; (n=12) was treated with coenzyme Q10 for six months and group-2 ;(n=13) received placebo for the same time. The primary aim was to compare the myocardial performance index (MPI), between the two groups at the end of six months. Data were analyzed by SPSS software (ver-16) and using T-Test. Results Twenty-five patients under study were divided into two groups of (Q10=12) and (placebo=13). Mean ages were 8.9±1.7 and 8.6±1.4 in Q10 and placebo groups (P=0.66). No significant difference was detected in MPI at all three views of mitral and tricuspid and septum respectively in two groups after the end of treatment (0.41±0.13, and 0.43±0.6; P=0.59), (0.45±0.12, and 0.46±0.1; P=0.05), and (0.45±0.06, and 0.45±0.1; P=0.31). Conclusion According to the results obtained from this study, coenzyme Q10 had no significant effect on improving the performance of echocardiographic parameters in patients with DMD. Trial registration The trial is registered at the Iranian Clinical Trial Registry (IRCT.ir) with the IRCT identification number IRCT2015070223018N1. Funding This research has been financially supported by the Research Council of Tehran University of Medical Sciences.
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Affiliation(s)
- Forod Salehi
- M.D., Pediatric Cardiologist, Assistant Professor, Birjand CardioVascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Aliakbar Zeinaloo
- M.D., Pediatric Cardiologist, Professor, Pediatric Cardiology Department, Children's Hospital Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamid Reza Riasi
- M.D., Neurologist, Associate Professor, Birjand University of Medical Sciences, Birjand, Iran
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Petryk A, Polgreen LE, Grames M, Lowe DA, Hodges JS, Karachunski P. Feasibility and tolerability of whole-body, low-intensity vibration and its effects on muscle function and bone in patients with dystrophinopathies: a pilot study. Muscle Nerve 2017; 55:875-883. [PMID: 27718512 PMCID: PMC5385164 DOI: 10.1002/mus.25431] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Revised: 10/03/2016] [Accepted: 10/06/2016] [Indexed: 12/12/2022]
Abstract
Introduction Dystrophinopathies are X‐linked muscle degenerative disorders that result in progressive muscle weakness complicated by bone loss. This study's goal was to evaluate feasibility and tolerability of whole‐body, low‐intensity vibration (WBLIV) and its potential effects on muscle and bone in patients with Duchenne or Becker muscular dystrophy. Methods This 12‐month pilot study included 5 patients (age 5.9–21.7 years) who used a low‐intensity Marodyne LivMD plate vibrating at 30–90 Hz for 10 min/day for the first 6 months. Timed motor function tests, myometry, and peripheral quantitative computed tomography were performed at baseline and at 6 and 12 months. Results Motor function and lower extremity muscle strength remained either unchanged or improved during the intervention phase, followed by deterioration after WBLIV discontinuation. Indices of bone density and geometry remained stable in the tibia. Conclusions WBLIV was well tolerated and appeared to have a stabilizing effect on lower extremity muscle function and bone measures. Muscle Nerve55: 875–883, 2017
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Affiliation(s)
- Anna Petryk
- Division of Pediatric Endocrinology, University of Minnesota Masonic Children's Hospital, 2450 Riverside Avenue, Minneapolis, Minnesota, 55454, USA.,Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Lynda E Polgreen
- Division of Pediatric Endocrinology and Metabolism, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA
| | - Molly Grames
- Department of Neurology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Dawn A Lowe
- Department of Physical Medicine and Rehabilitation, University of Minnesota, Minneapolis, Minnesota, USA
| | - James S Hodges
- Division of Biostatistics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Peter Karachunski
- Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA.,Department of Neurology, University of Minnesota, Minneapolis, Minnesota, USA
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Buckon C, Sienko S, Bagley A, Sison-Williamson M, Fowler E, Staudt L, Heberer K, McDonald CM, Sussman M. Can Quantitative Muscle Strength and Functional Motor Ability Differentiate the Influence of Age and Corticosteroids in Ambulatory Boys with Duchenne Muscular Dystrophy? PLOS CURRENTS 2016; 8:ecurrents.md.1ced64dff945f8958221fddcd4ee60b0. [PMID: 27500011 PMCID: PMC4956479 DOI: 10.1371/currents.md.1ced64dff945f8958221fddcd4ee60b0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
BACKGROUND In the absence of a curative treatment for Duchenne Muscular Dystrophy (DMD), corticosteroid therapy (prednisone, deflazacort) has been adopted as the standard of care, as it slows the progression of muscle weakness and enables longer retention of functional mobility. The ongoing development of novel pharmacological agents that target the genetic defect underlying DMD offer hope for a significant alteration in disease progression; however, substantiation of therapeutic efficacy has proved challenging. Identifying functional outcomes sensitive to the early, subtle changes in muscle function has confounded clinical trials. Additionally, the alterations in disease progression secondary to corticosteroid therapy are not well described making it difficult to ascertain the benefits of novel agents, often taken concurrently with corticosteroids. OBJECTIVE The purpose of this study was to examine outcome responsiveness to corticosteroid therapy and age at the onset of a natural history study of ambulatory boys with DMD. METHODS Eighty-five ambulatory boys with DMD (mean age 93 mo, range 49 to 180 mo) were recruited into this study. Fifty participants were on corticosteroid therapy, while 33 were corticosteroid naïve at the baseline assessment. Within each treatment group boys were divided in two age groups, 4 to 7 years and 8 and greater years of age. The Biodex System 3 Pro isokinetic dynamometer was used to assess muscle strength. Motor skills were assessed using the upper two dimensions (standing/walking, running & jumping) of the Gross Motor Function Measure (GMFM 88) and Timed Motor Tests (TMTs) (10-meter run, sit to stand, supine to stand, climb 4-stairs). Two way analysis of variance and Pearson correlations were used for analysis. RESULTS A main effect for age was seen in select lower extremity muscle groups (hip flexors, knee extensors and ankle dorsiflexors), standing dimension skills, and all TMTs with significantly greater weakness and loss of motor skill ability seen in the older age group regardless of treatment group. Interaction effects were seen for the walking, running, and jumping dimension of the GMFM with the naïve boys scoring higher in the younger group and boys on corticosteroid therapy scoring higher in the older group. The TMT of climb 4-stairs demonstrated a significant treatment effect with the boys on corticosteroid therapy climbing stairs faster than those who were naïve, regardless of age. Examination of individual items within the upper level GMFM dimensions revealed select motor skills are more informative of disease progression than others; indicating their potential to be sensitive indicators of alterations in disease progression and intervention efficacy. Analysis of the relationship between muscle group strength and motor skill performance revealed differences in use patterns in the corticosteroid versus naïve boys. CONCLUSION Significant muscle weakness is apparent in young boys with DMD regardless of corticosteroid treatment; however, older boys on corticosteroid therapy tend to have greater retention of muscle strength and motor skill ability than those who are naive. Quantification of muscle strength via isokinetic dynamometry is feasible and sensitive to the variable rates of disease progression in lower extremity muscle groups, but possibly most informative are the subtle changes in the performance characteristics of select motor skills. Further analysis of longitudinal data from this study will explore the influence of corticosteroid therapy on muscle strength and further clarify its impact on motor performance.
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Affiliation(s)
- Cathleen Buckon
- Shriners Hospitals for Children-Portland, Portland, Oregon, USA
| | - Susan Sienko
- Shriners Hospitals for Children-Portland, Portland, Oregon, USA
| | - Anita Bagley
- Shriners Hospitals for Children-Northern California, Sacramento, California, USA
| | - Mitell Sison-Williamson
- Research and Evaluation Section, California Department of Public Health, Shriners Hospitals for Children-Northern California, Sacramento, California, USA
| | - Eileen Fowler
- UCLA Department of Orthopaedic Surgery, Kameron Gait and Motion Analysis Laboratory, Los Angeles, California, USA
| | - Loretta Staudt
- UCLA Department of Orthopaedic Surgery, Los Angeles, California, USA
| | | | - Craig M McDonald
- Department of Physical Medicine and Rehabilitation, University of California-Davis, Shriners Hospitals for Children-Northern California, Sacramento, California, USA
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Perceived effectiveness and barriers to physical therapy services for families and children with Friedreich ataxia. Pediatr Phys Ther 2013; 25:305-13. [PMID: 23685741 PMCID: PMC3696476 DOI: 10.1097/pep.0b013e31828ed7cb] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE To describe the frequency, type, and perceived effectiveness of physical therapy interventions for children with Friedreich ataxia (FA); identify barriers to therapy; and solicit advice from parents. METHOD Parents of 30 children with FA participated in semistructured interviews. Qualitative and quantitative methods were used to analyze the data. RESULTS Sixty-seven percent of children received direct physical therapy service. Stretching and strengthening exercises were used most frequently, and their perceived usefulness increased as the children aged. Seventy-three percent received home exercise programs; 9% implemented these consistently. External barriers included a lack of expert providers and limited reimbursement. Internal barriers included limited time and energy, lack of awareness of services, and children's preferences not to be treated differently. Parents advised therapists to become experts, advocates, and use approaches based on family and child preferences. CONCLUSIONS Outcomes provide a starting point for developing further research, education, and effective interventions for children with FA.
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Grigg-Damberger MM, Wagner LK, Brown LK. Sleep Hypoventilation in Patients with Neuromuscular Diseases. Sleep Med Clin 2012. [DOI: 10.1016/j.jsmc.2012.09.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Shabanian R, Aboozari M, Kiani A, Seifirad S, Zamani G, Nahalimoghaddam A, Kocharian A. Myocardial Performance Index and Atrial Ejection Force in Patients with Duchenne's Muscular Dystrophy. Echocardiography 2011; 28:1088-94. [DOI: 10.1111/j.1540-8175.2011.01515.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
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Olby NJ, Sharp NJH, Nghiem PE, Keene BW, DeFrancesco TC, Sidley JA, Kornegay JN, Schatzberg SJ. Clinical progression of X-linked muscular dystrophy in two German Shorthaired Pointers. J Am Vet Med Assoc 2011; 238:207-12. [PMID: 21235374 DOI: 10.2460/javma.238.2.207] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
CASE DESCRIPTION 2 full-sibling male German Shorthaired Pointer (GSHP) puppies (dogs 1 and 2) with X-linked muscular dystrophy and deletion of the dystrophin gene (gene symbol, DMD) each had poor growth, skeletal muscle atrophy, pelvic limb weakness, episodic collapse, and episodes of coughing. CLINICAL FINDINGS Initial examination revealed stunted growth, brachygnathism, trismus, and diffuse neuromuscular signs in each puppy; clinical signs were more severe in dog 2 than in dog 1. Immunohistochemical analysis revealed a lack of dystrophin protein in both dogs. During the next 3 years, each dog developed hyperinflation of the lungs, hypertrophy of the cervical musculature, and hypertrophy of the lateral head of the triceps brachii muscle. TREATMENT AND OUTCOME Monitoring and supportive care were provided at follow-up visits during an approximately 7-year period. No other specific treatment was provided. Neuromuscular signs in both dogs remained stable after 3 years of age, with dog 2 consistently more severely affected than dog 1. The dogs had multiple episodes of aspiration pneumonia; dogs 1 and 2 were euthanatized at 84 and 93 months of age, respectively. CLINICAL RELEVANCE The clinical course of disease in these dogs was monitored for a longer period than has been monitored in previous reports of dystrophin-deficient dogs. The clinical progression of muscular dystrophy in the 2 GSHPs was compared with that for other breeds and species with dystrophin-deficient conditions, and the potential basis for the phenotypic variation observed between these littermates, along with potential therapeutic ramifications for dogs and humans, was evaluated.
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Affiliation(s)
- Natasha J Olby
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606, USA
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Meadows E, Flynn JM, Klein WH. Myogenin regulates exercise capacity but is dispensable for skeletal muscle regeneration in adult mdx mice. PLoS One 2011; 6:e16184. [PMID: 21264243 PMCID: PMC3021523 DOI: 10.1371/journal.pone.0016184] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2010] [Accepted: 12/15/2010] [Indexed: 11/19/2022] Open
Abstract
Duchenne muscular dystrophy (DMD) is the most prevalent inherited childhood muscle disorder in humans. mdx mice exhibit a similar pathophysiology to the human disorder allowing for an in-depth investigation of DMD. Myogenin, a myogenic regulatory factor, is best known for its role in embryonic myogenesis, but its role in adult muscle maintenance and regeneration is still poorly understood. Here, we generated an mdx:Myogflox/flox mouse harboring a tamoxifen-inducible Cre recombinase transgene, which was used to conditionally delete Myog during adult life. After tamoxifen treatment, three groups of mice were created to study the effects of Myog deletion: mdx:Myogflox/flox mice (mdx), Myogflox/flox mice (wild-type), and mdx:MyogfloxΔ/floxΔ:Cre-ER mice (mdx:Myog-deleted). mdx:Myog-deleted mice exhibited no adverse phenotype and behaved normally. When run to exhaustion, mdx:Myog-deleted mice demonstrated an enhanced capacity for exercise compared to mdx mice, running nearly as far as wild-type mice. Moreover, these mice showed the same signature characteristics of muscle regeneration as mdx mice. Unexpectedly, we found that myogenin was dispensable for muscle regeneration. Factors associated with muscle fatigue, metabolism, and proteolysis were significantly altered in mdx:Myog-deleted mice, and this might contribute to their increased exercise capacity. Our results reveal novel functions for myogenin in adult muscle and suggest that reducing Myog expression in other muscle disease models may partially restore muscle function.
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Affiliation(s)
- Eric Meadows
- Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
- Graduate Training Program in Genes and Development, The University of Texas School of Biomedical Sciences at Houston, Houston, Texas, United States of America
| | - Jesse M. Flynn
- Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
- Graduate Training Program in Genes and Development, The University of Texas School of Biomedical Sciences at Houston, Houston, Texas, United States of America
| | - William H. Klein
- Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
- * E-mail:
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Venance SL, Koopman WJ. DYSTROPHINOPATHIES IN ADULTHOOD. Continuum (Minneap Minn) 2009. [DOI: 10.1212/01.con.0000348875.86198.fa] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Current world literature. Curr Opin Neurol 2009; 22:554-61. [PMID: 19755870 DOI: 10.1097/wco.0b013e3283313b14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Vandenburgh H, Shansky J, Benesch-Lee F, Skelly K, Spinazzola JM, Saponjian Y, Tseng BS. Automated drug screening with contractile muscle tissue engineered from dystrophic myoblasts. FASEB J 2009; 23:3325-34. [PMID: 19487307 DOI: 10.1096/fj.09-134411] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Identification of factors that improve muscle function in boys with Duchenne muscular dystrophy (DMD) could lead to an improved quality of life. To establish a functional in vitro assay for muscle strength, mdx murine myoblasts, the genetic homologue of DMD, were tissue engineered in 96-microwell plates into 3-dimensional muscle constructs with parallel arrays of striated muscle fibers. When electrically stimulated, they generated tetanic forces measured with an automated motion tracking system. Thirty-one compounds of interest as potential treatments for patients with DMD were tested at 3 to 6 concentrations. Eleven of the compounds (insulin-like growth factor-1, creatine, beta-hydroxy-beta-methylbutyrate, trichostatin A, lisinopril, and 6 from the glucocorticoid family) significantly increased tetanic force relative to placebo-treated controls. The glucocorticoids methylprednisolone, deflazacort, and prednisone increased tetanic forces at low doses (EC(50) of 6, 19, and 56 nM, respectively), indicating a direct muscle mechanism by which they may be benefitting DMD patients. The tetanic force assay also identified beneficial compound interactions (arginine plus deflazacort and prednisone plus creatine) as well as deleterious interactions (prednisone plus creatine inhibited by pentoxifylline) of combinatorial therapies taken by some DMD patients. Since mdx muscle in vivo and DMD patients respond in a similar manner to many of these compounds, the in vitro assay will be a useful tool for the rapid identification of new potential treatments for muscle weakness in DMD and other muscle disorders.
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Affiliation(s)
- Herman Vandenburgh
- Department of Pathology, Brown Medical School-Miriam Hospital, Providence, Rhode Island, USA.
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